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Cellular pharmacology of quinone bioreductive alkylating agents

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Abstract

The cellular pharmacology of the mitomycin bioreductive alkylating agents is complex. This reflects in part the chemical characteristics of these quinones, which have multiple sites of reactivity and the capacity to produce a large number of different lesions of biological importance. Moreover, at least six different enzymes are capable of activating these compounds; the nature of the active species and the resultant biological lesions can vary with the activating enzyme. The relative activities of these reductases vary in different cell lines and can be modulated by pH and oxygenation. The effects of a quinone bioreductive alkylating agent therefore depend upon both the cell line and the microenvironment. DNA damage appears to be critical to the cytotoxic effects of these compounds. Both monoadducts and bis-adducts (forming interstrand and intrastrand crosslinks) have been identified in DNA from drug-treated cells. The pattern of adduct formation varies with the compound and the environment. Alkaline elution studies suggest a correlation between DNA cross-linking and cytotoxicity, both in air and in hypoxia. The rate of production of oxygen radicals and the importance of radical reactions in producing cytotoxic damage vary for different quinones and for different environments. While the potency of the bioreductive quinones varies with their redox potential, the direction and magnitude of the oxic/hypoxic differential cannot yet be predicted from the structures.

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References

  1. Iyer VN, Szybalski W: Mitomycins and porfiromycin: chemical mechanism of activation and cross-linking of DNA. Science 145: 55–58, 1964

    Google Scholar 

  2. Powis G: Metabolism and reactions of quinoid anticancer agents. Pharmacol Therap 35: 57–163, 1987

    Google Scholar 

  3. Tomasz M, Mercade CM, Olson J, Chatterjie N: The mode of interaction of mitomycin C with deoxyribonucleic acid and other polynucleotidesin vitro. Biochemistry 13: 4878–4887, 1974

    Google Scholar 

  4. Tomasz M, Chowdary R, Lipman R, Shimotakahara S, Veiro D, Walker V, Verdine GL: Reaction of DNA with chemically or enzymatically activated mitomycin C: isolation and structure of a major covalent adduct. Proc Natl Acad Sci USA 83: 6702–6704, 1986

    Google Scholar 

  5. Tomasz M, Lipman R, Chowdary D, Pawlak J, Verdine GL, Nakanishi K: Isolation and structure of a covalent cross-link adduct between mitomycin C and DNA. Science 235: 1204–1208, 1987

    Google Scholar 

  6. Pan S-S: Porfiromycin disposition in oxygen modulated P388 cells. Cancer Chemother Pharmacol 27: 187–193, 1990

    Google Scholar 

  7. Tomasz M, Hughes CS, Chowdary D, Keyes SR, Lipman R, Sartorelli AC, Rockwell S: Isolation, identification, and assay of [3H]-porfiromycin adducts of EMT6 mouse mammary tumor cell DNA: effects of hypoxia and dicoumarol on adduct patterns. Cancer Commun 3: 213–223, 1991

    Google Scholar 

  8. Basu AK, Hanrahan CJ, Kumar S, Tomasz M: Effects of sitespecifically located major mitomycin C-DNA adduct onin vitro DNA synthesis by DNA polymerase. Biochemistry in press, 1993

  9. Bizanek R, Tomasz M, Kasai M, Arai H, Hughes CS, Sartorelli AC, Rockwell S: Detection and identification of major adducts of3H-mitomycin C and DNA formed in EMT6 mouse mammary tumor cells. Proc Am Assoc Cancer Res 33: 402, 1992

    Google Scholar 

  10. Keyes SR, Fracasso PM, Heimbrook DC, Rockwell S, Sligar SG, Sartorelli AC: Role of NADPH-cytochrome c reductase and DT-diaphorase in the biotransformation of mitomycin C. Cancer Res 44: 5638–5643, 1984

    Google Scholar 

  11. Kennedy KA, Sligar SG, Polomski L, Sartorelli AC: Metabolic activation of mitomycin C by liver microsomes and nuclei. Biochem Pharmacol 31: 2011–2016, 1982

    Google Scholar 

  12. Tomasz M, Lipman R: Reactive metabolism and alkylating activity of mitomycin C induced by rat liver microsomes. Biochemistry 20: 5056–5061, 1981

