Nucleoside analogues: mechanisms of drug resistance and reversal strategies


Nucleoside analogues (NA) are essential components of AML induction therapy (cytosine arabinoside), effective treatments of lymphoproliferative disorders (fludarabine, cladribine) and are also used in the treatment of some solid tumors (gemcitabine). These important compounds share some general common characteristics, namely in terms of requiring transport by specific membrane transporters, metabolism and interaction with intracellular targets. However, these compounds differ in regard to the types of transporters that most efficiently transport a given compound, and their preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumors and others on neoplasia with a more protracted evolution. In this review, we analyze the available data concerning mechanisms of action of and resistance to NA, with particular emphasis on recent advances in the characterization of nucleoside transporters and on the potential role of activating or inactivating enzymes in the induction of clinical resistance to these compounds. We performed an extensive search of published in vitro and clinical data in which the levels of expression of nucleoside-activating or inactivating enzymes have been correlated with tumor response or patient outcome. Strategies aiming to increase the intracellular concentrations of active compounds are presented.


Nucleoside analogues (NA) constitute an important class of antimetabolites used in the treatment of hematological malignancies and, more recently, in solid tumors.1 These therapeutic compounds mimic physiological nucleosides in terms of uptake and metabolism and are incorporated into newly synthesized DNA resulting in synthesis inhibition and chain termination. Some of these drugs also inhibit key enzymes involved in the generation of the purine and pyrimidine nucleotides and RNA synthesis, and directly activate the caspase cascade. All of these effects may lead to cell death.

The NA family includes various pyrimidine and purine analogues. Among the pyrimidine analogues cytosine arabinoside (ara-C, cytarabine) is extensively used in the treatment of acute leukemia, while gemcitabine has more recently demonstrated activity in pancreatic, breast and lung cancer.2,3,4 The two first purine analogues to have been described were the thiopurines 6 mercaptopurine (6-MP) and 6-thioguanine (6-TG). These compounds could more appropriately be designated as ‘nucleobases’. Other new purine analogues are 2-chlorodeoxyadenosine (2-CdA) and fludarabine.5,6,7 These latter drugs have mostly been used in the treatment of low-grade hematological malignancies.8,9

The importance of NA chemotherapeutic agents has recently increased as a result of the introduction of new compounds into clinical use and the expansion of indications into the field of solid tumors. During the same period, there has been rapid progress in the understanding of mechanisms of drug resistance to NA. In this review, we highlight the current knowledge concerning the cellular mechanisms of resistance to NA and possible strategies that may be used to overcome such resistance.

Normal nucleoside transport and phosphorylation

Because physiologic nucleosides are generally hydrophilic and do not readily permeate the plasma membrane, their cellular uptake occurs primarily via nucleoside-specific membrane transport carriers (NT). Of the seven distinct NT activities observed in human cells, only four have been defined in molecular terms. These are classified into two categories: equilibrative (ENT) or concentrative (CNT).10,11 Human equilibrative NTs (hENTs) are found in virtually all studied cell types and have broad permeant selectivity, accepting both purine and pyrimidine nucleosides as substrates. The two cloned hENTs differ in their sensitivity to inhibition by nanomolar concentrations of nitrobenzylmercaptopurine ribonucleoside (NBMPR): hENT1 has es activity (equilibrative and NBMPR-sensitive) while hENT2 possesses ei (equilibrative and NBMPR-insensitive) nucleoside transport activity.12,13,14 The human concentrative nucleoside transporters (hCNT) are inwardly-directed transporters that are capable of transporting nucleosides against a concentration gradient by utilizing the transmembrane sodium concentration gradient.15,16,17 The hCNT1 protein has greater affinity for pyrimidine nucleosides but also transports adenosine, while the hCNT2 protein transports purine nucleosides and uridine.18 In all cases, human NTs accept only dephosphorylated compounds.

Deoxyribonucleotide triphosphate (dNTPs) pools present within cells come from two sources, the de novo pathway which is specifically activated in replicating cells, and the salvage pathway, which is the main source of nucleotides in quiescent cells.19,20 The key step in the de novo pathway is the conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates by ribonucleotide reductase (RR). Replicating hematopoietic cells are heavily dependent on the de novo pathway. Conversely in resting cells the salvage pathway, which recycles bases and nucleosides derived from DNA or RNA catabolism, is the unique provider of dNTPs. These compounds are first phosphorylated by nucleoside kinases such as deoxycytidine kinase (dCK), thymidine kinase 1 and 2, or deoxyguanosine kinase (dGK). This initial phosphorylation step constitutes the key step in the salvage pathway that concludes with the formation of triphosphate or deoxytriphosphate derivatives. There are thus two dNTP pools: one derived from the de novo pathway that is predominantly directed into replicating DNA and a second derived from salvage synthesis used for DNA repair.21,22

Mechanisms of action of nucleoside analogues and drug metabolism

All of the NA share common characteristics including active transport by membrane transporters (Table 1), activation by kinases such as dCK allowing retention of the monophosphate residues in the cell and the formation of the active triphosphates metabolites, and dephosphorylation by 5′-nucleotidase (5′-NU) (Figure 1). Moreover, most of them have the ability to ‘self-potentiate’ their own cytotoxic effects. However each of these compounds also possesses specific properties in terms of drug–target interactions which may explain their differences in activity in various diseases. In particular the cytotoxic effects of the purine analogues fludarabine and 2-CdA on quiescent cells may be explained by interaction with targets involving DNA repair rather than replication, and direct or indirect effects on mitochondria.

Table 1 Human nucleoside transporters (NT) mediating uptake of nucleoside analogues
Figure 1

Representation of the metabolism and drug target interactions of deoxynucleoside analogues in proliferating cells (NA). NA enters cells via specific nucleoside transporters. Once inside the cell, NA are phosphorylated by deoxycytidine kinase (DCK), NMPK and NDPK to the active 5′-triphosphate derivatives. NA catabolism can result from rapid deamination by cytidine deaminase to non-toxic metabolites. Cytoplasmic 5′-nucleotidase (5′Nucl) activity opposes that of DCK by dephosphorylating 5′-monophosphate derivatives, thereby preventing the production of the active form. NA exerts their action by incorporation into newly synthesized DNA resulting in chain termination and cell death. Also, some NA indirectly block DNA replication by inhibiting ribonucleotide reductase (RR) enzyme, that in turn inhibit reduction of ribonucleotides diphosphate (NDPs) to deoxyribonucleotides diphosphate (dNDPs). The decrease of deoxyribonucleotides triphosphate (dNTPs) pools favors incorporation of NA active 5′-triphosphate derivatives into DNA.


Ara-C (1-β-D-arabinofuranosylcytosine, cytosine arabinoside, cytarabine) is an structural analogue of deoxycytidine (dCyd) (Figure 2) used for the treatment of acute leukemias and lymphomas. Ara-C differs from dCyd by the presence of a hydroxyl group in the β-configuration at the 2′-position of the sugar moiety. Intracellular penetration of ara-C depends on plasma ara-C concentrations.23,24,25,26 Standard-dose ara-C (SD ara-C; 100–200 mg/m2) achieves steady-state plasma levels of 0.5–1 μM.27,28 At these concentrations the expression of the hENT1 protein is the rate-limiting factor in ara-C uptake. In the presence of plasma concentrations greater than 50 μM, such as those reached with high-dose ara-C (HD ara-C; 2–3 g/m2), simple inward diffusion rates exceed those of pump-mediated transport.29

Figure 2

Chemical structure of pyrimidine analogues.

Once inside the cell, ara-C is phosphorylated by dCK and pyrimidine kinases to the active 5′-triphosphate derivative ara-CTP.30,31 The catabolism of ara-C results from rapid deamination by cytidine deaminase (CDD) to the non-toxic metabolite arabinoside uridine while ara-CMP is dephosphorylated by the action of cytoplasmic 5′-nucleotidase (5′-NU).32 Ara-C cytotoxicity is believed to result from a combination of DNA polymerase inhibition and from incorporation of ara-CTP into DNA, in competition with deoxycytidine triphosphate (dCTP). This incorporation causes chain termination, resulting in a block of DNA synthesis.33,34,35 Sustained high cellular concentrations of ara-CTP relative to that of dCTP are thought to favor drug incorporation into replicating DNA, thereby initiating the leukemic cell death associated with therapeutic response.36 Low incorporation of ara-CTP into the DNA of blast cells in vitro has been shown to be predictive of an adverse outcome in AML patients receiving ara-C-based therapy.37,38


Gemcitabine (difluorodeoxycytidine, dFdC) (Figure 2) is a new pyrimidine analogue with promising activity in solid tumors.39,40 This compound is a dCyd analogue with two fluorine substituted for the two hydrogen atoms in the 2′ position of the deoxyribose sugar.41 After the initial phosphorylation into dFd-CMP by dCK,42 gemcitabine is subsequently phosphorylated by pyrimidine kinases to the active 5′-diphosphate (dFd-CDP) and triphosphate (dFd-CTP) derivatives.43 Inactivation of gemcitabine can occur by deamination into its inactive metabolite dFd-U by CDD or dephosphorylation of dFd-CMP by 5′-NU.44,45

dFd-CTP is incorporated into DNA by replication synthesis in the C sites of the growing DNA strand.46 Once incorporated into the DNA strand, an additional natural nucleoside is added, masking gemcitabine and preventing DNA repair by base pair excision. Thereafter, the DNA polymerases are unable to proceed,47 a process designated as ‘masked DNA chain termination’. The active diphosphate metabolite of gemcitabine also inhibits DNA synthesis indirectly through inhibition of RR.47 This effect blocks the de novo DNA synthesis pathway and self-potentiates gemcitabine activity by decreasing intracellular concentrations of normal dNTPs (particularly dCTP). Reduction in cellular dCTP results in increased gemcitabine nucleotide incorporation into DNA and increased formation of active gemcitabine di- and triphosphates, since dCK activity is down-regulated by high cellular dCTP levels. Other self-potentiating mechanisms of gemcitabine include a decreased elimination of gemcitabine nucleotides by direct inhibition of CDD.48 Gemcitabine is not only incorporated into DNA, but also into RNA.49

The spectrum of activity of gemcitabine in solid tumors may be due to different characteristics. Compared with ara-C, gemcitabine serves as a better transport substrate for membrane pumps, is phosphorylated more efficiently, and is eliminated more slowly, favoring a longer retention time of the active metabolite in tumor cells.48,50 Moreover, gemcitabine cytotoxicity is enhanced by a number of unique self-potentiating mechanisms that contribute to maintaining high intracellular concentrations of the active metabolites. This prolonged presence of active gemcitabine derivatives may explain part of its effect on slowly dividing tumor cells. These differences, together with greater lipophilicity, masked chain termination, RNA incorporation and RR inhibition, which are not observed with ara-C, may explain why gemcitabine is, and ara-C is not, active in solid tumors.


2-CdA (Figure 3) is an analogue of deoxyadenosine (dAdo) resistant to deamination by adenosine deaminase (ADA). 2-CdA is commonly used in the treatment of indolent lymphoid malignancies, in particular hairy-cell leukemia.51,52,53 2-CdA enters cells via NT54 and is phosphorylated to 2-CdATP by dCK, AMP kinase, and nucleoside diphosphate kinase. Mitochondrial dGK has also been identified as a 2-CdA phosphorylating enzyme.55 2-CdAMP can be dephosphorylated by 5′-NU. The net accumulation of the triphosphate derivative has been shown to depend on the relative concentrations of dCK and 5′-NU.56

Figure 3

Chemical structure of purine analogues.

