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Tumour cell resistance to anthracyclines — A review

  • Review
  • Tumor Cell Resistance, Anthracycline
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Summary

Resistance to anthracyclines is the major factor limiting their clinical utility. Laboratory studies using cultured experimental and human tumour cells have indicated that reduced intracellular drug accumulation is one important factor underlying resistance. In some systems this results from enhanced active drug efflux, a process which may be circumvented experimentally, for example by calcium antagonists. A specific glycoprotein which is produced in excess and is inherited has been identified in the cell membrane of certain anthracycline-resistant cells, while gene amplification with the appearance of double-minute chromosomes has been noted in others.

Thus it is possible that anthracycline resistance arises following inherited changes in the cell membrane resulting in failure of drug accumulation. However, other possibilities exist, including differences in drug binding, either to the cell membrane or to nuclei, differences in metabolism to the semiquinone free radical, and differences in drug penetration related to tumour morphology.

For each human tumour type the factor(s) involved may differ, but sufficient clues now exist to suggest that clinical testing of some of the therapeutic possibilities for circumventing anthracycline resistance may soon be appropriate.

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References

  1. Baskin F, Rosenberg RN, Dev V (1981) Correlation of double-minute chromosomes with unstable multidrug cross-resistance in uptake mutants of neuroblastoma cells. Proc Natl Acad Sci USA 78: 3654–3658

    Google Scholar 

  2. Beck WT (1983) Vinca-alkaloid-resistant phenotype in cultured human leukaemic lymphoblasts. Cancer Treat Rep 67: 875–882

    Google Scholar 

  3. Beck WT, Cirtain MC (1982) Continued expression of vinca-alkaloid resistance by CCRF-CEM cells after treatment with tunicamycin or pronase. Cancer Res 42: 184–189

    Google Scholar 

  4. Beck WT, Mueller TJ, Tanzer LR (1979) Altered surface membrane glycoproteins in vinca-alkaloid-resistant human leukemic lymphoblasts. Cancer Res 39: 2070–2076

    Google Scholar 

  5. Biedler JL, Riehm H, Peterson RHF, Spengler BA (1975) Membrane-mediated drug resistance and phenotypic reversion to normal growth behavior of Chinese hamster cells. J Natl Cancer Inst 55: 671–680

    Google Scholar 

  6. Biedler JL, Chang T, Meyers MB, Peterson RHF, Spengler BA (1983) Drug resistance in Chinese hamster lung and mouse tumor cells. Cancer Treat Rep 67: 859–868

    Google Scholar 

  7. Bonnadonna G, Monfardini S, Delara M (1970) Phase I and preliminary phase II evaluation of adriamycin. Cancer Res 30: 2572–2576

    Google Scholar 

  8. Bozzi A, Marelli I, Mondori B, Strom R, Rotilio G (1981) Differential cytotoxicity of daunomycin in tumor cells is related to glutathione-dependent hydrogen peroxide metabolism. Biochem J 194: 369–374

    Google Scholar 

  9. Carman MD, Shornagel JH, Rivest RS, Srimatkandanda S, Portlock CS, Duffy T, Bertino JR (1984) Resistance to methotrexate due to gene amplification in a patient with acute leukemia. J Clin Oncol 2: 16–20

    Google Scholar 

  10. Chitnis MP, Joshi SS, Gude RP, Menon RS (1982) Induced resistance in leukaemia L1210 to adriamycin and its cross resistance to vincristine and bouvardin. Exp Chemother 28: 209–212

    Google Scholar 

  11. Chlebowski RT, Block JB, Cundiff D, Dietrich MF (1982) Doxorubicin cytotoxicity enhanced by local anaesthetics in a human melanoma cell line. Cancer Treat Rep 66: 121–125

    Google Scholar 

  12. Chou T-H, Kessel D (1981) Effects of tumicamycin on anthracycline resistance in P388 murine leukaemia cells. Biochem Pharmacol 30: 3134–3136

    Google Scholar 

  13. Curt GA, Carney DN, Cowan KH (1983) Unstable methotrexate resistance in human small cell carcinoma associated with double-minute chromosomes. N Engl J Med 308: 199–202

    Google Scholar 

  14. Dalmark M, Storm HH (1981) A Fickian diffusion transport process with features of transport catalysis. J Gen Physiol 78: 349–364

    Google Scholar 

  15. Dano K (1971) Development of resistance to daunomycin in Ehrlich ascites tumor. Cancer Chemother Rep 55: 133–141

    Google Scholar 

  16. Dano K (1972) Cross resistance between vinca alkaloids and anthracyclines in Ehrlich ascites tumor in vivo. Cancer Chemother Rep 56: 701–708

    Google Scholar 

  17. Dano K (1973) Active outward transport of daunomycin in resistance Ehrlich ascites tumor cells. Biochim Biophys Acta 323: 466–483

    Google Scholar 

  18. Debenham PG, Kartner N, Siminovitch L, Riordan JR, Ling V (1982) DNA-mediated transfer of multiple drug resistance and plasma membrane glycoprotein expression. Mol Cell Biol 2: 881–889

    Google Scholar 

  19. Donehower RC, Myers CE, Chabner BA (1979) New developments on the mechanisms of action of neoplastic drugs. Life Sci 25: 1–14

    Google Scholar 

  20. Friche E, Skovsgaard T, Nissen NI, Dimarco A, Dano K (1983) Accumulation of daunorubicin analogues in daunorubicin-resistant cells and their effect on accumulation of 3H-daunorubucin. In: Hansen HH (ed) Anthracyclines and cancer therapy. Excerpta Medica, Amsterdam, pp 49–55

    Google Scholar 

  21. Garman D, Center MS (1982) Alterations in cell surface membranes in Chinese hamster lung cells resistant to adriamycin. Biochem Biophys Res Commun 105: 157–163

    Google Scholar 

  22. Goldie JH, Coldman AJ (1979) A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63: 1727–1733

    Google Scholar 

  23. Houghton PJ, Houghton JA (1983) Chemotherapeutic response in xenografts: inter- and intra-tumour heterogeneity. In: Chabner BA (ed) Rational basis for chemotherapy. Liss, New York, pp 61–69

    Google Scholar 

  24. Inaba M, Johnson RK (1978) Uptake and retention of adriamycin and daunorubicin by sensitive and anthracycline-resistant sublines of P388 leukaemia. Biochem Pharmacol 27: 2123–2130

    Google Scholar 

  25. Inaba M, Kobayasui H, Sakurai Y, Johnson RK (1979) Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines of P388 leukaemia. Cancer Res 39: 2200–2203

    Google Scholar 

  26. Inaba M, Fujikura R, Tsukagoshi S, Sakurai Y (1981) Restored in vitro sensitivity of adriamycin- and vincristine-resistant P388 leukaemia with reserpine. Biochem Pharmacol 30: 2191–2194

    Google Scholar 

  27. Johnson RK, Ovejera AA, Goldin A (1976) Activity of anthracyclines against and adriamycin-resistant subline of P388 leukaemia with special emphasis on cinerubin A. Cancer Treat Rep 60: 99–102

    Google Scholar 

  28. Johnson RK, Chitnis MP, Embrey WM, Gregory EB (1978) In vivo characteristics of resistance and cross-resistance of an adriamycin-resistant subline of P388 leukaemia. Cancer Treat Rep 62: 1535–1547

    Google Scholar 

  29. Kartner N, Riordan JR, Ling V (1983a) Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 221: 1285–1287

    Google Scholar 

  30. Kartner N, Shales M, Riordan JR, Ling V (1983b) Daunorubicin-resistant Chinese hamster ovary cells expressing multidrug resistance and a cell-surface P-glycoprotein. Cancer Res 43: 4413–4419