    Google Scholar 

  13. Komiyama T, Oki T, Inui T: Activation of mitomycin C and quinone drug metabolism by NADPH-cytochrome P-450 reductase. J Pharmacobio-Dyn 2: 407–410, 1979

    Google Scholar 

  14. Pan S-S, Andrews PA, Glover CJ, Bachur NR: Reductive activation of mitomycin C and mitomycin C metabolites catalyzed by NADPH-cytochrome P-450 reductase and xanthine oxidase. J Biol Chem 259: 959–966, 1984

    Google Scholar 

  15. Pan S-S, Iracki T: Metabolites and DNA adduct formation from flavoenzyme activated porfiromycin. Mol Pharmacol 34: 223–228, 1988

    Google Scholar 

  16. Kennedy KA, Mimnaugh EG, Trush MA, Sinha BK: Effects of glutathione and ethylxanthate on mitomycin C activation by isolated rat hepatic or EMT6 mouse mammary tumor nuclei. Cancer Res 45: 4071–4076, 1985

    Google Scholar 

  17. Siegel D, Gibson NW, Preusch PC, Ross D: Metabolism of mitomycin C by DT-diaphorase: role in mitomycin C-induced DNA damage and cytotoxicity in human colon carcinoma cells. Cancer Res 50: 7483–7489, 1990

    Google Scholar 

  18. Gustafson DL, Pritsos CA: Bioactivation of mitomycin C by xanthine dehydrogenase from EMT6 mouse mammary carcinoma tumors. J Natl Cancer Inst 84: 1180–1185, 1992

    Google Scholar 

  19. Hodnick WF, Sartorelli AC: Reductive activation of mitomycin C by NADH-cytochrome b5 reductase. Proc Am Assoc Cancer Res 32: 397, 1991

    Google Scholar 

  20. Dursre L, Rajagopalan S, Eliot HM, Covey JM, Sinha BK: DNA interstrand cross-link and free radical formation in a human multidrug-resistant cell line from mitomycin C and its analogues. Cancer Res 50: 648–652, 1990

    Google Scholar 

  21. Doroshow JH: Role of hydrogen peroxide and hydroxyl radical formation in the killing of Ehrlich tumor cells by anticancer quinones. Proc Natl Acad Sci USA 83: 4514–4518, 1986

    Google Scholar 

  22. Bachur NR, Gordon SL, Gee MV: A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res 38: 1745–1750, 1978

    Google Scholar 

  23. Pritsos CA, Sartorelli AC: Generation of reactive oxygen radicals through bioactivation of mitomycin antibiotics. Cancer Res 46: 3528–3532, 1986

    Google Scholar 

  24. Pritsos CA, Keyes SR, Sartorelli AC: Effect of the superoxide dismutase inhibitor, diethyldithiocarbamate, on the cytotoxicity of mitomycin antibiotics. Cancer Biochem Biophys 10: 289–298, 1989

    Google Scholar 

  25. Tomasz M: H2O2 generation during the redox cycle of mitomycin C and DNA bound mitomycin C. Chem Biol Interact 13: 89–97, 1976

    Google Scholar 

  26. Bachur NR, Gordon SL, Gee MV, Kon H: NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals. Proc Natl Acad Sci USA 76: 954–957, 1979

    Google Scholar 

  27. Lown JW, Chen HH: Evidence for the generation of free hydroxyl radicals from certain quinone antitumor antibiotics upon reductive activation in solution. Can J Chem 59: 390–395, 1981

    Google Scholar 

  28. Ward JF, Evans JW, Limoli CL, Calabro-Jones PM: Radiation and hydrogen peroxide induced free radical damage to DNA. Br J Cancer 55: Suppl VIII 105–112, 1987

    Google Scholar 

  29. Imlay JA, Linn S: DNA damage and oxygen radical toxicity. Science 240: 1302–1309, 1988

    Google Scholar 

  30. Riley RJ, Workman P: DT-diaphorase and chemotherapy. Biochem Pharmacol 8: 1657–1669, 1992

    Google Scholar 

  31. Begleiter A, Leith MK: Activation of mitomycin C by DT-diaphorase under hypoxic and acidic conditions. Proceedings BACR Workshop on Bioreductive Drugs