2-CdA is cytotoxic both to dividing and resting cells.57,58 In dividing cells, this compound inhibits DNA synthesis by incorporation of its triphosphate metabolite into DNA.59,60 Once incorporated 2-CdATP is capable of terminating chain elongation mediated by DNA polymerases, inducing an S phase-specific apoptosis.61 2-CdA also inhibits DNA replication indirectly through its inhibitory action on RR,62 causing a subsequent reduction of the dNTPs pool required for DNA synthesis.59,63 The reduction of intracellular dATP results in self-potentiation of 2-CdA as it enhances the incorporation of triphosphate metabolites into DNA. Moreover, the decrease in dCTP could result in an increased rate of phosphorylation of 2-CdA and other NA, since dCK activity is regulated by cellular dCTP levels. An original mechanism of 2-CdA cytotoxicity is related to the inhibition of ADA and S-adenosylhomocysteine hydrolase (SAHH).64 Inhibition of ADA could lead to increased levels of Ado and dAdo, thereby causing the inactivation of SAHH and reduced homocysteine formation. This might result in altered methylation reactions and indirectly inhibit nucleotide synthesis and cellular proliferation.65,66

Different mechanisms have been proposed to explain why 2-CdA is toxic to a cell that is not undergoing replicative DNA synthesis. First, 2-CdA-induced killing in non-dividing cells occurs by inhibition of cellular DNA repair processes. Incorporation of 2-CdATP into DNA by the repair machinery terminates the nucleotide excision repair process leading to the progressive accumulation of DNA single-strand breaks which eventually initiate apoptosis by p53-dependent or p53-independent pathways.67,68 p53 activation subsequently regulates the levels of expression of p53-dependent proteins such as Bcl-2 and Bax leading to the activation of the caspase pathway.69 Second, incorporation of 2-CdA into DNA may alter gene transcription with a consequent depletion of proteins required for cell survival. It has been demonstrated that when 2-CdA metabolites were present in one or both DNA strands, the yield of full-length transcripts was reduced.70 Moreover, RNA polymerase did not bind as well to 2-CdATP-containing promoters. In addition, on binding to the substituted promoter, RNA polymerase had an altered conformation that led to enhanced proteolytic clipping by endoproteinase Glu-C.70

Alternatively, it has been shown that 2-CdA cytotoxicity may involve alterations of mitochondrial function or integrity. 2-CdA has been shown to disrupt the integrity of mitochondria in CLL cells.69 The nucleoside-induced damage leads to the release of the pro-apoptotic mitochondrial protein cytochrome c, thereby initiating the caspase proteolytic cascade. Moreover, 2-CdATP can cooperate with cytochrome c and Apaf-1 to activate caspase-3 and trigger a caspase pathway.71,72 2-CdA also interferes either directly or indirectly with mitochondrial transcription that will eventually reduce the levels of mitochondrial proteins necessary for electron transport and oxidative phosphorylation. In vitro studies have demonstrated that 2-CdATP is incorporated into mitochondrial DNA by mitochondrial DNA polymerase.62 This incorporation may decrease transcription by mitochondrial RNA polymerase. On the other hand, high intracellular 2-CdATP levels could indirectly repress transcription of mitochondrial genes by inhibiting reduction of ADP to dADP.73 This leads to high ADP concentrations that cause a net influx of adenine nucleotides into mitochondria and an increase in the intramitochondrial ATP concentration.59,74 High intramitochondrial ATP levels in turn inhibit mitochondrial RNA polymerase activity.74

PARP activation has been suggested to be involved in p53-independent mechanisms of cell killing by 2-CdA.57 In addition to being a target for proteolytic cleavage during apoptosis, PARP is thought to play a role in DNA repair by signaling genomic damage.75 PARP binds to DNA breaks, becomes activated and, using NAD as a substrate, adds ADP-ribose polymers to a range of nuclear proteins including itself, histones and DNA repair enzymes.76,77 These and other findings have led to a proposed model of 2-CdA action involving the following sequence of events: inhibition of ongoing DNA repair by 2-CdA with accumulation of DNA breaks, PARP activation with resultant consumption of NAD, and depletion of total adenine nucleotides.57,76,77,78 Given that the cell membrane requires ATP for many of its functions, it seems likely that PARP-mediated ATP depletion might contribute to the cell membrane disruption that occurs during apoptosis.79


9-β-D-arabinosyl-2-fluoroadenine (F-ara-A) (Figure 3) is an analogue of adenosine (Ado) which is resistant to deamination by adenosine deaminase (ADA).80 F-ara-A is administered as the 5′-monophosphate form (fludarabine). The phosphate group on the 5′- position of the arabinose has the sole function of making the clinical formulation water-soluble. Before entering cells, fludarabine is rapidly dephosphorylated by membrane CD73 into F-ara-A which is transported inside the cell via hNTs.81 Like other NA, it requires phosphorylation to its triphosphate form, F-ara-ATP for cytotoxic activity.82,83 The initial step in this activation process is performed by dCK.

Like 2-CdA, F-ara-A is cytotoxic both against dividing and resting cells. In dividing cells, this compound inhibits DNA synthesis and RR.82 DNA synthesis inhibition is mediated by competition of the triphosphate metabolite with deoxyadenosine triphosphate (dATP) for incorporation into the A sites of elongating DNA by DNA polymerases.84 Once incorporated it is capable of terminating chain elongation mediated by DNA polymerases α (F-ara-ATP).85 RR inhibition causes a subsequent reduction of dNTPs pools.63,86 Similarly to 2-CdA, the decrease of cellular dATP and dCTP results in a self-potentiation of the drug and other NA. Other enzyme targets of F-ara-ATP in dividing cells include DNA primase, DNA polymerase α, DNA ligase and topoisomerase II.84 Thus, the mechanism of action of F-ara-A in proliferating cells is mainly cell cycle-specific, and incorporation of F-ara-A into DNA during S phase is required for the induction of apoptosis.87

In non-dividing cells, the inhibition of cellular DNA repair processes appears to be the major mechanism of cytotoxicity of F-ara-A. Incorporation of F-ara-AMP into DNA by the repair machinery terminates the polymerization step of the nucleotide excision repair process causing irreversible damage recognized by the cells, which would signal for p53-mediated or PARP-mediated apoptosis.20 As occurs after exposure to 2-CdA, fludarabine may induce PARP activation resulting in consumption of NAD and depletion of total adenine nucleotides with subsequent cell death.88

Other mechanisms of action of F-ara-A may explain its cytotoxicity in non-cycling cells.82 First, F-ara-AMP and F-ara-ATP incorporation into RNA results in premature termination of the RNA transcript, impairing its function as a template for protein synthesis.89 F-ara-ATP also inhibits RNA synthesis by suppressing the activity of RNA polymerase II.89 Inhibition of RNA transcription correlates with the cytotoxic action of fludarabine in CLL cells.90 Secondly, F-ara-ATP is the most potent nucleotide activator of APAF-1, with the consequent activation of the caspase-9 and caspase-3 pathways.71 Moreover, F-ara-A has been reported to downregulate Bcl-2 mRNA expression, thereby favoring apoptosis.91 Finally, F-ara-A affects mitochondria but only as a late event, suggesting an indirect mechanism related to the p53-apoptotic pathway.69 The different effects of F-ara-A and 2-CdA on mitochondria integrity may be related to the fact that 2-CdATP may accumulate more rapidly than F-ara-ATP in the mitochondria because it is converted with higher efficiency by mitochondrial dGK.92 It has also been stated that 2-chloro derivatives are slightly more hydrophobic than the corresponding 2-fluoro derivatives and therefore may be able to insert more easily into the mitochondrial membrane, thereby affecting their integrity.69 In summary inhibition of DNA repair, termination of mRNA transcription and the consequent depletion of proteins required for cell survival, as well as the capacity of F-ara-ATP to activate the apoptosome pathway appear to contribute to the cytotoxicity of fludarabine in non-dividing cells.

Mechanisms of resistance to nucleoside analogues

Three general mechanisms of resistance to NA have been described in cell lines and in clinical samples. A primary mechanism of resistance to NA arise from an insufficient intracellular concentration of NA triphosphates, which may result from inefficient cellular uptake, reduced levels of activating enzymes, increased NA degradation by increased 5′-NU or CDD activity, or expansion of the dNTP pools.93 A second type of resistance mechanism may be due to the inability to achieve sufficient alterations in DNA strands or dNTP pools, either by altered interaction with DNA polymerases, by lack of inhibition of RR, or because of inadequate p53 exonuclease activity. Finally, drug resistance may be a consequence of a defective induction of apoptosis.

Membrane transporters

In vitro studies have demonstrated that NT-deficient cells are highly resistant to NA.94 Several cell lines exhibit cross-resistance to a spectrum of NA because of reduced uptake.11,54,95 In isolated leukemic blasts, sensitivity to ara-C, fludarabine and 2-CdA correlated with the cellular abundance of hENT196,97 determined by cellular binding of NBMPR. In these cells, the number of such binding sites ranged from 500 to 27600 sites/cell.11,26 As initial rates of cellular drug uptake are, in general, proportional to hENT1 abundance, this wide variation suggests that transport-deficient cells would display a drug-resistant phenotype. In AML patients, Wiley et al98 observed that low transport rates correlated with poor clinical responsiveness to ara-C therapy. Although the measurement of hENT1 expression by a quantitative flow cytometric assay with the hENT1 ligand, SAENTA fluorescein, shows promise in identifying transport-deficient leukemic cells, the clinical significance of NT deficiency to in vivo resistance is not yet well established. This is due to the difficulty of assessing drug transport in clinical samples, the contribution of transporters other than hENT1, and the technical difficulties of quantifying NTs in neoplastic clones admixed with normal cells.11

Deoxycytidine kinase

Deoxycytidine kinase is the rate-limiting enzyme that catalyzes the initial step of the 5′-phosphorylation of dCyd to dCMP and of many NA to their corresponding monophosphates.99,100,101 The dCK activity is high in quiescent cells in which it phosphorylates nucleosides necessary for DNA repair and, depending on the cell type, may increase several-fold when the cells enter the S-phase of the cell cycle.102,103,104,105

Deoxycytidine kinase activity has been shown to be decreased or absent in different cell lines resistant to NA.106,107,108,109 Transfection of the dCK gene in dCK-deficient tumor cell lines restores in vitro sensitivity to ara-C.110,111 Moreover, in vitro models have shown crossresistance between 2-CdA, gemcitabine, fludarabine and ara-C with reduced dCK activity as the underlying determinant of resistance.109,112 It is noteworthy that in vitro only significant reductions in the levels of dCK activity (10% or less) are associated with a resistant phenotype, suggesting that under baseline conditions dCK is present in excess.

In the clinical setting, it is important to note that bone marrow and lymphoid tissues exhibit the highest activities of dCK resulting in the clinical success observed when treating these target tissues with NA.113,114 However, the relevance of dCK deficiency in clinical resistance to NA is controversial (Table 2). In childhood acute lymphoblastic leukemias (ALL),115,116 AML117,118 and lymphoproliferative disorders119 some authors observed decreased expression of the dCK gene or significant decrease in the activity level of this enzyme as one of the mechanisms responsible for clinical resistance to ara-C, fludarabine or 2-CdA. Conversely, other authors reported no significant relationship between dCK activity and clinical outcome to NA in these diseases.120,121

Table 2 Correlation between low levels of expression of dCK gene or low dCK activity and drug resistance in hematological malignancies

Structural analyses of the dCK gene have show inactivating mutations and deletions as a cause of dCK deficiency in vitro. Owens and co-workers122 claimed that to acquire a drug-resistant phenotype, cells required two independent mutations that markedly disrupt the catalytic activity of the enzyme. However, these cDNA mutations rarely occur in vivo and therefore may not constitute a major mechanism of clinical NA resistance.115,116,123 Moreover, it seems that most of the aminoacid replacements did not occur in a functionally relevant region of the enzyme.124 More recently alternatively spliced forms of dCK mRNA were detected in leukemic blasts from patients with clinically resistant AML but not in leukemic blasts from patients with sensitive AML.125 These alternatively spliced forms of dCK mRNA were shown to be inactive in an in vitro dCK activity assay. These data indicate that the presence of dCK splice products may contribute to the occurrence of clinical ara-C resistance.

Structural alterations of the dCK gene complex other than mutations may play a role in drug resistance to NA in vivo.126 Downregulation of dCK activity in cytarabine-resistant cells has been shown to correlate with hypermethylation of the promoter region of the gene.127,128 Decreased levels of dCK mRNA has been shown to be induced under various conditions in vitro.127,129 Finally dCK activity may be regulated post-translationally, since this enzyme is feedback-inhibited by dNTPs (particularly dCTP) and by some phosphorylated analogues such as ara-CTP.130

Deoxyguanosine kinase

Deoxyguanosine kinase (dGK) is another enzyme responsible for the phosphorylation of purine deoxynucleosides, in mammalian cells. This enzyme showed a broad substrate specificity towards natural purine deoxynucleosides, as well as towards nucleoside analogues such as ara-G and 2-CdA.55,73,92 dGK is located predominantly in the mitochondria.131 However, Petrakis et al132 described a novel amino-terminally truncated isoform that corresponds to about 14% of the total dGK mRNA population in mouse spleen. This isoform cannot translocate into the mitochondria and thus may represent a cytoplasmic enzyme.

Mitochondrial dGK is responsible for phosphorylation of purine deoxyribonucleosides and their analogues in the mitochondrial matrix providing the dNTPs necessary for mitochondrial DNA synthesis.133,134,135,136 Cytoplasmic dGK may also contribute to the supply of purine deoxynucleotides for nuclear DNA replication and repair.132 In this way, nucleoside analogues phosphorylated by dGK may exert their cytotoxic effects by interference with both mitochondrial and nuclear DNA synthesis. Whether inactivation of dGK is involved in resistance to NA is not presently known.


5′-NU dephosphorylates nucleoside monophosphates and cytotoxic mononucleotides through its hydrolysis of the ester-bond between the 5′-carbon and the phosphate group. 5′-NU activity therefore opposes that of dCK. 5′-NUs comprise a large and complex group of enzyme activities differing in cellular localization, pH sensitivity, and inhibition or stimulation by ATP (Table 3). Two broad classes of 5′-NU are implicated in drug resistance to NA: cytosolic and membrane-bound 5′-NUs. Membrane-bound or ‘ecto-5′-NU’ is also known as CD73, and is frequently expressed in acute leukemias.137,138 The physiological function of CD73 is the salvage of extracellular nucleotides into nucleosides capable of cellular entry by means of nucleoside transport proteins. In contrast, several intracellular 5′-NU activities have been identified and cloned to date.139,140,141 The ‘low-Michaelis-Menten constant’ (Km) 5′-NU is specific for pyrimidine monophosphates at low micromolar Km values and is inhibited by ATP. The other, high Km 5′-NU is purine selective at high micromolar Km values, and it is activated by ATP.142,143 In vitro, increased 5′-NU activity has been consistently associated with nucleoside drug resistance.45,58,109

Table 3 Human 5′-nucleotidase (5′-NU) activities involved in NA resistance

In the clinic, levels of cyto-5′-NU activity have been correlated to clinical response in CLL, HCL and AML (Table 4). In CLL and HCL, Kawasaki et al119 demonstrated that pretreatment levels of high Km 5′-NU allowed prediction of 2-CdA responsiveness, since 5′-NU levels were significantly lower in responders than in non-responding patients. In AML, we have reported that patients whose blasts expressed high Km 5′-NU mRNA had shorter time-to-relapse and overall survival than patients with no expression.144 However, due to the multiplicity of 5′-NU activities, and the limited ability of classical biochemical methodology to differentiate between these activities, the particular 5′-NU enzyme(s) with the largest impact on clinical resistance to NA have not yet been convincingly identified.145

Table 4 ′-NU and CDD enzyme activity measurements in hematological malignancies

Cytidine deaminase

Cytidine deaminase catalyses the inactivation of cytidine and dCyd to uridine and deoxyuridine, respectively. CDD also deaminates ara-C and gemcitabine.146 Several lines of evidence have indicated a role for increased levels of CDD in the development of resistance to ara-C.147,148,149 Different studies have revealed that transfection of the human CDD gene into murine fibroblasts and hematopoietic cells confers drug resistance to ara-C and gemcitabine.44,150,151

However, the in vivo correlation between CDD activity and ara-C resistance remains controversial and the relative contribution of CDD to drug resistance has not yet been fully elucidated (Table 4). The clinical relevance of a high level of CDD activity as a major cause of ara-C resistance in AML patients has been emphasized by several investigators.118,152,153,154 Conversely, Tattersal et al117 did not find a relationship between increased CDD activity and resistance to therapy in AML patients.