    Google Scholar 

  31. Kaufman RJ, Brown PC, Schimke RT (1979)_Amplified dihydrofolate reductase genes in unstably methotrexate-resistant cells are associated with double minute chromosomes. Proc Natl Acad Sci USA 76: 5669–5673

    Google Scholar 

  32. Kaye SB, Boden JA (1980) Cross-resistance between actinomycin-D, adriamycin and vincristine in a murine solid tumour in vivo. Biochem Pharmacol 29: 1081–1084

    Google Scholar 

  33. Kennedy KA, Sigfried JM, Sartorelli AC, Tritton TR (1983) Effects of anthracyclines on oxygenated and hypoxic tumor cells. Cancer Res 43: 54–59

    Google Scholar 

  34. Kessel D (1979) Enhanced glycosylation induced by adriamycin. Mol Pharmacol 16: 306–312

    Google Scholar 

  35. Kessel D, Botterill V, Wodinsky I (1968) Uptake and retention of daunomycin by mouse leukaemic cells as factors in drug response. Cancer Res 28: 938–941

    Google Scholar 

  36. Ling V (1982) Genetic basis of drug resistance in mammalian cells. In: Bruchovsky N, Goldie JH (eds) Drug and hormone resistance in neoplasis, vol 1. CRC Press, Boca Raton, pp 1–19

    Google Scholar 

  37. Markland SL, Westman NG, Lundgren E, Roos G (1982) Copper-and zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase and glutathione peroxidase in normal and neoplastic human cells and normal human tissues. Cancer Res 42: 1955–1959

    Google Scholar 

  38. Merry S, Freshney RI, Kaye SB (1983) Studies on the drug sensitivity of human glioma cell lines in culture. Br J Cancer 48: 118

    Google Scholar 

  39. Merry S, Kaye SB, Freshney RI (1984) Drug sensitivity of human glioma cells — the effects of verapamil. Br J Cancer (in press)

  40. Mungikar A, Chitnis M, Gothoskar B (1981) Mixed-function oxidase enzymes in adriamycin-sensitive and resistant sublines of P388 leukaemia. Chem Biol Interact 38: 119–124

    Google Scholar 

  41. Nishimura T, Muto K, Tanaka N (1978) Drug sensitivity of an adriamycin-resistant mutant subline of mouse lymphoblastoma L5178Y cells. J Antibiot (Tokyo) 31: 493–495

    Google Scholar 

  42. Peterson RHF, Meyers MB, Spengler BA, Biedler J (1983) Alteration of plasma membrane glycopeptides and gangliosides of Chinese hamster cells accompanying development of resistance to daunomycin and vincristine. Cancer Res 43: 222–228

    Google Scholar 

  43. Ramu A, Glaubiger D, Magrath IT, Joshie A (1983a) Plasma membrane lipid structural order in doxorubicin-sensitive and-resistant P388 cells. Cancer Res 43: 5533–5537

    Google Scholar 

  44. Ramu A, Shan T, Glaubiger D (1983b) Enhancement of doxorubicin and vinblastine sensitivity in anthracycline-resistant P388 cells. Cancer Treat Rep 67: 895–899

    Google Scholar 

  45. Riehm H, Biedler JL (1971) Cellular resistance to daunomycin in Chinese hamster cells in vitro. Cancer Res 31: 409–412

    Google Scholar 

  46. Robert J, Illiadis A, Hoerni B, Cano J-P, Durand M, Lagarde C (1982) Pharmacokinetics of adriamycin in patients with breast cancer: correlation between pharmacokinetic parameters and clinical short-term response, Eur J Cancer Clin Oncol 18: 739–745

    Google Scholar 

  47. Sato S, Iwaizumi M, Handa K, Tamura Y (1977) Electron spin resonance study on the mode of generation of free radicals of daunomycin, adriamycin and carbaquone in NAD(P)H-microsome system. Gan 68: 603–608

    Google Scholar 

  48. Schabel FM Jr, Skipper HE, Trader MW, Laster WR, Griswold DP Jr, Corbett TH (1983) Establishment of cross-resistance profiles for new agents. Cancer Treat Rep 67: 905–922