  32. Begleiter A, Leith MK: Activity of quinone alkylating agents in quinone-resistant cells. Cancer Res 50: 2872–2876, 1990

    Google Scholar 

  33. Marshall RS, Paterson MC, Rauth AM: Deficient activation by a human cell strain leads to mitomycin resistance under aerobic but not hypoxic conditions. Brit J Cancer 59: 341–346, 1989

    Google Scholar 

  34. Marshall RS, Paterson MC, Rauth AM: Studies on the mechanism of resistance to mitomycin C and porfiromycin in a human cell strain derived from a cancer-prone individual. Biochem Pharmacol 41: 1351–1360, 1991

    Google Scholar 

  35. Dulhanty AM, Li M, Whitmore GF: Isolation of Chinese hamster ovary cell mutants deficient in excision repair and mitomycin C bioactivation. Cancer Res 49: 117–122, 1989

    Google Scholar 

  36. Dulhanty AM, Whitmore GF: Chinese hamster ovary cell lines resistant to mitomycin C under aerobic but not hypoxic conditions are deficient in DT-diaphorase. Cancer Res 51: 1860–1865, 1991

    Google Scholar 

  37. Rockwell S, Keyes SR, Sartorelli AC: Modulation of the antineoplastic efficacy of mitomycin C by dicoumarolin vivo. Cancer Chemother Pharmacol 24: 349–353, 1989

    Google Scholar 

  38. Rockwell S, Keyes SR, Sartorelli AC: Modulation of the cytotoxicity of porfiromycin by dicoumarolin vitro andin vivo. Anticancer Res 9: 817–820, 1989

    Google Scholar 

  39. Keyes SR, Rockwell S, Sartorelli AC: Modification of the metabolism and cytotoxicity of bioreductive alkylating agents by dicoumarol in aerobic and hypoxic murine tumor cells. Cancer Res 49: 3310–3313, 1989

    Google Scholar 

  40. Doroshow JH: Reductive activation of mitomycin C: a delicate balance. J Natl Cancer Inst 84: 1138–1139, 1992

    Google Scholar 

  41. Hoban P, Walton MI, Robson C, Godden J, Stratford I, Workman P, Harris A, Hickson I: Decreased NADPH: cytochrome P-450 reductase activity and impaired drug activation in a mammalian cell line resistant to mitomycin C under aerobic but not hypoxic conditions. Cancer Res 50: 4692–4697, 1990

    Google Scholar 

  42. Keyes SR, Rockwell S, Sartorelli AC: Enhancement of mitomycin C cytotoxicity to hypoxic cells by dicoumarolin vivo andin vitro. Cancer Res 45: 213–216, 1985

    Google Scholar 

  43. Rockwell S, Keyes SR, Sartorelli AC: Modulation of the cytotoxicity of mitomycin C to EMT6 mouse mammary tumor cells by dicoumarolin vitro. Cancer Res 48: 5471–5474, 1988

    Google Scholar 

  44. Doroshow J, Akman S, Forrest G: Effect of DT-diaphorase overexpression on mitomycin C toxicity for Chinese hamster ovary cells. Proc Am Assoc Cancer Res 33: 507, 1992

    Google Scholar 

  45. Keyes SR, Rockwell S, Sartorelli AC: Porfiromycin as a bioreductive alkylating agent with selective toxicity to hypoxic EMT6 tumor cellsin vivo andin vitro. Cancer Res 45: 3642–3645, 1985

    Google Scholar 

  46. Rockwell S, Keyes SR, Sartorelli AC: Preclinical studies of porfiromycin as an adjunct to radiotherapy. Radiat Res 116: 100–113, 1988

    Google Scholar 

  47. Rockwell S, Keyes SR, Loomis R, Kelley M, Vyas DM, Wong H, Doyle TW, Sartorelli AC: Activity of C-7 substituted cyclic acetal derivatives of mitomycin C and porfiromycin against hypoxic and oxygenated EMT6 carcinoma cellsin vitro andin vivo. Cancer Commun 3: 191–198, 1991