Structural analyses of the CDD gene correlated polymorphism at codon 27 to substantially different deamination rates of ara-C in vitro.155 This structural aberration did not seem to represent a major cause of the observed differences of CDD activities between ara-C-sensitive and ara-C-resistant patients. Schröder and co-workers154 demonstrated a significant correlation of the amount of CDD mRNA with CDD enzyme activities in AML blasts suggesting that variations in CDD activity result from differences in gene expression. It therefore appears that CDD activity in vivo is correlated with transcriptional regulation rather than with CDD gene aberrations.

Levels of dCTP

Various cell lines and AML blasts containing high levels of dCTP have been found to be resistant to ara-C.126,156,157 dCTP levels regulate ara-C metabolism at three levels: by feedback inhibition of dCK activity with the consequent decrease in ara-C phosphorylation;117 by allosteric activation of the catabolic enzyme, CDD;126 and by competing with ara-CTP for incorporation into DNA.158,159 Moreover, Ohno and coworkers160 have shown that dCTP in sufficiently high concentrations can overcome ara-C DNA strand termination so that strand elongation continues past the ara-C incorporation site. dFd-CTP also compete with dCTP for DNA polymerase and for incorporation into DNA.46 Thus, elevated levels of dCTP will favor the survival of cells exposed to these NA.

Ribonucleotide reductase and DNA polymerases

RR consists of two non-identical proteins called M1 and M2, both of which are required for activity. Protein M1 contains the substrate and effector binding sites and is present throughout the cell cycle in proliferating cells. Protein M2 is a dimer that contains stoichiometric amounts of non-heme iron and a unique tyrosyl free radical essential for reductase activity. Its expression is specific of S phase and in quiescent cells M1 and M2 mRNA and proteins are not detectable.161 Clinically useful NA target RR, altering dNTPs concentrations.62,162 Recently, Goan et al163 reported a human KB cancer cell line resistant to gemcitabine with overexpression of the M2 subunit as the sole mechanism explaining this resistance.163

Most of the NA inhibit DNA polymerase activity by competing with dNTPs,164 thereby contributing to the inhibition of DNA synthesis.165 The degree of inhibition of DNA polymerases is not the same for all the NA. For example, DNA polymerase α has been shown to be more sensitive to inhibition by ara-CTP than DNA polymerase β.166 F-ara-ATP is not a potent inhibitor of DNA polymerases β and γ or DNA primase.84,162 In vitro, overexpression of DNA polymerases may be a significant factor in the development of drug resistance.167 Tanaka et al168 found that DNA polymerase α sensitivity to ara-CTP and F-ara-ATP was lower in blast cells obtained from ALL patients than in cells obtained from AML patients, and concluded that DNA polymerase α from ALL blast cells has a decreased affinity for NA.168

Defective cell death pathways and p53 exonuclease activity

DNA damage caused by NA induces expression of p53, leading to the induction of pro-apototic molecules such as Bax and to down-regulation of anti-apoptotic proteins, such as Bcl-2.169,170,171 These events lead to induction of apoptosis.172,173 Various investigators have shown that B-CLL and AML patients with mutations in the p53 gene displayed resistance to fludarabine, 2-CdA or ara-C and/or poorer response and shorter remission and/or overall survival174,175,176,177 (Table 5). Conversely, other authors failed to find any relationship between p53 abnormalities and resistance to NA in these diseases.178,179 Other genes regulating apoptosis, such as Bcl-2, Bcl-X/L, Mcl-1 or Bag-1, have been suggested to influence sensitivity to NA, although the results remain controversial.180,181,182,183,184,185,186,187

Table 5 Involvement of p53 protein in drug resistance to NA

Alterations in p53 function have been related to in vitro resistance to NA.68,188 p53 appears to have a specific role in resistance to NA since it possesses exonuclease activity, and may therefore be able to excise illegally DNA-incorporated NA. Recently, Feng et al reported that although the 3′-5′ exonuclease of wild-type p53 (wt-p53) protein was able to bind and excise gemcitabine residues from DNA in vitro, removal of the drug molecules from cellular DNA was slow in sensitive cells containing wt-p53, and undetectable in drug-resistant mut-p53 cells. Collectively, these data imply that molecular regulators of apoptosis should be taken into consideration when analyzing factors associated with resistance to NA.

Reversal strategies

It is now widely accepted that the antileukemic effect of NA requires sufficiently high intracellular concentrations of triphosphate analogues in tumor cells.38,82,189 One approach has been to develop compounds which are insensitive to degradation. Fludarabine and cladribine are resistant to the effect of ADA. Another approach could consist in the use of specific inhibitors of degradative enzymes, such as 5′-NU. Combinations of a 5′-NU inhibitor with a NA could be expected to potentiate the cytotoxicity of the NA. However, there is still uncertainty regarding the relevant 5′-NU enzyme(s) that mediate NA resistance, and there are currently no clinically available inhibitors of 5′-NU activity. Because many potential inhibitors of 5′-NU are themselves nucleoside analogues, competition with cytotoxic NA for membrane transporter sites may be problematic. Regulation of dCK activity could also be a target for modulation. It has been shown that dCK activity is stimulated after treatment with 2-CdA, as well as with fludarabine and ara-C in normal human lymphocytes and various leukemic cell lines.190,191 The increase of dCK activity induced by NA was considered to result from post- translational modifications of dCK during inhibition of DNA synthesis.192,193

The importance of the ratio of nucleoside analogues to normal nucleosides has been recognized more recently. Reducing the intracellular pools of normal nucleotides therefore appears to be a therapeutic alternative to increasing the concentrations of cytotoxic NA triphosphates. In practice, given the feedback inhibitory effects of dNTPs on NA activation, these two goals may be attained simultaneously. Various biochemical modulation strategies, based on NA combinations, have been suggested to increase the concentration of NA triphosphate in leukemic cells.

Inhibition of ribonucleotide reductase

Large amounts of dNTPs generated by RR are directed into replicating DNA, a process that effectively excludes NA from replicating DNA synthesis.194 Furthermore intracellular dNTP pools inhibit dCK activity, thereby reducing NA activation. Thus, drugs capable of depleting or reducing normal dNTPs by inhibiting RR might be expected to potentiate cytotoxicity of different NA. Sequential incubation of K562 human leukemia cells with F-ara-A followed by ara-C enhanced ara-CTP accumulation, thereby suggesting possible therapeutic synergism between ara-C and fludarabine.86 Subsequent clinical studies have demonstrated the effectiveness of this strategy.195,196 Lymphocytes isolated from patients with CLL and incubated with ara-C after in vitro F-ara-A incubation or a therapeutic infusion of fludarabine (25 or 30 mg/m2) displayed an increase in ara-CTP accumulation.197 The same phenomenon was observed in leukemic lymphocytes and AML blasts.198,199 This increase was caused by a higher rate of anabolism rather than by a slower rate of catabolism of ara-CTP. More recently, Seymour et al200 have shown that F-ara-ATP concentrations (30–50 μM, achieved with usual clinical doses of fludarabine), enhances both intracellular ara-CTP accumulation and incorporation into cellular DNA at concentrations of ara-C which are clinically achievable. Such drug combinations have induced responses in untreated and refractory patients with acute leukemias.201,202

This modulatory effect of fludarabine can be extended to other NA such as 9-β-D-arabinofuranosylguanine (ara-G).203 In vitro studies using human leukemia cell lines and primary leukemia cells obtained from patients established that the effectiveness of ara-G is due to intracellular accumulation of ara-GTP. The rate-limiting step of ara-GTP accumulation is the initial phosphorylation performed both by dGK and dCK. In vivo, Gandhi and coworkers demonstrated in a phase I clinical trial that patients who responded to therapy with the water-soluble ara-G prodrug GW506U achieved a significantly greater concentration of ara-GTP in their circulating cells than patients who did not respond.204,205 In this setting, the combination with fludarabine could increase the intracellular accumulation of ara-GTP in target cells and improve response rates in patients.205

Other inhibitors of RR can be used for the modulation of ara-C metabolism. Iwasaki and coworkers194 showed that inhibition of RR with gemcitabine and the consequent decrease in cellular dCTP pools favored ara-C incorporation into replicating DNA. Colly et al206 and Bhalla et al207 tested the ability of the RR inhibitor hydroxyurea to enhance ara-C metabolism and cytotoxicity in drug-sensitive and -resistant cell lines. This combination significantly reduced dCTP pools, increased DNA incorporation of ara-C and enhanced drug cytotoxicity, even in dCK deficient ara-C-resistant cell lines.

Similarly, as 2-CdA inhibits the reduction of CDP and ADP, a decrease in the dCTP and dATP pools is expected when cells are exposed to this compound. The decrease of these pools would increase the ratios of 2-CdATP to dATP and ara-CTP to dCTP. In vitro incubation of AML blasts with 2-CdA followed by ara-C produced a higher rate of ara-CTP accumulation than did ara-C alone.208 Gandhi and coworkers209 studied 17 patients with refractory AML receiving combination chemotherapy with ara-C and 2-CdA. Seven of nine patients studied during therapy had an increased rate of ara-CTP formation and peak ara-CTP concentrations in leukemic blasts. This modulation strategy increased the effective dose intensity of the active metabolite of ara-C by 40% in the tumor cells. The co-administration of 2-CdA and ara-C resulted in maximum inhibition of DNA synthesis, accumulation of higher concentrations of ara-CTP, greater ratios of analogue triphosphates to normal dNTPs and tandem incorporation of 2-Cl-dATP and ara-CTP in growing DNA strands.

Although potentially interesting, the usefulness of NA combinations in the clinic remains to be determined. In particular the toxicity to normal cells due to the increase of NA accumulation appears to be significant, casting doubt on an improvement of the therapeutic index in comparison to single agent NA therapy. A potential consequence related to NA modulation therapy may be the increased risk of secondary malignancies in a group of patients whose disease already places them at a great risk of second cancers, and dose-related effects like severe neurotoxicity.210,211 Apparently, the frequency and severity of neurotoxicity may be greater with the combination therapy than with either drug used alone.

Modulation of dCK and 5′-NU activitity with bryostatin

Bryostatin, a macrocyclic lactone and protein kinase C activator, has been shown to increase the ratio of dCK/5′-NU activity and thereby increase sensitivity to fludarabine and cladribine in CLL cells, both in vitro and in vivo.212,213 Phase I studies of single agent bryostatin have been completed and this compound is now in clinical trials in combination with NA.214

Use of hematopoietic growth factors

Different in vitro studies have shown that pretreatment of AML blasts by growth factors (GF) enhances ara-C mediated cytotoxicity against leukemic cells, possibly through their proliferation-inducing effects.215,216 GF may also enhance ara-C cytotoxicity by increasing hENT1 expression. High cellular proliferation rates are associated with high levels of hENT1- mediated activity that increase the nucleoside drug uptake.217,218 Wiley et al219 determined that in vitro treatment of isolated human leukemic cells with GM-CSF, resulted in an increase in hENT1 expression. Reuter et al220 established that blasts from AML patients treated with GM-CSF displayed an enhanced drug uptake after low or SDAC doses. In this study, GM-CSF also increased intracellular ara-CTP/dCTP pool ratios and enhanced ara-C incorporation into DNA by activation of DNA polymerases. In vivo, GM-CSF priming of leukemic blasts prior to induction therapy translates into a higher antileukemic activity as indicated by a prolonged survival of treated mice with advanced AML and a high rate of complete remission in patients with AML.221,222 However, various randomized clinical trials failed to demonstrate the effectiveness of the GF-priming strategy and concluded that administration of GF during and after induction chemotherapy does not improve the clinical outcome of ara-C-treated AML patients.223,224

DNA repair induction

Another way of enhancing incorporation of NA into DNA consists of using the DNA repair pathway after combined exposure of tumor cells to NA and DNA damaging agents.225 The recognition and repair of the damaged strand caused by the DNA damaging agent allow resynthesis using the opposite strand as a template. This creates an opportunity for the insertion of the NA instead of its normal counterpart into the DNA repair patch. The incorporated NA is relatively resistant to repair excision and causes irreversible damage recognized by the cell. Alternatively inhibition of DNA repair by NA may increase the accumulation and slow the removal of DNA lesions induced by DNA damaging agents, thereby potentiating the cytotoxicity of these latter compounds. In vitro, combination of gemcitabine and fludarabine with cisplatin generated synergistic cytotoxicity.225 Van Den Neste et al226 recently reported the in vitro synergistic cytotoxicity of 2-CdA and cyclophosphamide in B-CLL cells isolated from patients pretreated with alkylating agents.