    Google Scholar 

  49. Shoemaker RH, Curt GA, Carney DN (1983) Evidence for multidrug-resistant cells in human tumor cell populations. Cancer Treat Rep 67: 883–888

    Google Scholar 

  50. Siegfried JA, Kennedy KA, Sasrtorelli AC, Tritton TR (1983) Role of membranes in the mechanisms of action of the antineoplastic agent adriamycin. J Biol Chem 258: 339–343

    Google Scholar 

  51. Skovsgaard T (1978) Mechanisms of resistance to daunorubicin by sensitive and anthracycline-resistant sublines of P388 leukaemia. Biochem Pharmacol 27: 2123–2130

    Google Scholar 

  52. Skovsgaard T (1980) Circumvention of resistance to daunorubicin by N-acetyl daunorubicin in Ehrlich ascites tumor. Cancer Res 40: 1077–1081

    Google Scholar 

  53. Skovsgaard T, Friche E (1983) Circumvention of resistance to daunorubicin. In: Hansen HH (ed) Anthracyclines and cancer therapy. Excerpta Medica, Amsterdam, pp 39–48

    Google Scholar 

  54. Smith E, Stratford IJ, Adams GE (1980) Cytotoxicity of adriamycin on aerobic and hypoxic Chinese hamster V79 cells in vitro. J Cancer 42: 568–673

    Google Scholar 

  55. Smith HS, Hackett AJ, Lan S, Stampfer MR (1981) Use of an efficient method for culturing human mammary epithelial cells to study adriamycin sensitivity. Cancer Chemother Pharmacol 6: 237–240

    Google Scholar 

  56. Sutherland RM, Eddy HA, Bareham B, Reich K, Vanantwerp D (1979) Resistance to adriamycin in multicellular spheroids. Int J Radiat Oncol Biol Phys 5: 1225–1230

    Google Scholar 

  57. Tokes ZA, Rogers KE, Rembaum A (1982) Synthesis of adriamycin-coupled polyglutaraldehyde microspheres and evaluation of their cytostatic activity. Proc Natl Acad Sci USA 79: 2026–2030

    Google Scholar 

  58. Trent JM, Buick RN, Olson S, Horns RC Jr, Schimke RT (1984) Cytological evidence for gene amplification in methotrexate-resistant cells obtained from a patient with ovarian adenocarcinoma. J Clin Oncol 2: 8–15

    Google Scholar 

  59. Tritton TR, Yee G (1982) The anticancer agent adriamycin can be actively cytotoxic without entering cells. Science 217: 248–250

    Google Scholar 

  60. Tsuruo T, Ida H, Tsukagoshi S, Sakurai Y (1982) Increased accumulation of vincristine and adriamycin in drug-resistant P388 tumor cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Res 42: 4730–4733

    Google Scholar 

  61. Tsuruo T Iida H, Tsukagoshi S, Sakura Y (1983a) Potentiation of vincristine and adriamycin effects in human hemopoietic tumor cell lines by calcium antagonists and calmodulin inhibitors. Cancer Res 43: 2267–2272

    Google Scholar 

  62. Tsuruo T, Iida H, Nojiri M, Tsukagoshi S, Sakurai Y (1983b) Circumvention of vincristine and adriamycin resistance in vitro and in vivo by calcium influx blockers. Cancer Res 43: 2905–2910

    Google Scholar 

  63. Wheeler C, Rader R, Kessel D (1982) Membrane alterations associated with progressive adriamycin resistance. Biochem Pharmacol 31: 2691–2693

    Google Scholar 

  64. Young RC, Ozols RF, Myers CE (1981) The anthracycline antineoplastic drugs. N Engl J Med 305: 139–153

    Google Scholar 

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Kaye, S., Merry, S. Tumour cell resistance to anthracyclines — A review. Cancer Chemother. Pharmacol. 14, 96–103 (1985). https://doi.org/10.1007/BF00434344

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