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Effect of tamoxifen on mitoxantrone cytotoxicity in drug-sensitive and multidrug-resistant MCF-7 cells

  • Original Article
  • Mitoxantrone, Tamoxifer Multidrug Resistance
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Abstract

The influence of the antiestrogen tamoxifen (TAM) on the activity of mitoxantrone (MXN), was evaluated against wild-type MCF-7/WT and their multidrug-resistant variant MCF-7/ADR cells. Multidrug resistance (MDR) in this cell line which was selected for resistance to Adriamycin (ADR), is associated with increased expression of P-glycoprotein (P-gp). In a clonogenic assay it was observed that TAM (1–10 μM) significantly enhanced the activity of MXN in the MCF-7/ADR but not in the drug-sensitive cell line. Isobologram analysis indicated that the effect of the combination was additive in the parental MCF-7/WT cells and strongly synergistic in the MDR MCF-7/ADR cells. Also, TAM (10 μM) caused a three-fold increase in the steady-state levels (Css) of MXN in MCF-7/ADR cells but did not modulate MXN levels in MCF-7/WT cells. The observed synergism in MCF-7/ADR cells was perhaps due to the increase in Css of MXN that may involve interaction of TAM with P-gp. The combination of MXN and TAM may be useful in the treatment of drug-sensitive and drug-resistant breast cancer.

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References

  1. Batist G, Tulpule A, Sinha BK, Katki AG, Myers CE, Cowan KH (1986) Overexpression of novel anionic glutathione transferase in multidrug resistant human breast cancer cells. J Biol Chem 261:15544

    Google Scholar 

  2. Benjamin RS, Chawla SP, Ewer MS, Carrasco H, Mckay B, Holmes F (1985) Evaluation of mitoxantrone cardiac toxicity by nuclear angiography and endomyocardial biopsy: an update. Invest New Drugs 3:117

    Google Scholar 

  3. Berenbaum MC (1981) Criteria for analyzing interactions between biologically active agents. Adv Cancer Res 35:269

    Google Scholar 

  4. Berman E, Adams M, Duigou-Osterndorf R, Godfrey L, Clarkson B, Andreeff M (1991) Effect of tamoxifen on cell lines displaying multidrug resistance phenotype. Blood 77:818

    Google Scholar 

  5. Bradford M (1976) A rapid and sensitive method for quantitation of microgram quantities of proteins utilizing the principle of protein-dye binding. Anal Biochem 72:248

    Google Scholar 

  6. Buckley MT, Goa KL (1989) Drug evaluation: tamoxifen-A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic uses. Drugs 37:451

    Google Scholar 

  7. Cantwell B, Carmichael J, Millward MJ, Chatterjee M, Harris AL (1989) Intermittent high dose tamoxifen (HDT) with oral etoposide (EPO): phase I and II clinical studies. Br J Cancer 8:450

    Google Scholar 

  8. Chaterjee M, Harris AL (1990) Reversal of acquired resistance to adriamycin in CHO cells by tamoxifen and 4-hydroxytamoxifen: role of drug interaction with alpha-1 acid glycoprotein. Br J Cancer 62:712

    Google Scholar 

  9. Chou TC, Talalay T (1984) Quantitative analysis of dose effect relationshipL the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27

    Google Scholar 

  10. Clarke R, Currier S, Kaplan O, Lovelac E, Boulay V, Gottesman MM, Dickson RB (1992) Effect of P-glycoprotein expression on sensitivity to hormones in MCF-7 human breast cancer cells. J Natl Cancer Inst 84:1506–1512

    Google Scholar 

  11. Dalton WS, Durie BGM, Alberts DS, Gerlach JH, Cress AE (1988) Characterization of a new drug-resistant human myeloma cell line that expressed P-glycoprotein. Cancer Res 46:5125

    Google Scholar 

  12. Damle BD, Rajagopalan S, Desai PB (1994) Dipyridamole modulates multidrug resistance and intracellular as well as nuclear levels of doxorubicin in B16 melanoma cells. Int J Cancer 56:113

    Google Scholar 

  13. Deffie AM, Alam T, Seneviratne C, Beenken SW, Batra JK, Shea TC, Henner WD, Goldenberg GJ (1988) Multifactorial resistance to adriamycin: relationship of DNA repair, glutathione transferase activity, drug efflux, and P-glycoprotein in cloned cell lines of adriamycin-sensitive and-resistant P388 leukemia. Cancer Res 48:3595

    Google Scholar 

  14. Fairchild CR, Ivy SP, Kao-Shan C, Peng-Whang J, Rosen M, Israel MA, Melera PW, Cowan KH, Goldsmith ME (1987) Isolation of amplified and overexpressed DNA sequences from Adriamycin resistant human breast cancer cells. Cancer Res 47:5141

    Google Scholar 

  15. Gerlach JH, Kartner N, Bell DR, Ling V (1986) Multidrug resistance. Cancer Surv 5:25

    Google Scholar 

  16. Goldstein LJ, Galski H, Fojo AT, Willingham MC, Lai SL, Gazdar A, Piker R, Green A, Crist W, Brodfeur GM, Lieber M, Cossman J, Gottesman MM, Pastan I (1989) Expression of a multidrug resistance gene in human tumors and tissues. J Natl Cancer Inst 81:116

