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Sensitization of C6 glioma to carboplatin cytotoxicity by hyperthermia and thymidine

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Summary

Thymidine (a nucleoside metabolite) and 41.8° C hyperthermia were used to sensitize C6 glioma cells to carboplatin cytotoxicity in vitro. Clinically achievable thymidine concentrations (0, 200, 400, or 1000 µg/ml × 24 hours) significantly enhanced carboplatin killing. Clinically achievable hyperthermia exposures (40.5 or 41.8° C x 1 hour) also enhanced carboplatin killing; 41.8° C was more effective than was 40.5° C. Thymidine and 41.8°C hyperthermia together enhanced carboplatin killing significantly more than did the thymidine-carboplatin or hyperthermia-carboplatin combinations. These results illustrate the concept of ‘combination chemosensitization’ for simultaneously addressing the divergent drug resistance mechanisms of malignant gliomas.

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References

  1. Kornblith PL, Walker MD: Chemotherapy for malignant gliomas. J Neurosurg 68: 1–17, 1988

    Google Scholar 

  2. Kornblith PL, Walker MD, Cassady JR: Neoplasms of the central nervous system. In: DeVita VT, Hellman S and Rosenberg SA (eds) Cancer Principles and Practice of Oncology, 2nd edition. J.B. Lippincott, Philadelphia, 1985, pp 1437–1622

    Google Scholar 

  3. Greig NH: Optimizing drug delivery to brain tumors. Cancer Treat Rev 14: 1–28, 1987

    Google Scholar 

  4. DeVita Jr. VT: Principles of Chemotherapy. In: DeVita VT, Hellman S and Rosenberg SA (eds) Cancer Principles and Practice of Oncology, 2nd edition. J.B. Lippincott, Philadelphia, 1985, pp 257–286

    Google Scholar 

  5. Andrews PA, Velury S, Mann SC, Howell SB: cis-Diamminedichloroplatinum (II) accumulation in sensitive and resistant human ovarian carcinoma cells. Cancer Res 48: 68–73, 1988

    Google Scholar 

  6. Durkacz BW, Omidiji O, Gray DA, Shall S: (ADP-ribose)n participates in DNA excision repair. Nature 283: 593–596,1980.

    Google Scholar 

  7. O'Dwyer PJ, King SA, Hoth DF, Leyland-Jones B: Role of thymidine in biochemical modulation: a review. Cancer Res 47: 3911–3919, 1987

    Google Scholar 

  8. Nduka N, Skidmore CJ, Shall S: The enhancement of cytotoxicity of N-methyl-N-nitrosourea and of gamma-radiation by inhibitors of poly (ADP-ribose) polymerase. Eur J Biochem 105:525–530,1980

    Google Scholar 

  9. Fox M: The effects of pyrimidine nucleotides on alkylating agent induced cytotoxicity and spontaneous and induced mutation to purine analog resistance in V79 cells. In: de Serres FJ, Sheridan W (eds) Basic Life Sciences, Vol. 31. Plenum Press, Inc., New York, NY, 1985, pp 435–451

    Google Scholar 

  10. Drewinko B, Corry P, Bergerat JP, Barlogie B: The lethal activity of platinum compounds in combination with pyrimidine derivatives. In: Prestayko AW, Crooke ST, and Carter SK. (eds). Cisplatin: Current Status and New Developments. Academic Press, New York, 1980, pp 37–55

    Google Scholar 

  11. Kufe DW, Beardsley P, Karp D, Parker L, Rosowsky A, Canellos G, Frei E III: High-dose thymidine infusions in patients with leukemia and lymphoma. Blood 55: 580–589, 1980

    Google Scholar 

  12. Kufe DW, Egan EM, Rosowsky A, Ensminger W, Frei E III: Thymidine arrest and synchrony of cellular growth in vivo. Cancer Treat Rep 64: 1307–1317, 1980

    Google Scholar 

  13. Blumenreich MS, Woodcock TM, Andreeff M, Hiddemann W, Chou TC, Vale K, O'Hehir M, Clarkson BD, and Young CW: Effect of very high-dose thymidine infusions on leukemia and lymphoma patients. Cancer Res 4: 2203–2207, 1984

    Google Scholar 

  14. Zaharko DS, Bolten BJ, Kobayashi T, Blasberg RG, Lee SS, Giovanella BC, Stehlin JS, Jr: Thymidine and thymine in biologic fluids during high-dose infusions of thymidine in mice, monkeys, and man. Cancer Treat Rep 63: 945–949, 1979

