Taurolidine has been shown to have remarkable cytotoxic activity against selected human tumor cells at concentrations that spare normal cells. In this study we have extended this observation and assessed the ability of Taurolidine to purge tumor cells from chimeric mixtures of bone marrow (BM) and neoplastic cells. Normal murine BM and human leukemic (HL-60) or ovarian (PA-1) tumor cell lines were used as models. Exposure of tumor cells to 2.5 mM Taurolidine for 1 h resulted in the complete elimination of viable cells. In contrast, exposure of BM to 5 mMTaurolidine for 1 h reduced CFU-GM, BFU-E and CFU-GEEM colony formation by only 23.0%, 19.6% and 25.2%, respectively. Inhibition of long-term BM culture (LTBMC) growth following a 1 h exposure to 5 mM Taurolidine also was ∼20% compared to untreated LTBMC. Finally, chimeric cultures were generated from BM and HL-60GR or PA-1GR cells (tumor cells transfected with the geneticin resistance gene). Exposure of these chimeric cultures to 5 mM Taurolidine for 1 h totally eliminated viable cancer cells while minimally reducing viable BM cells. This finding was confirmed by subsequent positive selection for surviving tumor cells with geneticin. These findings reveal that Taurolidine holds promise for use in BM purging.
Bone Marrow Transplantation (2002) 29, 313–319. doi:10.1038/sj.bmt.1703359
Autologous BM transplantation (ABMT) may be a therapeutic option for the treatment of patients with advanced neoplastic disease. The presence of clonogenic tumor cells in cell collections, however, appears to contribute to post-transplantation relapse, regardless of whether cells from marrow or peripheral blood progenitor cells (PBPCs) serve as the graft. Indeed, ‘mobilization’ of tumor cells along with HSCs was shown to occur after treatment with chemotherapy and G-CSF.1 Gene-marking studies in patients with acute myelogenous leukemia (AML) or chronic myelogenous leukemia (CML) following ABMT substantiate these observations and support this therapeutic concern.2,3
During the past two decades, investigators have developed a wide range of techniques to remove tumor cells from hematopoietic cell grafts. These negative purging techniques include ex vivo treatment of marrow aspirates or peripheral blood cell collections with chemical agents (such as 4-hydroperoxycyclophosphamide or mafosfamide), monoclonal antibodies (MoAbs), toxins, or chemotherapeutic agents, used alone or in various combinations.4,5,6,7,8,9,10,11,12,13,14,15,16,17 Prospective randomized trials to assess the potential superiority of purged grafts over unmanipulated grafts are not available, however, reflecting the high cost, limited availability and technically demanding nature of the purging methods. Therefore, the development of effective, safe and simple purging methods remains a highly desirable goal.
Taurolidine was developed in the 1970s as a broad-spectrum antibiotic18,19,20,21,22 (Figure 1). Its mechanism of action as an antibiotic appears to be related to a chemical reaction between the active Taurolidine derivatives, methylol taurinamide and methylol taurultam, and structures on the wall of bacteria23,24 that results in a disruption of bacterial cell adhesion accompanied by a prevention of infection. It has also been reported that Taurolidine can neutralize endotoxins, exotoxins and lipopolysaccharides released by bacteria.25,26,27,28 Clinically, intraperitoneal Taurolidine has been used for the treatment of diffuse peritonitis, either as monotherapy or in combination with systemic antibiotics.18,29 In this setting, its use has resulted in statistically significant improvements in postoperative morbidity and mortality and there have been no observed acute or chronic toxic effects on hematological and biochemical parameters.