In vivo, the combination of a DNA damaging agent and a NA may prove to be particularly useful to destroy cancer cells without significant DNA replication activity such as CLL and indolent lymphomas. The combination of fludarabine with doxorubicin and prednisone is clinically active against CLL.227 Fludarabine and ara-C with or without cisplatin, have been administered to patients with CLL with cytoreductive activity.228 Results of clinical studies using mitoxantrone (which induces protein-associated DNA strand breaks), fludarabine, and dexamethasone demonstrated a high response rate, especially in follicular lymphomas, with a number of patients achieving complete remission.229,230 A combination of mitoxantrone and ara-C for the treatment of acute leukemia has been encouraging.231,232 Moreover, clinical trials evaluating NA in combination with DNA damaging agents have shown effectiveness against solid tumors with low growth fractions.233,234

New nucleoside analogues

The broadening of the spectrum of nucleoside analog activity to solid tumors has triggered renewed interest in this class of antimetabolites. Many new nucleoside drugs have been synthesized and studied over the past decade, with several that are in early phase clinical trials, and others that have become standardly prescribed agents (gemcitabine and capecitabine). We will review the most promising of these agents: troxacitabine, and the GW506U78, an ara-G prodrug. We have excluded from this discussion 5-FU prodrugs such as capecitabine since their mechanisms of action and resistance mechanisms differ substantially from those of other anticancer nucleosides.


Troxacitabine (BCH-4556; (−)-2-(S)-hydroxymethyl-4-(s)-(cytosin-1′-yl)-1,3-dioxolane; β-L-dioxalane cytidine) (Figure 4) is a stereochemically synthetic nucleoside analogue that has potent antitumor activity in preclinical models.235,236,237 It is phosphorylated in vitro by deoxycytidine kinase (dCK) with a Km similar to its natural substrate, dCyd, but unlike gemcitabine and ara-C, it is not a substrate of CDD. Troxacitabine triphosphate can be incorporated into cellular DNA,235 which causes rapid chain termination. However, neither ribonucleotide reductase nor mitochondrial DNA synthesis are inhibited by troxacitabine in cell culture. Because of its broad preclinical spectrum with cytotoxicity both against leukemic and epithelial malignancies, and promising phase I activity demonstrated in acute leukemia,238 phase II testing is now being carried out in several diseases.

Figure 4

Chemical structure of troxacitabine.


In 1983, Cohen et al239reported that the deoxyguanosine derivative ara-G (9-β-D-arabinofuranosylguanine) (Figure 5) was resistant to cleavage by purine nucleoside phosphorylase (PNP) and was toxic to T-lymphocytes. The devolopment of this drug was limited by water insolubility. However, 2-amino-9-β-D-arabinosyl-6-methoxy-9H-guanine (GW506U78) is 10-fold more soluble, and is rapidly converted to ara-G by plasma adenosine deaminase activity.

Figure 5

Chemical structure of ara-G.

In phase I clinical testing, this agent has shown particular promise in the therapy of T cell malignancies,240 where 54% of patients achieved partial or complete remissions after one to two cycles of drug treatment. Of particular interest, neurotoxicity was dose limiting, with little clinical myelosuppression.241 This raises the possibility of successful combination therapy with other active agents, including other hematologically active NA. Although no formal studies have been performed to demonstrate mechanisms of ara-G resistance, accumulation of ara-GTP in leukemic blasts correlated with the cytotoxic activity against malignant cells.241 This suggests that the early steps of uptake and metabolism of ara-G may be major determinants of cellular drug sensitivity, as for other NA.


During the past decade there has been dramatic progress in the understanding of the individual mechanisms of resistance to nucleoside analogues, including the role of cellular drug uptake, drug metabolism, interaction with cellar targets, and the resulting apoptotic cascade. However, most studies have focused on a single mechanism of resistance, thereby failing to provide the relative importance of the different known mechanisms of resistance. It is clear that malignancies are heterogeneous in terms of mechanisms of resistance, and that the clinical benefit of resistance-reversal strategies will only be demonstrated when targeted to the appropriate subgroup of patients.

The ultimate goal of research into anticancer therapy remains improving patient survival. However, in diseases such as CLL or indolent lymphoma in which several treatments are effective but not curative, a realistic goal would be the identification of tumor cell traits which could allow tailored or targetted therapy. In such patients, a predictive assay to determine a phenotype of probable resistance to certain NA would be of great value in the choice of optimal therapy, and the avoidance of ineffective but toxic treatments.

In diseases such as AML in which curative drug combinations exist, the objective is to optimize the efficacy of currently available NA and to develop newer, more effective analogues that are less susceptible to the resistance mechanisms described above. Efforts to increase intracellular levels and DNA incorporation of phosphorylated NA are very promising. NA therapy combined with agents modulating apototic responses are expected to provide additional benefit. In the same way that combination chemotherapy has provided curative treatment of certain cancers, a multifactorial approach of drug resistance should allow significant progress in the treatment of currently chemoresistant disease.


  1. 1

    Cheson BD . New antimetabolites in the treatment of human malignancies Semin Oncol 1992 19: 695–706

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Rustum YM, Raymakers RA . 1-Beta-arabinofuranosylcytosine in therapy of leukemia: preclinical and clinical overview Pharmacol Ther 1992 56: 307–321

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD . Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial J Clin Oncol 1997 15: 2403–2413

    PubMed  PubMed Central  Google Scholar 

  4. 4

    Kaye SB . Gemcitabine: current status of phase I and II trials (editorial) J Clin Oncol 1994 12: 1527–1531

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Bryson HM, Sorkin EM . Cladribine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies Drugs 1993 46: 872–894

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Robertson LE, Huh YO, Butler JJ, Pugh WC, Hirsch-Ginsberg C, Stass S, Kantarjian H, Keating MJ . Response assessment in chronic lymphocytic leukemia after fludarabine plus prednisone: clinical, pathologic, immunophenotypic, and molecular analysis Blood 1992 80: 29–36

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Ross SR, McTavish D, Faulds D . Fludarabine. A review of its pharmacological properties and therapeutic potential in malignancy Drugs 1993 45: 737–759

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Juliusson G, Liliemark J . Long-term survival following cladribine (2-chlorodeoxyadenosine) therapy in previously treated patients with chronic lymphocytic leukemia Ann Oncol 1996 7: 373–379

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Sorensen JM, Vena DA, Fallavollita A, Chun HG, Cheson BD . Treatment of refractory chronic lymphocytic leukemia with fludarabine phosphate via the group C protocol mechanism of the National Cancer Institute: five-year follow-up report J Clin Oncol 1997 15: 458–465

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Boleti H, Coe IR, Baldwin SA, Young JD, Cass CE . Molecular identification of the equilibrative NBMPR-sensitive (es) nucleoside transporter and demonstration of an equilibrative NBMPR-insensitive (ei) transport activity in human erythroleukemia (K562) cells Neuropharmacology 1997 36: 1167–1179

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Baldwin SA, Mackey JR, Cass CE, Young JD . Nucleoside transporters: molecular biology and implications for therapeutic development Mol Med Today 1999 5: 216–224

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Crawford CR, Patel DH, Naeve C, Belt JA . Cloning of the human equilibrative, nitrobenzylmercaptopurine riboside (NBMPR)-insensitive nucleoside transporter ei by functional expression in a transport-deficient cell line J Biol Chem 1998 273: 5288–5293

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Griffiths M, Beaumont N, Yao SY, Sundaram M, Boumah CE, Davies A, Kwong FY, Coe I, Cass CE, Young JD, Baldwin SA . Cloning of a human nucleoside transporter implicated in the cellular uptake of adenosine and chemotherapeutic drugs Nat Med 1997 3: 89–93

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Griffiths M, Yao SY, Abidi F, Phillips SE, Cass CE, Young JD, Baldwin SA . Molecular cloning and characterization of a nitrobenzylthioinosine-insensitive (ei) equilibrative nucleoside transporter from human placenta Biochem J 1997 328: 739–743

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Crawford CR, Ng CY, Noel LD, Belt JA . Nucleoside transport in L1210 murine leukemia cells. Evidence for three transporters J Biol Chem 1990 265: 9732–9736

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Belt JA, Marina NM, Phelps DA, Crawford CR . Nucleoside transport in normal and neoplastic cells Adv Enzyme Regul 1993 33: 235–252

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Graham KA, Leithoff J, Coe IR, Mowles D, Mackey JR, Young JD, Cass CE . Differential transport of cytosine-containing nucleosides by recombinant human concentrative nucleoside transporter protein hCNT1 Nucleosides Nucleotides Nucleic Acids 2000 19: 415–434

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Schaner ME, Wang J, Zhang L, Su SF, Gerstin KM, Giacomini KM . Functional characterization of a human purine-selective, Na+-dependent nucleoside transporter (hSPNT1) in a mammalian expression system J Pharmacol Exp Ther 1999 289: 1487–1491

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Kufe DW, Weichselbaum R, Egan EM, Dahlberg W, Fram RJ . Lethal effects of 1-beta-D-arabinofuranosylcytosine incorporation into deoxyribonucleic acid during ultraviolet repair Mol Pharmacol 1984 25: 322–326

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Sandoval A, Consoli U, Plunkett W . Fludarabine-mediated inhibition of nucleotide excision repair induces apoptosis in quiescent human lymphocytes Clin Cancer Res 1996 2: 1731–1741

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Nicander B, Reichard P . Relations between synthesis of deoxyribonucleotides and DNA replication in 3T6 fibroblasts J Biol Chem 1985 260: 5376–5381

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Xu YZ, Huang P, Plunkett W . Functional compartmentation of dCTP pools. Preferential utilization of salvaged deoxycytidine for DNA repair in human lymphoblasts J Biol Chem 1995 270: 631–637

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Shrecker AW, Urshel MJ . Metabolism of 1-beta-D-arabinofuranosylcytosine in leukemia L1210: studies with intact cells Cancer Res 1968 28: 793–801

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Plagemann PG, Marz R, Wohlhueter RM . Transport and metabolism of deoxycytidine and 1-beta-D-arabinofuranosylcytosine into cultured Novikoff rat hepatoma cells, relationship to phosphorylation, and regulation of triphosphate synthesis Cancer Res 1978 38: 978–989

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Capizzi RL, Yang JL, Rathmell JP, White JC, Cheng E, Cheng YC, Kute T . Dose-related pharmacologic effects of high-dose ara-C and its self-potentiation Semin Oncol 1985 12: 65–74

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Wiley JS, Taupin J, Jamieson GP, Snook M, Sawyer WH, Finch LR . Cytosine arabinoside transport and metabolism in acute leukemias and T cell lymphoblastic lymphoma J Clin Invest 1985 75: 632–642

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Weinstein HJ, Griffin TW, Feeney J, Cohen HJ, Propper RD, Sallan SE . Pharmacokinetics of continuous intravenous and subcutaneous infusions of cytosine arabinoside Blood 1982 59: 1351–1353

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Ho DH, Frei E . Clinical pharmacology of 1-beta-d-arabinofuranosyl cytosine Clin Pharmacol Ther 1971 12: 944–954

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Capizzi RL, Yang JL, Cheng E, Bjornsson T, Sahasrabudhe D, Tan RS, Cheng YC . Alteration of the pharmacokinetics of high-dose ara-C by its metabolite, high ara-U in patients with acute leukemia J Clin Oncol 1983 1: 763–771

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Plunkett W, Liliemark JO, Estey E, Keating MJ . Saturation of ara-CTP accumulation during high-dose ara-C therapy: pharmacologic rationale for intermediate-dose ara-C Semin Oncol 1987 14: 159–166

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Liliemark JO, Plunkett W, Dixon DO . Relationship of 1-beta-D-arabinofuranosylcytosine in plasma to 1-beta-D-arabinofuranosylcytosine 5′-triphosphate levels in leukemic cells during treatment with high-dose 1-beta-D-arabinofuranosylcytosine Cancer Res 1985 45: 5952–5957

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Dumontet C, Fabianowska-Majewska K, Mantincic D, Callet Bauchu E, Tigaud I, Gandhi V, Lepoivre M, Peters GJ, Rolland MO, Wyczechowska D, Fang X, Gazzo S, Voorn DA, Vanier-Viornery A, Mackey JR . Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562 Br J Haematol 1999 106: 78–85

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Major PP, Egan EM, Beardsley GP, Minden MD, Kufe DW . Lethality of human myeloblasts correlates with the incorporation of arabinofuranosylcytosine into DNA Proc Natl Acad Sci USA 1981 78: 3235–3239

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Major PP, Egan EM, Herrick DJ, Kufe DW . Effect of ARA-C incorporation on deoxyribonucleic acid synthesis in cells Biochem Pharmacol 1982 31: 2937–2940

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Kufe DW, Major PP, Egan EM, Beardsley GP . Correlation of cytotoxicity with incorporation of ara-C into DNA J Biol Chem 1980 255: 8997–8900