    Google Scholar 

  15. Adams GE and Stratford IJ. Hypoxia-mediated nitro-heterocyclic drugs in the radio- and chemotherapy of cancer. Biochem Pharmacol 35: 71–76, 1986

    Google Scholar 

  16. Siemann DW and Mulcahy RT. Sensitization of cancer chemotherapeutic agents by nitroheterocyclics. Biochem Pharmacol 35: 111–115, 1986

    Google Scholar 

  17. Salcman M, Samaras GM, and Eng P. Hyperthermia for brain tumors: Biophysical rationale. Neurosurgery 9: 327–335, 1981

    Google Scholar 

  18. Lyons BE, Strohbehn JW, Roberts DW: Interstitial microwave hyperthermia for the treatment of brain tumors. In: Anghileri LJ, Robert J (eds) Hyperthermia in Cancer Treatment, Vol 3. CRC Press Inc, Boca Raton, FL, 1986, pp 26–43

    Google Scholar 

  19. Selker RG, Jacobs SA, Stoller R, Kristofik M, and Randall M. On the limits of human tolerance to whole body hyperthermia and simultaneous chemotherapy. Radiation Res 94:550,1983

    Google Scholar 

  20. Cohen JD and Robins HI: Hyperthermic enhancement of cis-diammine- 1,1-cyclobutane dicarboxylate platinum (II) cytotoxicity in human leukemia cells in vitro. Cancer Res 47:4335–4337,1987

    Google Scholar 

  21. Robins HI, Dennis WH, Neville AJ, Shecterle LM, Martin PA, Grossman J, Davis TE, Neville SR, Gillis WK, Rusy BF: A nontoxic system for 41.8°C whole body hyperthermia: results of a phase I study using a radiant heat device. Cancer Res 45: 3937–3944, 1985

    Google Scholar 

  22. Corry PM, Robinson S, Getz SG: Hyperthermic effects on DNA repair mechanisms. Radiology 123: 475–482, 1977

    Google Scholar 

  23. Cohen JD, Robins HI, Mulcahey RT, Gipp JJ, Bouck N: Interactions between hyperthermia and irradiation in two human lymphoblastic leukemia cell lines in vitro. Cancer Res 48: 3576–3580, 1988

    Google Scholar 

  24. Riviere JE, Page RL, Dewhirst MW, Tyczkowska K, Thrall DE: Effect of hyperthermia on cisplatin pharmacokinetics in normal dogs. Int J Hyperthermia 2: 351–358, 1986

    Google Scholar 

  25. Zakris EL, Dewhirst MW, Riviere JE, Hoopes PJ, Page RL, Oleson JR: Pharmacokinetics and toxicity of intraperitoneal cisplatin combined with regional hyperthermia. J Clin Oncol 5: 1613–1620, 1987

    Google Scholar 

  26. Wallner KE, DeGregorio MW, Li GC: Hyperthermic potentiation of cis-diamminedichloroplatinum (II) cytotoxicity in Chinese hamster ovary cells resistant to the drug. Cancer Res 46: 6242–6245, 1986

    Google Scholar 

  27. Eichholtz-Wirth H, Hietel B: The relationship between cisplatin sensitivity and drug uptake into mammalian cells in vitro. Br J Cancer 54: 239–243, 1986

    Google Scholar 

  28. Lane P, Vichi P, Bain DL, Tritton TR: Temperature dependence studies of adriamycin uptake and cytotoxicity. Cancer Res 47: 4038–42, 1987

    Google Scholar 

  29. Wallner KE, Banda M, Li GC: Hyperthermic enhancement of cell killing by mitomycin C in mitomycin C-resistant Chinese hamster ovary cells. Cancer Res 47: 1308–1312, 1987

    Google Scholar 

  30. Brown DM, Cohen MS, Sayerman RH: Influence of heat on the intracellular uptake and radiosensitization of 2-nitroimidazole hypoxic cell sensitizers in vitro. Cancer Res 43:3138–3142,1983

    Google Scholar 

  31. Frankfurt OS: Flow cytometry analysis of DNA damage and the evaluation of cytotoxicity of alkylating agents. Cancer Res 47: 5537–5541, 1987

    Google Scholar 

  32. Stewart DJ, Leavens M, Maor M, Feun L, Luna M, Bonura J, Caprioli R, Loo TL, Benjamin RS: Human central nervous system distribution of cis-diamminedichloroplatinum and use as a radiosensitizer in malignant brain tumors. Cancer Res 42: 2474–2479, 1982

    Google Scholar 

  33. Hugander A, Robins HI, Martin P, Schmitt C: Temperature distribution during radiant heat whole-body hyperthermia: experimental studies in the dog. Int J Hyperthermia 3: 199–208, 1978