    Google Scholar 

  17. Hainsworth JD, Andrews MB, Johnson DH, Greco FA (1991) Mitoxantrone, fluorouracil and high dose leucovorin: an effective well tolerated regimen for metastatic breast cancer. J Clin Oncol 9:1731

    Google Scholar 

  18. Harker WG, Slade DL, Dalton WS, Meltzer PS, Trent JM (1989) Multidrug resistance in mitoxantrone-selected HL-60 leukemia cells in the absence of P-glycoprotein overexpression. Cancer Res 49:4542

    Google Scholar 

  19. Henderson CI, Allegra JC, Woodcock T, Wolff S, Bryan S, Cartwright K, Dukart G, Henry D (1986) Randomized clinical trials comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer. J Clin Oncol 4:672

    Google Scholar 

  20. Jordan VC, Robinson SP, Welsons WW (1989) Resistance to antiestrogen therapy. In: D. Kessel (ed) Resistance to antineoplastic drugs. CRC Press, Boca Raton, p 403

    Google Scholar 

  21. Kirk J, Houlbrook S, Stuart NSA, Stratford IJ, Harris AL, Carmichael J (1993) Differential modulation of doxorubicin toxicity to multidrug and intrinsically drug resistant cell lines by anti-oestrogens and their major metabolites. Br J Cancer 67: 1189–1195

    Google Scholar 

  22. Leonessa F, Jacobson M, Boyle B, Lippman J, McGarvey M, Clarke R (1994) Effect of tamoxifen on the multidrug-resistant phenotype in human breast cancer cells: isobologram, drug accumulation, and Mr 170,000 glycoprotein (gp 170) binding studies. Cancer Res 54:441–447

    Google Scholar 

  23. Neidhart JA, Gochnour D, Roach R, Hoth D, Young D (1986) A comparison of mitoxantrone and doxorubicin in breast cancer. J Clin Oncol 4:672

    Google Scholar 

  24. Pastan I, Gottesman MM (1991) Multidrug resistance. Annu Rev Med 42:277

    Google Scholar 

  25. Peng YM, Ormberg D, Alberts DS (1982) Improved high performance liquid chromatography of the new antineoplastic agents bisanterene and mitoxantrone. J Chromatogr 233:235

    Google Scholar 

  26. Posner LE, Dukart G, Goldberg J, Bernstein T, Cartwright K (1985) Mitoxantrone: an overview of safety and toxicity. Invest New Drugs 3:123

    Google Scholar 

  27. Powles TJ, Smith IE, Ford HT, Combers RC, Mary J, Gazet JC (1980) Failure of chemotherapy to prolong survival in a group of patients with metastatic breast cancer. Lancet 1:580

    Google Scholar 

  28. Ramu A, Glaubiger D, Fuks Z (1984) Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by tamoxifen and other triparanol analogues. Cancer Res 44:4392

    Google Scholar 

  29. Riordan JR, Ling V (1985) Genetic and biochemical characterization of multidrug resistance. Pharmacol Ther 28:51

    Google Scholar 

  30. Sinha BK, Katki AG, Batist G, Cowan KH, Myers CE (1987) Differential formation of hydroxyl radicals by Adriamycin in sensitive and resistant MCF-7 human breast cancer tumor cells: implications for the mechanism of action. Biochem 26:3776

    Google Scholar 

  31. Soule HD, Vazquez J, Long A, Alberts S, Brennan M (1973) A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst 51:1409

    Google Scholar 

  32. Tong W, Berman E, Lin S (1992) Pharmacokinetic study of high dose tamoxifen with daunorubicin: a phase I trial with escalation of tamoxifen. Proc Am Assoc Cancer Res 33:528

    Google Scholar 

  33. Tormey DC (1975) Adriamycin (NSC 123127) in breast cancer: an overview of studies. Cancer Chemother Rep 6:319

    Google Scholar 

  34. Trump DL, Smith DC, Ellis PG, Rogers MP, Schol SC, Winer EP, Panella TJ, Jordan VC, Fine RL (1992) High-dose oral tamoxifen, a potential multidrug-resistant-reversal agent: phase I trial in combination with vinblastine. J Natl Cancer Inst 84: 1811–1816

    Google Scholar 

  35. Van Hoff DD, Layard MV, Basa P (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710

    Google Scholar 

  36. Vickers PJ, Dickson RB, Shoemaker R, Cowan KH (1988) A multidrug resistant MCF-7 human breast cancer cell line which exhibits cross-resistance to antiestrogens and hormone-independent tumor growth in vivo. Mol Endocrinol 2(10):886

    Google Scholar 

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  1. Division of Medicinal Chemistry and Pharmaceutics School of Pharmacy, Northeast Louisiana University, 71209-0470, Monroe, LA, USA

    Pankaj B. Desai, Renu Bhardwaj & Bharat Damle

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  1. Pankaj B. Desai
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  2. Renu Bhardwaj
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  3. Bharat Damle
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Desai, P.B., Bhardwaj, R. & Damle, B. Effect of tamoxifen on mitoxantrone cytotoxicity in drug-sensitive and multidrug-resistant MCF-7 cells. Cancer Chemother. Pharmacol. 36, 368–372 (1995). https://doi.org/10.1007/BF00686184

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  • DOI: https://doi.org/10.1007/BF00686184

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