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Gunji H, Kharbanda S, Kufe D . Induction of internucleosomal DNA fragmentation in human myeloid leukemia cells by 1-beta-D-arabinofuranosylcytosine Cancer Res 1991 51: 741–743

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Raza A, Gezer S, Anderson J, Lykins J, Bennett J, Browman G, Goldberg J, Larson R, Vogler R, Preisler HD . Relationship of [3H]Ara-C incorporation and response to therapy with high-dose Ara-C in AML patients: a Leukemia Intergroup study Exp Hematol 1992 20: 1194–1200

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Estey E, Plunkett W, Dixon D, Keating M, McCredie K, Freireich EJ . Variables predicting response to high dose cytosine arabinoside therapy in patients with refractory acute leukemia Leukemia 1987 1: 580–583

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Kaye SB . New antimetabolites in cancer chemotherapy and their clinical impact Br J Cancer 1998 78: 1–7

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Possinger K . Gemcitabine in advanced breast cancer Anticancer Drugs 1995 6 (Suppl. 6): 55–59

    Google Scholar 

  41. 41

    Baker CH, Banzon J, Bollinger JM, Stubbe J, Samano V, Robins MJ, Lippert B, Jarvi E, Resvick R . 2′-Deoxy-2′-methylenecytidine and 2′-deoxy-2′,2′-difluorocytidine 5′-diphosphates: potent mechanism-based inhibitors of ribonucleotide reductase J Med Chem 1991 34: 1879–1884

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine J Clin Oncol 1991 9: 491–498

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V . Gemcitabine: metabolism, mechanisms of action, and self-potentiation Semin Oncol 1995 22: 3–10

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Neff T, Blau CA . Forced expression of cytidine deaminase confers resistance to cytosine arabinoside and gemcitabine Exp Hematol 1996 24: 1340–1346

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Schirmer M, Stegmann AP, Geisen F, Konwalinka G . Lack of cross-resistance with gemcitabine and cytarabine in cladribine-resistant HL60 cells with elevated 5′-nucleotidase activity Exp Hematol 1998 26: 1223–1228

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W . Action of 2′,2′-difluorodeoxycytidine on DNA synthesis Cancer Res 1991 51: 6110–6117

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Huang P, Plunkett W . Induction of apoptosis by gemcitabine Semin Oncol 1995 22: 19–25

    PubMed  PubMed Central  Google Scholar 

  48. 48

    Plunkett W, Huang P, Gandhi V . Preclinical characteristics of gemcitabine Anticancer Drugs 1995 6 (Suppl. 6): 7–13

    Google Scholar 

  49. 49

    Ruiz van Haperen VW, Veerman G, Vermorken JB, Peters GJ . 2′,2′-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines Biochem Pharmacol 1993 46: 762–766

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Cartei G, Sacco C, Sibau A, Pella N, Iop A, Tabaro G . Cisplatin and gemcitabine in non-small-cell lung cancer Ann Oncol 1999 10: S57–S62

    PubMed  PubMed Central  Google Scholar 

  51. 51

    Hoffman MA, Janson D, Rose E, Rai KR . Treatment of hairy-cell leukemia with cladribine: response, toxicity, and long-term follow-up J Clin Oncol 1997 15: 1138–1142

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Jehn U, Bartl R, Dietzfelbinger H, Vehling-Kaiser U, Wolf-Hornung B, Hill W, Heinemann V . Long-term outcome of hairy cell leukemia treated with 2-chlorodeoxyadenosine Ann Hematol 1999 78: 139–144

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Lauria F, Rondelli D, Zinzani PL, Bocchia M, Marotta G, Salvucci M, Raspadori D, Ventura MA, Birtolo S, Forconi F, Tura S . Long-lasting complete remission in patients with hairy cell leukemia treated with 2-CdA: a 5-year survey Leukemia 1997 11: 629–632

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    King KM . Membrane transport of 2′-chloro-2′-deoxyadenosine and 2-chloro-2′arabinofluoro-2′-deoxyadenosine is required for cytotoxicity Proc Am Assoc Cancer Res 1994 35: A3436

    Google Scholar 

  55. 55

    Wang L, Karlsson A, Arner ES, Eriksson S . Substrate specificity of mitochondrial 2′-deoxyguanosine kinase. Efficient phosphorylation of 2-chlorodeoxyadenosine J Biol Chem 1993 268: 22847–22852

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Carson DA, Kaye J, Wasson DB . The potential importance of soluble deoxynucleotidase activity in mediating deoxyadenosine toxicity in human lymphoblasts J Immunol 1981 126: 348–352

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Seto S, Carrera CJ, Kubota M, Wasson DB, Carson DA . Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes J Clin Invest 1985 75: 377–383

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Carson DA, Wasson DB, Taetle R, Yu A . Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes Blood 1983 62: 737–743

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Griffig J, Koob R, Blakley RL . Mechanisms of inhibition of DNA synthesis by 2-chlorodeoxyadenosine in human lymphoblastic cells Cancer Res 1989 49: 6923–6928

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Hentosh P, Koob R, Blakley RL . Incorporation of 2-halogeno-2′-deoxyadenosine 5-triphosphates into DNA during replication by human polymerases alpha and beta J Biol Chem 1990 265: 4033–4040

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Lassota P, Kazimierczuk Z, Darzynkiewicz Z . Apoptotic death of lymphocytes upon treatment with 2-chloro-2′-deoxyadenosine (2-CdA) Arch Immunol Ther Exp 1994 42: 17–23

    CAS  Google Scholar 

  62. 62

    Parker WB, Bapat AR, Shen JX, Townsend AJ, Cheng YC . Interaction of 2-halogenated dATP analogs (F, Cl, and Br) with human DNA polymerases, DNA primase, and ribonucleotide reductase Mol Pharmacol 1988 34: 485–491

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Plunkett W, Huang P, Gandhi V . Metabolism and action of fludarabine phosphate Semin Oncol 1990 17: 3–17

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Fabianowska-Majewska K, Wasiak TJ, Warzocha K, Marlewski M, Fairbanks L, Smolenski RT, Duley J, Simmonds A . A new mechanism of toxicity of 2-chlorodeoxyadenosine (2CdA) Adv Exp Med Biol 1994 370: 125–128

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Abeles RH, Tashjian AH Jr, Fish S . The mechanism of inactivation of S-adenosylhomocysteinase by 2′-deoxyadenosine Biochem Biophys Res Commun 1980 95: 612–617

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Wolos JA, Frondorf KA, Davis GF, Jarvi ET, McCarthy JR, Bowlin TL . Selective inhibition of T cell activation by an inhibitor of S-adenosyl- L-homocysteine hydrolase J Immunol 1993 150: 3264–3273

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Pettitt AR, Clarke AR, Cawley JC, Griffiths SD . Purine analogues kill resting lymphocytes by p53-dependent and -independent mechanisms Br J Haematol 1999 105: 986–988

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Pettitt AR, Sherrington PD, Cawley JC . The effect of p53 dysfunction on purine analogue cytotoxicity in chronic lymphocytic leukaemia Br J Haematol 1999 106: 1049–1051

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Genini D, Adachi S, Chao Q, Rose DW, Carrera CJ, Cottam HB, Carson DA, Leoni LM . Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria Blood 2000 96: 3537–3543

    CAS  Google Scholar 

  70. 70

    Hentosh P, Tibudan M . In vitro transcription of DNA containing 2-chloro-2′-deoxyadenosine monophosphate Mol Pharmacol 1995 48: 897–904

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Genini D, Budihardjo I, Plunkett W, Wang X, Carrera CJ, Cottam HB, Carson DA, Leoni LM . Nucleotide requirements for the in vitro activation of the apoptosis protein-activating factor-1-mediated caspase pathway J Biol Chem 2000 275: 29–34

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Leoni LM, Chao Q, Cottam HB, Genini D, Rosenbach M, Carrera CJ, Budihardjo I, Wang X, Carson DA . Induction of an apoptotic program in cell-free extracts by 2-chloro-2′-deoxyadenosine 5′-triphosphate and cytochrome c Proc Natl Acad Sci USA 1998 95: 9567–9571

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Hentosh P, Tibudan M . 2-Chloro-2′-deoxyadenosine, an antileukemic drug, has an early effect on cellular mitochondrial function Mol Pharmacol 1997 51: 613–619

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Enriquez JA, Fernandez-Silva P, Perez-Martos A, Lopez-Perez MJ, Montoya J . The synthesis of mRNA in isolated mitochondria can be maintained for several hours and is inhibited by high levels of ATP Eur J Biochem 1996 237: 601–610

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    de Murcia G, Menissier de Murcia J . Poly(ADP-ribose) polymerase: a molecular nick-sensor (published erratum appears in Trends Biochem Sci 1994; 19: 250) Trends Biochem Sci 1994 19: 172–176

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    D'Amours D, Desnoyers S, D'Silva I, Poirier GG . Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions Biochem J 1999 342: 249–268

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Althaus FR, Richter C . ADP-ribosylation of proteins. Enzymology and biological significance Mol Biol Biochem Biophys 1987 37: 1–237

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Carson DA, Carrera CJ, Wasson DB, Yamanaka H . Programmed cell death and adenine deoxynucleotide metabolism in human lymphocytes Adv Enzyme Regul 1988 27: 395–404

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, Susin SA, Petit PX, Mignotte B, Kroemer G . Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death J Exp Med 1995 182: 367–377

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Brockman RW, Schabel FM Jr, Montgomery JA . Biologic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine, a metabolically stable analog of 9-beta-D-arabinofuranosyladenine Biochem Pharmacol 1977 26: 2193–2196

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Mackey JR, Baldwin SA, Young JD, Cass CE . The role of nucleoside transport in anticancer drug resistance Drug Resistance Updates 1998 1: 310–324

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Plunkett W, Gandhi V, Huang P, Robertson LE, Yang LY, Gregoire V, Estey E, Keating MJ . Fludarabine: pharmacokinetics, mechanisms of action, and rationales for combination therapies Semin Oncol 1993 20: 2–12

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Plunkett W, Saunders PP . Metabolism and action of purine nucleoside analogs Pharmacol Ther 1991 49: 239–268

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Tseng WC, Derse D, Cheng YC, Brockman RW, Bennett LL Jr . In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells Mol Pharmacol 1982 21: 474–477

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Huang P, Chubb S, Plunkett W . Termination of DNA synthesis by 9-beta-D-arabinofuranosyl-2-fluoroadenine. A mechanism for cytotoxicity J Biol Chem 1990 265: 16617–16625

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Gandhi V, Plunkett W . Modulation of arabinosylnucleoside metabolism by arabinosylnucleotides in human leukemia cells Cancer Res 1988 48: 329–334

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Consoli U, El-Tounsi I, Sandoval A, Snell V, Kleine HD, Brown W, Robinson JR, DiRaimondo F, Plunkett W, Andreeff M . Differential induction of apoptosis by fludarabine monophosphate in leukemic B and normal T cells in chronic lymphocytic leukemia Blood 1998 91: 1742–1748

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Pettitt AR, Sherrington PD, Cawley JC . Role of poly(ADP-ribosyl)ation in the killing of chronic lymphocytic leukemia cells by purine analogues Cancer Res 2000 60: 4187–4193

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Huang P, Plunkett W . Action of 9-beta-D-arabinofuranosyl-2-fluoroadenine on RNA metabolism Mol Pharmacol 1991 39: 449–455

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Huang P, Sandoval A, Van Den Neste E, Keating MJ, Plunkett W . Inhibition of RNA transcription: a biochemical mechanism of action against chronic lymphocytic leukemia cells by fludarabine Leukemia 2000 14: 1405–1413

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Gottardi D, De Leo AM, Alfarano A, Stacchini A, Circosta P, Gregoretti MG, Bergui L, Aragno M, Caligaris-Cappio F . Fludarabine ability to down-regulate Bcl-2 gene product in CD5+ leukaemic B cells: in vitro/in vivo correlations Br J Haematol 1997 99: 147–157

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Sjoberg AH, Wang L, Eriksson S . Substrate specificity of human recombinant mitochondrial deoxyguanosine kinase with cytostatic and antiviral purine and pyrimidine analogs Mol Pharmacol 1998 53: 270–273

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Galmarini CM, Thomas X, Calvo F, Rousselot P, Dumontet C . Mechanisms of resistance to cytarabine in relapsing acute myeloid leukemia (AML) patients Blood 1999 94: 1249A

    Google Scholar 

  94. 94

    White JC, Rathmell JP, Capizzi RL . Membrane transport influences the rate of accumulation of cytosine arabinoside in human leukemia cells J Clin Invest 1987 79: 380–387

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, Crawford CR, Cass CE . Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines Cancer Res 1998 58: 4349–4357

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Gati WP, Paterson AR, Larratt LM, Turner AR, Belch AR . Sensitivity of acute leukemia cells to cytarabine is a correlate of cellular es nucleoside transporter site content measured by flow cytometry with SAENTA-fluorescein Blood 1997 90: 346–353

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Gati WP, Paterson AR, Belch AR, Chlumecky V, Larratt LM, Mant MJ, Turner AR . Es nucleoside transporter content of acute leukemia cells: role in cell sensitivity to cytarabine (araC) Leuk Lymphoma 1998 32: 45–54

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Wiley JS, Jones SP, Sawyer WH, Paterson AR . Cytosine arabinoside influx and nucleoside transport sites in acute leukemia J Clin Invest 1982 69: 479–489

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Coleman CN, Stoller RG, Drake JC, Chabner BA . Deoxycytidine kinase: properties of the enzyme from human leukemic granulocytes Blood 1975 46: 791–803

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Carson DA, Wasson DB, Kaye J, Ullman B, Martin DW Jr, Robins RK, Montgomery JA . Deoxycytidine kinase-mediated toxicity of deoxyadenosine analogs toward malignant human lymphoblasts in vitro and toward murine L1210 leukemia in vivo Proc Natl Acad Sci USA 1980 77: 6865–6869

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Heinemann V, Hertel LW, Grindey GB, Plunkett W . Comparison of the cellular pharmacokinetics and toxicity of 2′,2′-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine Cancer Res 1988 48: 4024–4031

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Wan CW, Mak TW . Deoxycytidine kinase and cytosine nucleoside deaminase activities in synchronized cultures of normal rat kidney cells Cancer Res 1978 38: 2768–2772

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Arner ES, Flygar M, Bohman C, Wallstrom B, Eriksson S . Deoxycytidine kinase is constitutively expressed in human lymphocytes: consequences for compartmentation effects, unscheduled DNA synthesis, and viral replication in resting cells Exp Cell Res 1988 178: 335–342

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Terai C, Wasson DB, Carrera CJ, Carson DA . Dependence of cell survival on DNA repair in human mononuclear phagocytes J Immunol 1991 147: 4302–4306

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Hengstschlager M, Denk C, Wawra E . Cell cycle regulation of deoxycytidine kinase. Evidence for post-transcriptional control FEBS Lett 1993 321: 237–240

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Verhoef V, Sarup J, Fridland A . Identification of the mechanism of activation of 9-beta-D-arabinofuranosyladenine in human lymphoid cells using mutants deficient in nucleoside kinases Cancer Res 1981 41: 4478–4483

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Bhalla K, Nayak R, Grant S . Isolation and characterization of a deoxycytidine kinase-deficient human promyelocytic leukemic cell line highly resistant to 1-beta-D-arabinofuranosylcytosine Cancer Res 1984 44: 5029–5037

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Stegmann AP, Honders MW, Kester MG, Landegent JE, Willemze R . Role of deoxycytidine kinase in an in vitro model for AraC- and DAC-resistance: substrate-enzyme interactions with deoxycytidine, 1-beta-D-arabinofuranosylcytosine and 5-aza-2′-deoxycytidine Leukemia 1993 7: 1005–1011

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Dumontet C, Fabianowska-Majewska K, Mantincic D, Callet Bauchu E, Tigaud I, Gandhi V, Lepoivre M, Peters GJ, Rolland MO, Wyczechowska D, Fang X, Gazzo S, Voorn DA, Vanier-Viornery A, MacKey J . Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562 Br J Haematol 1999 106: 78–85

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Stegmann AP, Honders WH, Willemze R, Ruiz van Haperen VW, Landegent JE . Transfection of wild-type deoxycytidine kinase (dck) cDNA into an AraC- and DAC-resistant rat leukemic cell line of clonal origin fully restores drug sensitivity Blood 1995 85: 1188–1194

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Hapke DM, Stegmann AP, Mitchell BS . Retroviral transfer of deoxycytidine kinase into tumor cell lines enhances nucleoside toxicity Cancer Res 1996 56: 2343–2347

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Orr RM, Talbot DC, Aherne WG, Fisher TC, Serafinowski P, Harrap KR . 2′-Deoxycytidine kinase deficiency is a major determinant of 2-chloro-2′-deoxyadenosine resistance in lymphoid cell lines Clin Cancer Res 1995 1: 391–398

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Ho DH . Distribution of kinase and deaminase of 1-beta-D-arabinofuranosylcytosine in tissues of man and mouse Cancer Res 1973 33: 2816–2820

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Spasokoukotskaja T, Arner ES, Brosjo O, Gunven P, Juliusson G, Liliemark J, Eriksson S . Expression of deoxycytidine kinase and phosphorylation of 2-chlorodeoxyadenosine in human normal and tumour cells and tissues Eur J Cancer 1995 2: 202–208

    Google Scholar 

  115. 115

    Kakihara T, Fukuda T, Tanaka A, Emura I, Kishi K, Asami K, Uchiyama M . Expression of deoxycytidine kinase (dCK) gene in leukemic cells in childhood: decreased expression of dCK gene in relapsed leukemia Leuk Lymphoma 1998 31: 405–409

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Stammler G, Zintl F, Sauerbrey A, Volm M . Deoxycytidine kinase mRNA expression in childhood acute lymphoblastic leukemia Anticancer Drugs 1997 8: 517–521

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Tattersall MH, Ganeshaguru K, Hoffbrand AV . Mechanisms of resistance of human acute leukaemia cells to cytosine arabinoside Br J Haematol 1974 27: 39–46

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Colly LP, Peters WG, Richel D, Arentsen-Honders MW, Starrenburg CW, Willemze R . Deoxycytidine kinase and deoxycytidine deaminase values correspond closely to clinical response to cytosine arabinoside remission induction therapy in patients with acute myelogenous leukemia Semin Oncol 1987 14: 257–261

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Kawasaki H, Carrera CJ, Piro LD, Saven A, Kipps TJ, Carson DA . Relationship of deoxycytidine kinase and cytoplasmic 5′-nucleotidase to the chemotherapeutic efficacy of 2-chlorodeoxyadenosine Blood 1993 81: 597–601

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Albertioni F, Lindemalm S, Reichelova V, Pettersson B, Eriksson S, Juliusson G, Liliemark J . Pharmacokinetics of cladribine in plasma and its 5′-monophosphate and 5′-triphosphate in leukemic cells of patients with chronic lymphocytic leukemia Clin Cancer Res 1998 4: 653–658

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Leiby JM, Snider KM, Kraut EH, Metz EN, Malspeis L, Grever MR . Phase II trial of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5′-monophosphate in non-Hodgkin's lymphoma: prospective comparison of response with deoxycytidine kinase activity Cancer Res 1987 47: 2719–2722

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Owens JK, Shewach DS, Ullman B, Mitchell BS . Resistance to 1-beta-XD-arabinofuranosylcytosine in human T-lymphoblasts mediated by mutations within the deoxycytidine kinase gene Cancer Res 1992 52: 2389–2393

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Momparler RL, Cote S, Eliopoulos N . Pharmacological approach for optimization of the dose schedule of 5-Aza-2′-deoxycytidine (Decitabine) for the therapy of leukemia Leukemia 1997 11 (Suppl. 1): S1–S6

    Google Scholar 

  124. 124

    Flasshove M, Strumberg D, Ayscue L, Mitchell BS, Tirier C, Heit W, Seeber S, Schutte J . Structural analysis of the deoxycytidine kinase gene in patients with acute myeloid leukemia and resistance to cytosine arabinoside Leukemia 1994 8: 780–785

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Veuger MJ, Honders MW, Landegent JE, Willemze R, Barge RM . High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia Blood 2000 96: 1517–1524

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Chiba P, Tihan T, Szekeres T, Salamon J, Kraupp M, Eher R, Koller U, Knapp W . Concordant changes of pyrimidine metabolism in blasts of two cases of acute myeloid leukemia after repeated treatment with ara-C in vivo Leukemia 1990 4: 761–765

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Chottiner EG, Shewach DS, Datta NS, Ashcraft E, Gribbin D, Ginsburg D, Fox IH, Mitchell BS . Cloning and expression of human deoxycytidine kinase cDNA Proc Natl Acad Sci USA 1991 88: 1531–1535

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Nyce J, Liu L, Jones PA . Variable effects of DNA-synthesis inhibitors upon DNA methylation in mammalian cells Nucleic Acids Res 1986 14: 4353–4367

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Antonsson BE, Avramis VI, Nyce J, Holcenberg JS . Effect of 5-azacytidine and congeners on DNA methylation and expression of deoxycytidine kinase in the human lymphoid cell lines CCRF/CEM/0 and CCRF/CEM/dCk-1 Cancer Res 1987 47: 3672–3678

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Harris AL, Grahame-Smith DG . Cytosine arabinoside triphosphate production in human leukaemic myeloblasts: interactions with deoxycytidine Cancer Chemother Pharmacol 1981 5: 185–192

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Arner ES, Eriksson S . Mammalian deoxyribonucleoside kinases Pharmacol Ther 1995 67: 155–186

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Petrakis TG, Ktistaki E, Wang L, Eriksson S, Talianidis I . Cloning and characterization of mouse deoxyguanosine kinase. Evidence for a cytoplasmic isoform J Biol Chem 1999 274: 24726–24730

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Johansson M, Karlsson A . Cloning and expression of human deoxyguanosine kinase cDNA Proc Natl Acad Sci USA 1996 93: 7258–7262

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Johansson M, Karlsson A . Cloning of the cDNA and chromosome localization of the gene for human thymidine kinase 2 J Biol Chem 1997 272: 8454–8458

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Wang L, Hellman U, Eriksson S . Cloning and expression of human mitochondrial deoxyguanosine kinase cDNA FEBS Lett 1996 390: 39–43

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Wang L, Munch-Petersen B, Herrstrom Sjoberg A, Hellman U, Bergman T, Jornvall H, Eriksson S . Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates FEBS Lett 1999 443: 170–174

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Resta R, Yamashita Y, Thompson LF . Ecto-enzyme and signaling functions of lymphocyte CD73 Immunol Rev 1998 161: 95–109

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Pieters R, Thompson LF, Broekema GJ, Huismans DR, Peters GJ, Pals ST, Horst E, Hahlen K, Veerman AJ . Expression of 5′-nucleotidase (CD73) related to other differentiation antigens in leukemias of B-cell lineage Blood 1991 78: 488–492

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Spychala J, Mitchell BS . Regulation of low Km (ecto-) 5′-nucleotidase gene expression in leukemic cells Adv Exp Med Biol 1994 370: 683–687

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Rampazzo C, Gazziola C, Ferraro P, Gallinaro L, Johansson M, Reichard P, Bianchi V . Human high-Km 5′-nucleotidase effects of overexpression of the cloned cDNA in cultured human cells Eur J Biochem 1999 261: 689–697

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Rampazzo C, Johansson M, Gallinaro L, Ferraro P, Hellman U, Karlsson A, Reichard P, Bianchi V . Mammalian 5′(3′)-deoxyribonucleotidase, cDNA cloning, and overexpression of the enzyme in Escherichia coli and mammalian cells J Biol Chem 2000 275: 5409–5415

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Spychala J, Madrid-Marina V, Fox IH . Evidence for ‘low Km’ and ‘high Km’ soluble 5′-nucleotidases in human tissues and rat liver Adv Exp Med Biol 1989 253: 129–134

    Google Scholar 

  143. 143

    Madrid-Marina V, Lestan B, Nowak PJ, Fox IH, Spychala J . Altered properties of human T-lymphoblast soluble low Km 5′-nucleotidase: comparison with B-lymphoblast enzyme Leuk Res 1993 17: 231–240

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Galmarini CM, Thomas X, Calvo F, Rousselot P, El Jaffari A, Cros E, Dumontet C . Expression of cytoplasmic 5′-nucleotidase in leukemic blasts is an adverse prognostic factor in AML patients treated with cytarabine Blood 2000 96: 101a

    Google Scholar 

  145. 145

    Mansson E, Spasokoukotskaja T, Sallstrom J, Eriksson S, Albertioni F . Molecular and biochemical mechanisms of fludarabine and cladribine resistance in a human promyelocytic cell line Cancer Res 1999 59: 5956–5963

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Laliberte J, Momparler RL . Human cytidine deaminase: purification of enzyme, cloning, and expression of its complementary DNA Cancer Res 1994 54: 5401–5407

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Capizzi RL, White JC, Powell BL, Perrino F . Effect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabine Semin Hematol 1991 28: 54–69

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Honma Y, Onozuka Y, Okabe-Kado J, Kasukabe T, Hozumi M . Hemin enhances the sensitivity of erythroleukemia cells to 1-beta-D-arabinofuranosylcytosine by both activation of deoxycytidine kinase and reduction of cytidine deaminase activity Cancer Res 1991 51: 4535–4538

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Momparler RL, Laliberte J . Induction of cytidine deaminase in HL-60 myeloid leukemic cells by 5-aza-2′-deoxycytidine Leuk Res 1990 14: 751–754

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Momparler RL, Eliopoulos N, Bovenzi V, Letourneau S, Greenbaum M, Cournoyer D . Resistance to cytosine arabinoside by retrovirally mediated gene transfer of human cytidine deaminase into murine fibroblast and hematopoietic cells Cancer Gene Ther 1996 3: 331–338

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Schroder JK, Kirch C, Flasshove M, Kalweit H, Seidelmann M, Hilger R, Seeber S, Schutte J . Constitutive overexpression of the cytidine deaminase gene confers resistance to cytosine arabinoside in vitro Leukemia 1996 10: 1919–1924

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Steuart CD, Burke PJ . Cytidine deaminase and the development of resistance to arabinosyl cytosine Nat New Biol 1971 233: 109–110

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Jahns-Streubel G, Reuter C, Auf der Landwehr U, Unterhalt M, Schleyer E, Wormann B, Buchner T, Hiddemann W . Activity of thymidine kinase and of polymerase alpha, as well as activity and gene expression of deoxycytidine deaminase in leukemic blasts are correlated with clinical response in the setting of granulocyte–macrophage colony-stimulating factor-based priming before and during TAD-9 induction therapy in acute myeloid leukemia Blood 1997 90: 1968–1976