    Google Scholar 

  34. Cohen JD, Robins HI, Schmitt CL: Interactions of hyperthermia with carboplatin, cisplatin, and etoposide in human leukemia cells in vitro. Cancer Letters, 44: 205–210, 1989

    Google Scholar 

  35. Gerad H, Egorin MJ, Whitacre M, Van Echo DA, Aisner J: Renal failure and platinum pharmacokinetics in three patients treated with cis-diamminedichloroplatinum (II) and whole body hyperthermia. Cancer Chemother Pharmacol 11: 162–166, 1983

    Google Scholar 

  36. Wondergem J, Bulger RE, Strebel FR, Newman RA, Travis EL, Stephens, LC, Bull JMC: Effect of cis-diamminedichloroplatinum (II) combined with whole body hyperthermia on renal injury. Cancer Res 48: 440–446, 1988

    Google Scholar 

  37. Canetta R, Franks C, Smaldone L, Bragman K, Rozencweig M: Clinical status of carboplatin. Oncology 5: 61–70, 1987

    Google Scholar 

  38. Calvert AH, Harland SJ, Newell DR, Siddik ZH, Jones AC, McElwain TJ, Raju S, Wiltshaw E, Smith IE, Baker JM, Peckham MJ, Harrap KR: Early clinical studies with cis-diammine-1,1-cyclobutane dicarboxylate platinum II. Cancer Chemother Pharmacol 9: 140–147, 1982

    Google Scholar 

  39. Nichols C, Williams S, Tricot G, Loehrer P, Akard L, Einhorn L, Jansen J: Phase I study of high dose VP-16 plus carboplatin (CBDCA) withautologous bone marrow rescue (ABMT) in refractory germ cell cancer. Proc American Society for Clinical Oncology 7: Abst 454, 1988

  40. van Hennik MB, van der Vijgh WJF, Klein I, Elferink F, Vermoken JB, Winograd B, Pinedo HM: Comparative pharmacokinetics of cisplatin and three analogues in mice and humans. Cancer Res 47: 6297–6301, 1987

    Google Scholar 

  41. Auer RN, Del Maestro RF, Anderson R: A simple and reproducible experimental in vivo glioma model. Canad J Neurol Sci 8: 325–331, 1981

    Google Scholar 

  42. Kaye AH, Morstyn G, Gardner I, Pyke K. Development of a xenograft glioma model in mouse brain. Cancer Res 46: 1367–1373,1986

    Google Scholar 

  43. Albright N: A User's Guide to Computer Programs for the Analysis of Cellular Survival Data. University of California Press, Berkeley, CA, 1988.

    Google Scholar 

  44. Elkind MM and Sutton H: Radiation response of mammalian cells grown in culture. Radiation Res 13: 556–593,1960

    Google Scholar 

  45. Lee SS, Giovanella BC, Stehlin JS: Selective lethal effect of thymidine on human and mouse tumor cells. J Cell Physiol 29:401–406,1977

    Google Scholar 

  46. Reynolds EC, Harris AW, Finch LR: Deoxyribonucleoside triphosphate pools and differential thymidine sensitivities of cultured mouse lymphoma and myeloma cells. Biochim Biophys Acta 561–110, 1979

  47. Tsuboi K. and Kwong L.K. Antiproliferative agents: differential survival between normal and cancer cells. Cancer 38: 3745–3750,1978

    Google Scholar 

  48. Lee SS, Giovanella BC, Stehlin JS, Brunn JC: Regression of human tumors established in nude mice after continuous infusion of thymidine. Cancer Res 39: 2928–2933, 1979

    Google Scholar 

  49. Lockshin A, Giovanella BC, Stehlin JS Jr., Kozielski T, Quian C, Apperson RW: Antitumor activity and minimal toxicity of concentrated thymidine infused in nude mice. Cancer Res 45: 1797–1802, 1985

    Google Scholar 

  50. Kufe DW, Wick MM, Moschella S, Major P: Effect of high-dose thymidine infusions in patients with mycosis fungoides. Cancer 48: 1513–1516, 1981

    Google Scholar 

  51. Tapazoglou E, Robins HI, Khatana A, Schmitt CL, Cohen J, Franken K, Corry P, Sapareto SA: Whole body hyperthermia (WBH) potentiation of carboplatin (CBDCA) cytotoxicity in murine AKR leukemia. Proc North American Hyperthermia Group, Abst Cd-13, 1988

  52. Page RL, McEntee MC, Heidner GL, Riviere JE, