Abstract
Dexrazoxane combined with doxorubicin (+ 5-fluorouracil + cyclophosphamide – the FAC regime) leads to a significant decrease in doxorubicin cardiotoxicity and a significant increase in median survival time for patients with advanced breast cancer responsive to FAC. The reason for this increase in survival may be due to interference with the mechanism involved in the emergence of multidrug resistance (MDR). In order to test this hypothesis, we induced resistance to doxorubicin in the K562 cell line by growing cells in increasing concentrations of doxorubicin (10–30 nM) in the presence and absence of dexrazoxane (20 nM). The doxorubicin sensitivity of all resultant sublines was measured using the MTT assay. Flow cytometry was used to assess the MDR1 phenotype, measuring P-glycoprotein expression with MRK 16 antibody and drug accumulation in the presence and absence of PSC 833 for functional P-glycoprotein. Long-term growth in doxorubicin increased the cellular resistance (IC50) of K562 cells in a concentration-dependent manner (r2 = 0.908). Doxorubicin resistance was not induced in the presence of dexrazoxane (P< 0.0001) for several months. In parallel, the expression of functional P-glycoprotein was delayed after concomitant addition of dexrazoxane to the selecting medium (P< 0.001). Dexrazoxane did not act as a conventional modulator of P-glycoprotein. These results suggest that dexrazoxane may delay the development of MDR1, thus allowing responders to the FAC regime to continue to respond. © 2001 Cancer Research Campaign
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References
Advani R, Saba HI, Tallman MS, Rowe JM, Wiernik PH, Ramek J, Dugan K, Lum B, Villena J, Davis E, Paietta E, Litchman M, Sikic BI and Greenberg PI (1999) Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar). Blood 93: 787–795
Bordow SB, Haber M, Madafiglio J, Cheung B, Marshall GM and Norris MD (1994) Expression of the multidrug resistance-associated protein (MRP) gene correlates with amplification and overexpression of the N- myc oncogene in childhood neuroblastoma. Cancer Res 54: 5036–5040
Chaudhary PM and Roninson IB (1993) Induction of multidug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst 85: 632–639
Chomczynski P and Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159
Elgie AW, Sargent JM, Williamson CJ, Lewandowicz GM and Taylor CG (1999) Comparison of P-glycoprotein expression and function with in vitro sensitivity to anthracyclines in AML. Adv Exp Med Biol 457: 29–33
Futscher BW, Foley NE, Gleason-Guzman MC, Meltzer PS, Sullivan DM and Dalton WS (1996) Verapamil suppresses the emergence of P-glycoprotein-mediated multi-drug resistance. Int J Cancer 66: 520–525
Hasinoff BB, Hellmann K, Herman EH and Ferrans VJ (1998) Chemical biological and clinical aspects of dexrazoxane and other bisdioxopiperazines. Curr Med Chem 5: 1–28
Kato S, Ideguchi H, Muta K, Nishimura J and Natawa H (1990) Mechanisms involved in the development of adriamycin resistance in human leukemic cells. Leuk Res 14: 567–573
Kaye SB (1999) New drug development: its role in reversing drug resistance. Br J Cancer 80: 116–121
Lemez P and Maresova J (1998) Efficacy of dexrazoxane as a cardioprotective agent in patients receiving mitoxantrone-and daunorubicin-based chemotherapy. Semin Oncol 25: 61–65
Lucci A, Han TY, Liu YY, Giuliano AE and Cabot MC (1999) Multidrug resistance modulators and doxorubicin synergize to elevate ceramide levels and elicit apoptosis in drug-resistant cancer cells. Cancer 86: 300–311
Pearlman ML, Pagliaro LC, Liu B and Freireich EJ (1997) Dexrazoxane is cytotoxic to AML blasts and does not abrogate sensitivity to doxorubicin in vitro. Proc Amer Assoc Cancer Res 38: 608, Abstr 4081
Sargent JM and Taylor CG (1989) Appraisal of the MTT assay as a rapid test of chemosensitivity in acute myeloid leukaemia. Br J Cancer 60: 206–210
Scambia G, Della Bitta R, Benedetti Panici P, De Vincenzo R, Contu G, Ercoli A, Bonanno G, Pierelli L and Mancuso S (1995) Bisdioxopiperazine, (+)-1,2-Bis (3,5-dioxopiperazinyl-1-yl)propane (ICRF 187), enhances the antiproliferative effect of cisplatin on human ovarian cancer cells. Gynecol Oncol 57: 16–22
Sharpe HBA, Field EO and Hellmann K (1970) Mode of action of the cytostatic agent ‘ICRF 159’. Nature 226: 524–526
Sikic BI, Fisher GA, Lum BL, Halsey J, Beketic-Oreskovic L and Chen G (1997) Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein. Cancer Chemother Pharmacol 40: S13–S19
Swain SM, Whaley FS, Gerber MC, Ewer MS, Bianchine JR and Gams RA (1997) Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 15: 1333–1340
Synold T, Spencer M and Doroshow J (1997) Dexrazoxane (DX) potentiates the cytotoxic activity of topotecan (T) in a sequence and schedule dependent manner. Proc Amer Assoc Cancer Res 38: 322, abstr 2161
Synold TW, Tetef ML and Doroshow JH (1998) Antineoplastic activity of continuous exposure to dexrazoxane: potential new role as a novel topoisomerase II inhibitor. Semin Oncol 25: 93–99
Trock BJ, Leonessa F and Clarke R (1997) Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance. J Natl Cancer Inst 89: 917–931
Weiss RB (1999) The randomized trials of dose-intensive therapy for breast cancer: What do they mean for patient care and where do we go from here?. Oncologist 4: 450–458
Yanagisawa T, Newman A, Coley H, Renshaw J, Pinkerton CR and Pritchard-Jones K (1999) BRICODAR (VX-710; Incel™): an effective chemosensitizer in neuroblastoma. Br J Cancer 80: 1190–1196
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Sargent, J., Williamson, C., Yardley, C. et al. Dexrazoxane significantly impairs the induction of doxorubicin resistance in the human leukaemia line, K562. Br J Cancer 84, 959–964 (2001). https://doi.org/10.1054/bjoc.2001.1697
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DOI: https://doi.org/10.1054/bjoc.2001.1697
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