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Schröder JK, Kirch C, Seeber S, Schutte J . Structural and functional analysis of the cytidine deaminase gene in patients with acute myeloid leukaemia Br J Haematol 1998 103: 1096–1103

    PubMed  PubMed Central  Google Scholar 

  155. 155

    Kirch HC, Schroder J, Hoppe H, Esche H, Seeber S, Schutte J . Recombinant gene products of two natural variants of the human cytidine deaminase gene confer different deamination rates of cytarabine in vitro Exp Hematol 1998 26: 421–425

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Chabner BA, Hande KR, Drake JC . Ara-C metabolism: implications for drug resistance and drug interactions Bull Cancer 1979 66: 89–92

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Liliemark JO, Plunkett W . Regulation of 1-beta-D-arabinofuranosylcytosine 5′-triphosphate accumulation in human leukemia cells by deoxycytidine 5′-triphosphate Cancer Res 1986 46: 1079–1083

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Kunz BA . Mutagenesis and deoxyribonucleotide pool imbalance Mutat Res 1988 200: 133–147

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Meuth M . The molecular basis of mutations induced by deoxyribonucleoside triphosphate pool imbalances in mammalian cells Exp Cell Res 1989 181: 305–316

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Ohno Y, Spriggs D, Matsukage A, Ohno T, Kufe D . Effects of 1-beta-D-arabinofuranosylcytosine incorporation on elongation of specific DNA sequences by DNA polymerase beta Cancer Res 1988 48: 1494–1498

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Bjorklund S, Skog S, Tribukait B, Thelander L . S-phase-specific expression of mammalian ribonucleotide reductase R1 and R2 subunit mRNAs Biochemistry 1990 29: 5452–5458

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Parker WB, Shaddix SC, Chang CH, White EL, Rose LM, Brockman RW, Shortnacy AT, Montgomery JA, Secrist JAd, Bennett LL, Jr . Effects of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5′-triphosphate Cancer Res 1991 51: 2386–2394

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Goan YG, Zhou B, Hu E, Mi S, Yen Y . Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line Cancer Res 1999 59: 4204–4207

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Graham FL, Whitmore GF . Studies in mouse L-cells on the incorporation of 1-beta-D-arabinofuranosylcytosine into DNA and on inhibition of DNA polymerase by 1-beta-D-arabinofuranosylcytosine 5′-triphosphate Cancer Res 1970 30: 2636–2644

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Allaudeen HS, Kozarich JW, Sartorelli AC . Comparative effects of the 5′-triphosphates of 9-beta-(2′-azido-2′-deoxy-D-arabino-furanosyl)adenine and 9-beta-D-arabinofuranosyladenine on DNA polymerases from L1210 leukemia cells Nucleic Acids Res 1982 10: 1379–1387

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Yoshida S, Yamada M, Masaki S . Inhibition of DNA polymerase-alpha and -beta of calf thymus by 1-beta-D-arabinofuranosylcytosine-5′-triphosphate Biochim Biophys Acta 1977 477: 144–150

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Higashigawa M, Ido M, Nagao Y, Kuwabara H, Hori H, Ohkubo T, Kawasaki H, Sakurai M . Decreased DNA polymerase sensitivity to 1-beta-D-arabinofuranosylcytosine 5′-triphosphate in P388 murine leukemic cells resistant to vincristine Leuk Res 1991 15: 675–681

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Tanaka M, Yoshida S . Altered sensitivity to 1-beta-D-arabinofuranosylcytosine 5′-triphosphate of DNA polymerase alpha from leukemic blasts of acute lymphoblastic leukemia Cancer Res 1982 42: 649–653

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Reed JC . Bcl-2 and the regulation of programmed cell death J Cell Biol 1994 124: 1–6

    CAS  Google Scholar 

  170. 170

    Miyashita T, Harigai M, Hanada M, Reed JC . Identification of a p53-dependent negative response element in the bcl-2 gene Cancer Res 1994 54: 3131–3135

    CAS  Google Scholar 

  171. 171

    Miyashita T, Reed JC . Tumor suppressor p53 is a direct transcriptional activator of the human bax gene Cell 1995 80: 293–299

    CAS  Google Scholar 

  172. 172

    Avramis VI, Nandy P, Kwock R, Solorzano MM, Mukherjee SK, Danenberg P, Cohen LJ . Increased p21/WAF-1 and p53 protein levels following sequential three drug combination regimen of fludarabine, cytarabine and docetaxel induces apoptosis in human leukemia cells Anticancer Res 1998 18: 2327–2338

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Gartenhaus RB, Wang P, Hoffman M, Janson D, Rai KR . The induction of p53 and WAF1/CIP1 in chronic lymphocytic leukemia cells treated with 2-chlorodeoxyadenosine J Mol Med 1996 74: 143–147

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    el Rouby S, Thomas A, Costin D, Rosenberg CR, Potmesil M, Silber R, Newcomb EW . p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression Blood 1993 82: 3452–3459

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I, Morel P, Fenaux P . p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies Blood 1994 84: 3148–3157

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

    Johnston JB, Daeninck P, Verburg L, Lee K, Williams G, Israels LG, Mowat MR, Begleiter A . P53, MDM-2, BAX and BCL-2 and drug resistance in chronic lymphocytic leukemia Leuk Lymphoma 1997 26: 435–449

    CAS  Google Scholar 

  177. 177

    Dohner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G, Diehl D, Schlenk R, Coy J, Stilgenbauer S et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias Blood 1995 85: 1580–1589

    CAS  Google Scholar 

  178. 178

    Lens D, Dyer MJ, Garcia-Marco JM, De Schouwer PJ, Hamoudi RA, Jones D, Farahat N, Matutes E, Catovsky D . p53 abnormalities in CLL are associated with excess of prolymphocytes and poor prognosis Br J Haematol 1997 99: 848–857

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Kasimir-Bauer S, Ottinger H, Meusers P, Beelen DW, Brittinger G, Seeber S, Scheulen ME . In acute myeloid leukemia, coexpression of at least two proteins, including P-glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat-shock protein 27, is predictive of the response to induction chemotherapy Exp Hematol 1998 26: 1111–1117

    CAS  Google Scholar 

  180. 180

    Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S, Wang HG, Zhang X, Bullrich F, Croce CM, Rai K, Hines J, Reed JC . Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses Blood 1998 91: 3379–3389

    CAS  Google Scholar 

  181. 181

    Lomo J, Smeland EB, Krajewski S, Reed JC, Blomhoff HK . Expression of the Bcl-2 homologue Mcl-1 correlates with survival of peripheral blood B lymphocytes Cancer Res 1996 56: 40–43

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

    Gottardi D, Alfarano A, De Leo AM, Stacchini A, Aragno M, Rigo A, Veneri D, Zanotti R, Pizzolo G, Caligaris-Cappio F . In leukaemic CD5+ B cells the expression of BCL-2 gene family is shifted toward protection from apoptosis Br J Haematol 1996 94: 612–618

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Thomas A, El Rouby S, Reed JC, Krajewski S, Silber R, Potmesil M, Newcomb EW . Drug-induced apoptosis in B-cell chronic lymphocytic leukemia: relationship between p53 gene mutation and bcl-2/bax proteins in drug resistance Oncogene 1996 12: 1055–1062

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    McConkey DJ, Chandra J, Wright S, Plunkett W, McDonnell TJ, Reed JC, Keating M . Apoptosis sensitivity in chronic lymphocytic leukemia is determined by endogenous endonuclease content and relative expression of BCL-2 and BAX J Immunol 1996 156: 2624–2630

    CAS  Google Scholar 

  185. 185

    Bromidge TJ, Turner DL, Howe DJ, Johnson SA, Rule SA . In vitro chemosensitivity of chronic lymphocytic leukaemia to purine analogues – correlation with clinical course Leukemia 1998 12: 1230–1235

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186

    Zaja F, Di Loreto C, Amoroso V, Salmaso F, Russo D, Silvestri F, Fanin R, Damiani D, Infanti L, Mariuzzi L, Beltrami CA, Baccarani M . BCL-2 immunohistochemical evaluation in B-cell chronic lymphocytic leukemia and hairy cell leukemia before treatment with fludarabine and 2-chloro-deoxy-adenosine Leuk Lymphoma 1998 28: 567–572

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    Morabito F, Filangeri M, Callea I, Sculli G, Callea V, Fracchiolla NS, Neri A, Brugiatelli M . Bcl-2 protein expression and p53 gene mutation in chronic lymphocytic leukemia: correlation with in vitro sensitivity to chlorambucil and purine analogs Haematologica 1997 82: 16–20

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Feng L, Achanta G, Pelicano H, Zhang W, Plunkett W, Huang P . Role of p53 in cellular response to anticancer nucleoside analog-induced DNA damage Int J Mol Med 2000 5: 597–604

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189

    Plunkett W, Iacoboni S, Estey E, Danhauser L, Liliemark JO, Keating MJ . Pharmacologically directed ara-C therapy for refractory leukemia Semin Oncol 1985 12: 20–30

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190

    Sasvari-Szekely M, Spasokoukotskaja T, Szoke M, Csapo Z, Turi A, Szanto I, Eriksson S, Staub M . Activation of deoxycytidine kinase during inhibition of DNA synthesis by 2-chloro-2′-deoxyadenosine (Cladribine) in human lymphocytes Biochem Pharmacol 1998 56: 1175–1179

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191

    Spasokoukotskaja T, Sasvari-Szekely M, Keszler G, Albertioni F, Eriksson S, Staub M . Treatment of normal and malignant cells with nucleoside analogues and etoposide enhances deoxycytidine kinase activity Eur J Cancer 1999 35: 1862–1867

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Sasvari-Szekely M, Csapo Z, Spasokoukotskaja T, Eriksson S, Staub M . Activation of deoxycytidine kinase during inhibition of DNA synthesis in human lymphocytes Adv Exp Med Biol 1998 431: 519–523

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193

    Spasokoukotskaja T, Sasvari-Szekely M, Hullan L, Albertioni F, Eriksson S, Staub M . Activation of deoxycytidine kinase by various nucleoside analogues Adv Exp Med Biol 1998 431: 641–645

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194

    Iwasaki H, Huang P, Keating MJ, Plunkett W . Differential incorporation of ara-C, gemcitabine, and fludarabine into replicating and repairing DNA in proliferating human leukemia cells Blood 1997 90: 270–278

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

    Gandhi V, Kemena A, Keating MJ, Plunkett W . Fludarabine infusion potentiates arabinosylcytosine metabolism in lymphocytes of patients with chronic lymphocytic leukemia Cancer Res 1992 52: 897–903

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196

    Suki S, Kantarjian H, Gandhi V, Estey E, O'Brien S, Beran M, Rios MB, Plunkett W, Keating M . Fludarabine and cytosine arabinoside in the treatment of refractory or relapsed acute lymphocytic leukemia Cancer 1993 72: 2155–2160

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    Gandhi V, Nowak B, Keating MJ, Plunkett W . Modulation of arabinosylcytosine metabolism by arabinosyl-2-fluoroadenine in lymphocytes from patients with chronic lymphocytic leukemia: implications for combination therapy Blood 1989 74: 2070–2075

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198

    Gandhi V, Estey E, Keating MJ, Plunkett W . Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy J Clin Oncol 1993 11: 116–124

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199

    Gandhi V, Robertson LE, Keating MJ, Plunkett W . Combination of fludarabine and arabinosylcytosine for treatment of chronic lymphocytic leukemia: clinical efficacy and modulation of arabinosylcytosine pharmacology Cancer Chemother Pharmacol 1994 34: 30–36

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

    Seymour JF, Huang P, Plunkett W, Gandhi V . Influence of fludarabine on pharmacokinetics and pharmacodynamics of cytarabine: implications for a continuous infusion schedule Clin Cancer Res 1996 2: 653–658

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201

    Keating MJ, Estey E, O'Brien S, Kantarjian H, Robertson LE, Plunkett W . Clinical experience with fludarabine in leukaemia Drugs 1994 47: 39–49

    PubMed  PubMed Central  Google Scholar 

  202. 202

    Avramis VI, Wiersma S, Krailo MD, Ramilo-Torno LV, Sharpe A, Liu-Mares W, Kowck R, Reaman GH, Sato JK . Pharmacokinetic and pharmacodynamic studies of fludarabine and cytosine arabinoside administered as loading boluses followed by continuous infusions after a phase I/II study in pediatric patients with relapsed leukemias. The Children's Cancer Group Clin Cancer Res 1998 4: 45–52

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203

    Shewach DS, Mitchell BS . Differential metabolism of 9-beta-D-arabinofuranosylguanine in human leukemic cells Cancer Res 1989 49: 6498–6502

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    Gandhi V, Kisor D, Rodriguez Jr C, Mitchell B, Kurtzberg J, Keating M, Plunkett W . Pharmacokinetics of arabinosylguanine (ara-G) and its triphosphate (ara-GTP) during a phase I trial of compound GW506U in refractory hematological malignancies: correlation with response Blood 1996 88: 670a

    Google Scholar 

  205. 205

    Rodriguez CO Jr, Legha JK, Estey E, Keating MJ, Gandhi V . Pharmacological and biochemical strategies to increase the accumulation of arabinofuranosylguanine triphosphatein primary human leukemia cells Clin Cancer Res 1997 3: 2107–2113