Based on these observations, experiments were initiated in our laboratory to evaluate the potential ability of Taurolidine to inhibit tumor cell adhesion and growth. The results of these studies revealed that Taurolidine inhibited the growth of a variety of human tumor cells and that this effect was associated with the induction of a potent apoptotic effect.30 Equally important, this cytotoxic effect was not observed in ‘normal’ cells such as NIH-3T3 (murine) and NHLF (human) fibroblasts. In vivo studies confirmed that Taurolidine exerted a potent antineoplastic effect in nude mice bearing xenografts of ovarian, melanoma or glioblastoma human tumor cells.30,31,32 Reflecting this remarkable tumor cell-specific effect, we hypothesized that Taurolidine could possess utility as a BM purging agent. We now report that a 1 h exposure to 2.5 mM Taurolidine completely eliminated viable cells in human leukemic (HL-60) and ovarian (PA-1) tumor cell cultures but produced only a minimal growth inhibitory effect against normal murine marrow. Similarly, exposing chimeric cultures of marrow plus tumor cells to this Taurolidine regimen also eliminated tumor cells but only minimally affecting normal marrow viability. These findings suggest that Taurolidine may represent a new class of highly selective agents for purging autologous BM or HSC collection. Preliminary aspects of this work have been presented.33
Materials and methods
Taurolidine was kindly provided by Carter Wallace Inc (Cranbury, NJ, USA) as a 2% solution in 5% Kollidon 17PF. RPMI 1640, Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum (FBS) and medium supplements were purchased from Gibco/Life Technologies (Grand Island, NY, USA). Long-term BM culture (LTBMC) medium (MyeloCult M5300) and methylcellulose for colony assays (MethoCult GF M3434) were purchased from StemCell Technologies (Vancouver, BC, Canada). All other chemicals were obtained from the Sigma Chemical Company (St Louis, MO, USA).
HL-60 and HL-60GR cells (HL-60 cells transfected with the gene conferring resistance to geneticin) used in this study were kindly provided by Dr Z Han (Department of Molecular and Cell Biology, Brown University), and were maintained in RPMI 1640 medium supplemented with 10% FBS, 1 mM nonessential amino acids, and 1 mM sodium pyruvate. The PA-1 and PA-1GR cells were provided by Dr KA Whartenby (Department of Medicine, Brown University). The PA-1 cell lines were maintained in DMEM at high glucose concentration (4.5 g/l) supplemented with 10% FBS. All cell cultures were mantained at 37°C in a humidified incubator under 5% CO2. Under these conditions the doubling time for all cell lines used in this study was ∼24 h.
C57BL/6 female mice (38–56 days old) were purchased from Charles River (Wilmington, MA, USA). Mice were killed by CO2 asphyxiation and the marrow of femurs and tibias from a single animal (∼4 × 107 cells) was harvested under sterile conditions by flushing the marrow cavity with 10 ml of RPMI 1640 + 10% FBS, using a 27 gauge needle fitted to a 1 ml syringe. Cells were washed twice, cell number determined electronically (Coulter Particle Counter; Beckman Coulter, Miami, FL, USA), resuspended in medium, and used in experiments as described below.
Assessment of cellular sensitivity to Taurolidine in normal marrow
Aliquots of BM cells (∼2 × 107) were exposed to high concentrations of Taurolidine (1–10 mM) for 1 h at room temperature. Matched cell aliquots, obtained from the same donor mouse, were treated similarly with supplemented RPMI medium alone or with medium plus 5% Kollidon 17PF and served as control. After this 1 h incubation period, cells were washed, counted electronically and plated in 35 mm tissue culture dishes (Costar, Corning Incorporated, NY, USA) at a density of 3.75 × 106 cells/ml, in a final volume of 2 ml MyeloCult M5300 supplemented with 1 μM hydrocortisone sodium hemisuccinate. At weekly intervals the cultures were fed by replacing 50% of the supernatant with fresh medium. After 3 weeks, the feeder/stromal layer was established and clusters of hematopoietic cells with a cobblestone-like appearance were recognizable. At this time point, cells taken from the adherent and nonadherent layers were assayed separately. The medium containing the nonadherent cells was removed and reserved. Then the wells were washed with 2 ml of fresh medium and, after gentle agitation, the washing was pooled with the reserved non-adherent cell aliquot. Adherent cells were harvested by trypsinization (Sigma Chemical Company). The cell number in both the adherent and non-adherent cell fractions was determined electronically. From this differential count and the total number of cells recovered from each well the absolute number of myeloid and nonmyeloid (adherent) cells/well was determined.