    Google Scholar 

  48. Keyes SR, Loomis R, DiGiovanna MP, Pritsos CA, Rockwell S, Sartorelli AC: Cytotoxicity and DNA cross-links produced by mitomycin analogs in aerobic and hypoxic EMT6 cells. Cancer Commun 3: 351–356, 1991

    Google Scholar 

  49. Hughes CS, Irvin CG, Rockwell S: Effects of deficiencies in DNA repair on the toxicity of mitomycin C and porfiromycin to CHO cells under aerobic and hypoxic conditions. Cancer Commun 3: 29–35, 1991

    Google Scholar 

  50. Marshall RS, Rauth AM: Oxygen and exposure kinetics as factors influencing the cytotoxicity of porfiromycin, a mitomycin C analogue, in Chinese hamster ovary cells. Cancer Res 48: 5655–5659, 1988

    Google Scholar 

  51. Marshall RS, Rauth AM: Modification of the cytotoxic activity of mitomycin C by oxygen and ascorbic acid in Chinese hamster ovary cells and a repair-deficient mutant. Cancer Res 46: 2709–2713, 1986

    Google Scholar 

  52. Fracasso PM, Sartorelli AC: Cytotoxicity and DNA lesions produced by mitomycin C and porfiromycin in hypoxic and aerobic EMT6 and Chinese hamster ovary cells. Cancer Res 46: 3939–3944, 1986

    Google Scholar 

  53. Rauth AM, Barton B, Lee CPY: Effects of caffeine on Lcells exposed to mitomycin C. Cancer Res 30: 2724–2729, 1970

    Google Scholar 

  54. Rockwell S: Effect of some proliferative and environmental factors on the toxicity of mitomycin C to tumor cellsin vitro. Int J Cancer 38: 229–235, 1986

    Google Scholar 

  55. Kennedy KA, McGurl JD, Leondaridis L, Alabaster O: pH dependence of mitomycin C-induced cross-linking activity in EMT6 tumor cells. Cancer Res 45: 3541–3547, 1985

    Google Scholar 

  56. Kennedy KA: Hypoxic cells as specific drug targets for chemotherapy. Anti-Cancer Drug Design 2: 181–194, 1987

    Google Scholar 

  57. Laurencot CM: The role of intracellular pH in the cytotoxicity of cisplatin and porfiromycin to EMT6 cells: Ph.D. Thesis, George Washington University, 1993

  58. Keyes SR, Rockwell S, Sartorelli AC: Correlation between drug uptake and selective toxicity of porfiromycin to hypoxic EMT6 cells. Cancer Res 47: 5654–5657, 1987

    Google Scholar 

  59. Pan S-S, Johnson R, Gonzalez H, Thohan V: Mechanism of transport and intracellular binding of porfiromycin in HCT 116 human colon carcinoma cells. Cancer Res 49: 5048–5053, 1989

    Google Scholar 

  60. Sartorelli AC: Therapeutic attack of hypoxic cells of solid tumors: presidential address. Cancer Res 48: 775–778, 1988

    Google Scholar 

  61. Rockwell S: Use of hypoxia-directed drugs in the therapy of solid tumors. Semin Oncol 19: Suppl 11 29–40, 1992

    Google Scholar 

  62. Doll DC, Weiss RB, Issell BF: Mitomycin: ten years after approval for marketing. J Clin Oncol 3: 276–286, 1985

    Google Scholar 

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Authors and Affiliations

  1. Departments of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, 06510-8040, New Haven, CT, USA

    Sara Rockwell

  2. Departments of Pharmacology, Yale University School of Medicine, 333 Cedar Street, 06510-8040, New Haven, CT, USA

    Alan C. Sartorelli

  3. Department of Chemistry, Hunter College, 695 Park Avenue, 10021, New York, NY, USA

    Maria Tomasz

  4. Department of Pharmacology, George Washington University, 2300 Eye Street, N.W., 20037, Washington, DC, USA

    Katherine A. Kennedy

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  1. Sara Rockwell
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  2. Alan C. Sartorelli
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  3. Maria Tomasz
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  4. Katherine A. Kennedy
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Rockwell, S., Sartorelli, A.C., Tomasz, M. et al. Cellular pharmacology of quinone bioreductive alkylating agents. Cancer Metast Rev 12, 165–176 (1993). https://doi.org/10.1007/BF00689808

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