    PubMed  PubMed Central  Google Scholar 

  206. 206

    Colly LP, Richel DJ, Arentsen-Honders MW, Kester MG, ter Riet PM, Willemze R . Increase in Ara-C sensitivity in Ara-C-sensitive and -resistant leukemia by stimulation of the salvage and inhibition of the de novo pathway Ann Hematol 1992 65: 26–32

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207

    Bhalla K, Swerdlow P, Grant S . Effects of thymidine and hydroxyurea on the metabolism and cytotoxicity of 1-B-D-arabinofuranosylcytosine in highly resistant human leukemia cells Blood 1991 78: 2937–2944

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208

    Gandhi V, Estey E, Keating MJ, Plunkett W . Biochemical modulation of arabinosylcytosine for therapy of leukemias Leuk Lymphoma 1993 10: 109–114

    PubMed  PubMed Central  Google Scholar 

  209. 209

    Gandhi V, Estey E, Keating MJ, Chucrallah A, Plunkett W . Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: pharmacokinetic, pharmacodynamic, and molecular interactions Blood 1996 87: 256–264

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210

    Baker WJ, Royer GL Jr, Weiss RB . Cytarabine and neurologic toxicity J Clin Oncol 1991 9: 679–693

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211

    Cheson BD, Vena DA, Foss FM, Sorensen JM . Neurotoxicity of purine analogs: a review J Clin Oncol 1994 12: 2216–2228

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212

    Mohammad RM, Beck FW, Katato K, Hamdy N, Wall N, Al-Katib A . Potentiation of 2-chlorodeoxyadenosine activity by bryostatin 1 in the resistant chronic lymphocytic leukemia cell line (WSU-CLL): association with increased ratios of dCK/5′-NT and Bax/Bcl-2 Biol Chem 1998 379: 1253–1261

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213

    Mohammad RM, Limvarapuss C, Hamdy N, Dutcher BS, Beck FW, Wall NR, Al-Katib AM . Treatment of a de novo fludarabine resistant-CLL xenograft model with bryostatin 1 followed by fludarabine Int J Oncol 1999 14: 945–950

    CAS  PubMed  PubMed Central  Google Scholar 

  214. 214

    Varterasian ML, Mohammad RM, Eilender DS, Hulburd K, Rodriguez DH, Pemberton PA, Pluda JM, Dan MD, Pettit GR, Chen BD, Al-Katib AM . Phase I study of bryostatin 1 in patients with relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukemia J Clin Oncol 1998 16: 56–62

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215

    Miyauchi J, Kelleher CA, Wang C, Minkin S, McCulloch EA . Growth factors influence the sensitivity of leukemic stem cells to cytosine arabinoside in culture Blood 1989 73: 1272–1278

    CAS  PubMed  PubMed Central  Google Scholar 

  216. 216

    Butturini A, Santucci MA, Gale RP, Perocco P, Tura S . GM-CSF incubation prior to treatment with cytarabine or doxorubicin enhances drug activity against AML cells in vitro: a model for leukemia chemotherapy Leuk Res 1990 14: 743–749

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 217

    Wiley JS, Snook MB, Jamieson GP . Nucleoside transport in acute leukaemia and lymphoma: close relation to proliferative rate Br J Haematol 1989 71: 203–207

    CAS  PubMed  PubMed Central  Google Scholar 

  218. 218

    Petersen AJ, Brown RD, Pope BB, Jamieson GP, Paterson AR, Gibson J, Wiley JS, Joshua DE . Multiple myeloma: expression of nucleoside transporters on malignant plasma cells and their relationship to cellular proliferation Leuk Lymphoma 1994 13: 491–499

    CAS  PubMed  PubMed Central  Google Scholar 

  219. 219

    Wiley JS, Cebon JS, Jamieson GP, Szer J, Gibson J, Woodruff RK, McKendrick JJ, Sheridan WP, Biggs JC, Snook MB et al. Assessment of proliferative responses to granulocyte–macrophage colony-stimulating factor (GM-CSF) in acute myeloid leukaemia using a fluorescent ligand for the nucleoside transporter Leukemia 1994 8: 181–185

    CAS  PubMed  PubMed Central  Google Scholar 

  220. 220

    Reuter C, Auf der Landwehr U, Schleyer E, Zuhlsdorf M, Ameling C, Rolf C, Wormann B, Buchner T, Hiddemann W . Modulation of intracellular metabolism of cytosine arabinoside in acute myeloid leukemia by granulocyte–macrophage colony-stimulating factor Leukemia 1994 8: 217–225

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 221

    Ben-Ishay Z, Prindull G, Sharon S . Improved prognosis in mice with advanced myeloid leukemia following administration of GM-CSF and cytosine arabinoside Leuk Res 1991 15: 321–325

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222

    Bettelheim P, Valent P, Andreeff M, Tafuri A, Haimi J, Gorischek C, Muhm M, Sillaber C, Haas O, Vieder L et al. Recombinant human granulocyte–macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia Blood 1991 77: 700–711

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223

    Lowenberg B, Suciu S, Archimbaud E, Ossenkoppele G, Verhoef GE, Vellenga E, Wijermans P, Berneman Z, Dekker AW, Stryckmans P, Schouten H, Jehn U, Muus P, Sonneveld P, Dardenne M, Zittoun R . Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group Blood 1997 90: 2952–2961

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224

    Ohno R, Naoe T, Kanamaru A, Yoshida M, Hiraoka A, Kobayashi T, Ueda T, Minami S, Morishima Y, Saito Y et al. A double-blind controlled study of granulocyte colony-stimulating factor started two days before induction chemotherapy in refractory acute myeloid leukemia. Kohseisho Leukemia Study Group Blood 1994 83: 2086–2092

    CAS  PubMed  PubMed Central  Google Scholar 

  225. 225

    Yang LY, Li L, Keating MJ, Plunkett W . Arabinosyl-2-fluoroadenine augments cisplatin cytotoxicity and inhibits cisplatin-DNA cross-link repair Mol Pharmacol 1995 47: 1072–1079

    CAS  PubMed  PubMed Central  Google Scholar 

  226. 226

    Van Den Neste E, Bontemps F, Delacauw A, Cardoen S, Louviaux I, Scheiff JM, Gillis E, Leveugle P, Deneys V, Ferrant A, Van den Berghe G . Potentiation of antitumor effects of cyclophosphamide derivatives in B-chronic lymphocytic leukemia cells by 2-chloro-2′-deoxyadenosine Leukemia 1999 13: 918–925

    CAS  PubMed  PubMed Central  Google Scholar 

  227. 227

    Robertson LE, O'Brien S, Kantarjian H, Koller C, Beran M, Andreeff M, Lerner S, Keating MJ . Fludarabine plus doxorubicin in previously treated chronic lymphocytic leukemia Leukemia 1995 9: 943–945

    CAS  PubMed  PubMed Central  Google Scholar 

  228. 228

    Keating MJ, O'Brien S, Robertson LE, Kantarjian H, Dimopoulos M, McLaughlin P, Cabanillas F, Gregoire V, Li YY, Gandhi V et al. The expanding role of fludarabine in hematologic malignancies Leuk Lymphoma 1994 14: 11–16

    PubMed  PubMed Central  Google Scholar 

  229. 229

    McLaughlin P, Hagemeister FB, Swan F Jr, Cabanillas F, Pate O, Romaguera JE, Rodriguez MA, Redman JR, Keating M . Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma J Clin Oncol 1994 12: 575–579

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230

    McLaughlin P, Hagemeister FB, Romaguera JE, Sarris AH, Pate O, Younes A, Swan F, Keating M, Cabanillas F . Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma J Clin Oncol 1996 14: 1262–1268

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 231

    Kantarjian HM, Walters RL, Keating MJ, Estey EH, O'Brien S, Schachner J, McCredie KB, Freireich EJ . Mitoxantrone and high-dose cytosine arabinoside for the treatment of refractory acute lymphocytic leukemia Cancer 1990 65: 5–8

    CAS  PubMed  PubMed Central  Google Scholar 

  232. 232

    Heinemann V, Murray D, Walters R, Meyn RE, Plunkett W . Mitoxantrone-induced DNA damage in leukemia cells is enhanced by treatment with high-dose arabinosylcytosine Cancer Chemother Pharmacol 1988 22: 205–210

    CAS  PubMed  PubMed Central  Google Scholar 

  233. 233

    Crino L, Scagliotti G, Marangolo M, Figoli F, Clerici M, De Marinis F, Salvati F, Cruciani G, Dogliotti L, Pucci F, Paccagnella A, Adamo V, Altavilla G, Incoronato P, Trippetti M, Mosconi AM, Santucci A, Sorbolini S, Oliva C, Tonato M . Cisplatin–gemcitabine combination in advanced non-small-cell lung cancer: a phase II study J Clin Oncol 1997 15: 297–303

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 234

    Mosconi AM, Crino L, Tonato M . Combination therapy with gemcitabine in non-small cell lung cancer Eur J Cancer 1997 33 (Suppl. 1): S14–S17

    Google Scholar 

  235. 235

    Grove KL, Guo X, Liu SH, Gao Z, Chu CK, Cheng YC . Anticancer activity of beta-L-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration Cancer Res 1995 55: 3008–3011

    CAS  PubMed  PubMed Central  Google Scholar 

  236. 236

    Grove KL, Cheng YC . Uptake and metabolism of the new anticancer compound beta-L-(−)-dioxolane-cytidine in human prostate carcinoma DU-145 cells Cancer Res 1996 56: 4187–4191

    CAS  PubMed  PubMed Central  Google Scholar 

  237. 237

    Kadhim SA, Bowlin TL, Waud WR, Angers EG, Bibeau L, DeMuys JM, Bednarski K, Cimpoia A, Attardo G . Potent antitumor activity of a novel nucleoside analogue, BCH-4556 (beta-L-dioxolane-cytidine), in human renal cell carcinoma xenograft tumor models Cancer Res 1997 57: 4803–4810

    CAS  PubMed  PubMed Central  Google Scholar 

  238. 238

    Giles F, Cortes J, Thomas DA, Koller C, Beran M, Proulx L, Jolivet J, Freireich E, Bivins CA, Estey E, Kantarjian HM . Troxacitabine, (BCH-4556), a novel dioxolane nucleoside analog, has anti-leukemic activity Proc Am Soc Hemat 1999 94: 4231A

    Google Scholar 

  239. 239

    Cohen A, Lee JW, Gelfand EW . Selective toxicity of deoxyguanosine and arabinosyl guanine for T-leukemic cells Blood 1983 61: 660–666

    CAS  PubMed  PubMed Central  Google Scholar 

  240. 240

    Aguayo A, Cortes JE, Kantarjian HM, Beran M, Gandhi V, Plunkett W, Kurtzberg J, Keating MJ . Complete hematologic and cytogenetic response to 2-amino-9-beta-D-arabinosyl-6-methoxy-9H-guanine in a patient with chronic myelogenous leukemia in T-cell blastic phase: a case report and review of the literature Cancer 1999 85: 58–64

    CAS  PubMed  PubMed Central  Google Scholar 

  241. 241

    Kurtzberg J, Ernst T, Keating M, Gandhi V, Hodge J, Kisor D, Therriault R, Stephens C, Levin J, Krenitsky T, Elion G, Mitchell B . A phase I study of 2-amino-9-B-D-arabinosyl-6-methoxy-9H-purine (506U78) administered on a consecutive five-day schedule in children and adults with refractory hematologic malignancies Proc Am Soc Hematol 1999 94: 2794A

    Google Scholar 

  242. 242

    Jamieson GP, Snook MB, Bradley TR, Bertoncello I, Wiley JS . Transport and metabolism of 1-beta-D-arabinofuranosylcytosine in human ovarian adenocarcinoma cells Cancer Res 1989 49: 309–313

    CAS  PubMed  PubMed Central  Google Scholar 

  243. 243

    Avery TL, Rehg JE, Lumm WC, Harwood FC, Santana VM, Blakley RL . Biochemical pharmacology of 2-chlorodeoxyadenosine in malignant human hematopoietic cell lines and therapeutic effects of 2-bromodeoxyadenosine in drug combinations in mice Cancer Res 1989 49: 4972–4978

    CAS  PubMed  PubMed Central  Google Scholar 

  244. 244

    Hoglund L, Reichard P . Cytoplasmic 5′(3′)-nucleotidase from human placenta J Biol Chem 1990 265: 6589–6595

    CAS  PubMed  PubMed Central  Google Scholar 

  245. 245

    Misumi Y, Ogata S, Ohkubo K, Hirose S, Ikehara Y . Primary structure of human placental 5′-nucleotidase and identification of the glycolipid anchor in the mature form Eur J Biochem 1990 191: 563–569

    CAS  PubMed  PubMed Central  Google Scholar 

  246. 246

    Zimmermann H . 5′-Nucleotidase: molecular structure and functional aspects Biochem J 1992 285: 345–365

    CAS  PubMed  PubMed Central  Google Scholar 

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Carlos Galmarini is a recipient of the ‘Michel Clavel’ grant. The authors acknowledge the support of the Ligue Contre le Cancer du Rhône and the Alberta Cancer Foundation and National Cancer Institute of Canada.

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Galmarini, C., Mackey, J. & Dumontet, C. Nucleoside analogues: mechanisms of drug resistance and reversal strategies. Leukemia 15, 875–890 (2001).

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  • nucleoside analogues
  • nucleoside transporters
  • 5′-nucleotidase
  • drug resistance

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