Aliquots of BM cells (∼2 × 107) were exposed to Taurolidine (1–10 mM) for 1 h, washed, counted and plated in 35 mm culture dishes in MethoCult GF M3434 at a density of 2.0 × 104 cells/dish in a final volume of 1.1 ml. Control cells were treated similarly with RPMI medium alone or medium plus 5% Kollidon 17PF. Triplicate cultures were incubated in a humidified atmosphere of 5% CO2 at 37°C. Benzidine-positive colonies were designated erythroid burst-forming units (BFU-E) and benzidine-negative colonies as granulocyte–macrophage colony-forming units (CFU-GM). BFU-E or CFU-GM were scored at day 7 or 10 while CFU-GEMM were scored at day 12. In all cases, colonies were defined as aggregates greater than 50 cells.
Assessment of tumor cell sensitivity to Taurolidine
The sensitivity of the HL-60, PA-1, HL-60GR and PA-1GR cell lines to Taurolidine was assessed by an MTT assay. Specifically, 1 × 106 tumor cells were exposed to various concentrations (1–5 mM) of Taurolidine for 1 h at room temperature and then washed. Cells (1 × 106) were then added to a 25 cm2 flask in 10 ml of appropiate growth media. After 21 days the cells were harvested and aliquots containing 1 × 104 cells were added to each well of 96-well flat-bottom plate (Costar, Corning Incorporated). Cells not exposed to Taurolidine, or medium containing no cells, were used as positive or negative controls, respectively. Thereafter, 100 μl of a 2 mg/ml MTT solution (3–4, 5-dimethylthiazol-2, 5-diphenyl tetrazolium biomide) in PBS was added to each well and incubated for 3 h at 37°C. After this period, the cells were centrifuged at 200 g for 10 min. The resulting solute was aspirated and replaced with 200 μl of DMSO. After gently shaking, the absorbance of each well at 560 nm was determined using a Bio-Tek EL800 Universal microplate reader. An absorbance 2× that of the negative control was considered positive of the presence of viable cells.
Assessment of cellular sensitivity to geneticin (G418)
2 × 106 cells (PA-1, PA-1GR, HL-60, HL-60GR or BM) in appropriate growth media were exposed to 1 mg/ml of genticin (G-418) for 28 days. Cells were then harvested, washed, and plated in a 96-well plate at a density of 1 × 104 cells/well. The presence of viable cells was then determined by the MTT assay, exactly as described above. Medium alone or cells unexposed to G-418, were used as negative or positive controls, respectively.
BM cells were mixed 2:1 with HL-60GR or PA-1GR cells to achieve a final density of 1.5 × 106 cells/ml. The resulting chimeric mixture was exposed to 5 mM Taurolidine for 1 h at room temperature, washed, and cells plated in a 12-well plate at a density of 3 × 106 cells/well in 1 ml of MyeloCult M5300 supplemented with 1 mM hydrocortisone sodium hemisuccinate. After 14 days, the medium of the resulting cultures was completely discarded and fresh medium ± 1 mg/ml of G-418 was added. Cells were then incubated for an additional 28 days, harvested, plated in a 96-well dish and analyzed for viability by the MTT assay, as previously described. Medium alone, untreated murine BM alone, untreated tumor cells alone, or tumor cells plus BM exposed to G-418 were used as negative or positive controls, respectively.
To determine the cytotoxic effect of Taurolidine in the HL-60, HL-60GR, PA-1 or PA-1GR lines, cells were incubated for 1 h in medium containing high concentrations (1–10 mM) of this agent. Thereafter, Taurolidine was removed and cell viability determined 3 weeks later by employing an MTT assay. This 21 day outgrowth period allowed any surviving cells to repopulate the cultures. The results of this analysis revealed that Taurolidine, at a concentration of 2.5 mM, completely eliminated viable cells from each of the neoplastic cell cultures employed (Table 1). Importantly, the sensitivity of these tumor cell lines to Taurolidine was not affected by transfection with the gene conferring resistance to G-418. To determine the effect of Taurolidine on normal BM, parallel experiments were conducted using marrow cells freshly harvested from C57BL/6 mice and similarly exposed to high concentrations of Taurolidine for 1 h. Thereafter, the ability of exposed marrow to generate LTBMC or form specific progenitor colonies was assessed (Figures 2 and 3). Exposure of BM to 5 mM Taurolidine slightly reduced the total number of viable cells recovered 21 days after exposure (∼23%) as compared to untreated LTBMC controls. This method assessed all myeloid and adherent marrow cells. To examine more closely fluctuations in specific marrow cell populations as a consequence of Taurolidine exposure, differential cell analysis was also performed. The results showed that this exposure to Taurolidine induced a decrease in the growth rate of adherent and myeloid cells by 24% and 18%, respectively, as compared to controls (Figure 2). Progenitor colony assays confirmed this slight anti-proliferative effect. These colony assays, however, also revealed the absence of a significant inhibitory effect on progenitor-specific (CFU-GM, BFU-E and CFU-GEMM) colony formation after Taurolidine exposure. Taurolidine-induced inhibition of the colony-formation was 23% for CFU-GM, 20% for BFU-E, and 25% for CFU-GEMM, compared to colony formation by untreated marrow cells (Figure 3).
Experiments that mimicked the clinical setting were next initiated using fresh murine BM mixed with HL-60GR or PA-1GR cells. In these studies HL-60 and PA-1 cell lines transfected with the gene conferring resistance to geneticin were used to allow the positive selection of surviving, viable, tumor cells from these chimeric mixtures following purging with Taurolidine. Initial experiments assessed the sensitivity of either BM alone or transfected tumor cells alone to either G-418 or Taurolidine. As expected, a 7 day exposure of BM cells to 1 mg/ml G-418 resulted in the complete elimination of viable cells. In contrast, neither transfected cell line was affected by this G-418 selection regimen (Table 2). Exposure of a chimeric mixture of BM + tumor cells to only G-418 for 28 days resulted in viable cultures, presumable containing transfected tumor cells. Exposing BM alone to 5 mM Taurolidine for 1 h resulted in cultures containing viable cells when assessed 14 days after drug exposure. In contrast, exposure of transfected tumor cells alone to this Taurolidine regimen completely eliminated viable cells, as measured by the MTT assay 14 days after drug exposure (Table 2).
Finally, to determine if Taurolidine specifically eliminated tumor cells from the chimeric cell population, these mixed cultures were exposed to 5 mM Taurolidine for 1 h, washed, and then incubated in fresh media for 14 days. After this outgrowth period, only viable BM was expected to be present. To determine if this was indeed the case, the resultant cell cultures were positively selected for tumor cells by exposure to G-418 (1 mg/ml) for 28 days. Any tumor cells that survived Taurolidine purging would have had 42 days to recover, resume proliferation and repopulate the culture under G-418 selection. However, at the end of the G-418 incubation period MTT analysis revealed no viable cells following this dual selection regimen (Table 2) (Figure 4).
The reinfusion of neoplastic cells has always been a concern in autologous BM transplant protocols. Direct evidence that the reinfusion of malignant cells may contribute to relapse after autologous marrow transplantation in AML and CML has been demonstrated by gene-marking studies that reveal the presence of clonogenic tumor cells after transplant.2,3 Protocols to purge tumor cells from marrow or HSCs, while potentially beneficial, are not without risks. Specifically, purging with chemotherapeutic agents may result in varying losses of hematopoietic stem cells and thus may add to the hematologic toxicity of ABMT. For this reason there is a continuous need for new compounds that selectively remove cancer cells, while sparing normal hematopoietic progenitor cells.
In this study we determined that highly selective and effective BM purging could be achieved with Taurolidine, an agent that, when given systemically at high doses, is without significant toxicity. In the cancer cell lines used in this study, ablative tumor cell killing was observed following 1 h exposure to Taurolidine at a concentration of 2.5 mM. This exposure regimen induced a total depletion of cancer cells (6 log reduction in viable cell number) in a chimeric mixture of marrow and neoplastic cells. The magnitude of this observed depletion in tumor cell number is clinically acceptable. Indeed, harvested BM from leukemic patients in remission may contain 106 leukemic cells/ml. Therefore, any ‘prospective’ purging agent should be able to eliminate selectively at least 6 logs of contaminating neoplastic cells.34,35 Of interest, this same exposure condition induced only a ∼20% depletion of normal marrow elements, supporting our previous observation that Taurolidine exerted a selective cytotoxic effect in various human cancer cell lines.
The mechanism(s) responsible for this selective cytotoxic effect is unknown but may be unrelated to its proposed mechanism of antibiotic action. As an antibiotic, Taurolidine was shown to interfere with bacterial adherence. We have observed that Taurolidine is cytotoxic against hematological tumor cells, cells that grow in suspension. Presumably these cells would be much less affected by a drug with anti-adherence activity. Furthermore, experiments in our laboratory have revealed that Taurolidine-induced tumor cell death was associated with the induction of apoptosis.30 In contrast, a 72 h exposure of ‘normal’ murine or human fibroblasts to Taurolidine did not induce apoptosis and resulted in only a temporary cell growth arrest, with full recovery when Taurolidine was removed from the medium. Of interest, preliminary mechanistic evaluation of Taurolidine in cultures of HL-60 cells has shown that cleavage of procaspase 8, 7 and 3 occurred within 3 h of drug exposure.36 This finding suggests that the apoptotic cascade triggered by Taurolidine may involve surface signaling events. Studies to elucidate the mechanism of action of Taurolidine are in progress.
The ability of Taurolidine to efficiently purge tumor cells from marrow was evaluated in chimeric cultures using normal murine bone marrow and human cancer cells transfected with the gene conferring resistance to G418. These transfected cancer cell lines allowed the positive selection of surviving, clonogenic, tumor cells after Taurolidine purging. Chimeric cell cultures were maintained in drug-free medium for 14 days after Taurolidine purging and then incubated for an additional 28 days in tumor cell selection medium containing G-418. In this setting, a single cancer cell that survived Taurolidine purging would have had sufficient time to repopulate the chimeric culture (Figure 5). Indeed, we observed that both HL-60GR and PA-1GR cells alone survived and proliferated during this G-418 selection regimen. However, neither viable tumor nor BM was detected following dual selection with Taurolidine and G-418. Thus, Taurolidine was able to selectively and completely purge contaminating tumor cells from the chimeric culture. The choice to use this biologic method as an alternative to PCR-based methods was made because of its ability to detect viable, clonogenic, cancer cells in the purged chimeric cultures. Indeed, while PCR can reproducibly detect a limited number of tumor cells this analytical method cannot identify cells with clonogenic potential. This limitation of qualitative PCR in the detection of minimal residual disease after BM transplant has already been highlighted in previous studies37,38,39 that underlined the clinical finding that a PCR-negative result is not predictive of complete eradication of the leukemic clone. For these reasons we chose to use this functional method to assess the efficiency of Taurolidine as a purging agent.
Our findings reveal that a 5–6 log depletion in the number of cancer cells from a chimeric mixture of BM and cancer cells can readily be achieved with this agent. Since PSCs have replaced marrow as source of stem cells for autotransplantation, we are planning to repeat these studies using PBSC. Indeed, preliminary studies have shown that Taurolidine exposure of human T cells, obtained from the peripheral blood of healthy donors, does not significantly affect their viability or ability to be activated. Concomitant studies are also underway to assess the in vivo marrow purging potential of Taurolidine in a murine model system. In conclusion, our present results reveal that efficient and highly selective purging of infiltrated BM is possible with this agent. Based on this finding, and the observed low toxicity associated with the clinical use of this agent, further evaluation of the purging potential of Taurolidine is warranted.
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This work was supported by Carter Wallace, Inc., Rhode Island Hospital, Associazione Cristina Bassi contro le Leucemie Acute dell'Adulto and PhARMA Foundation.
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Ribizzi, I., Darnowski, J., Goulette, F. et al. Taurolidine: preclinical evaluation of a novel, highly selective, agent for bone marrow purging. Bone Marrow Transplant 29, 313–319 (2002). https://doi.org/10.1038/sj.bmt.1703359
- bone marrow purging
- positive selection
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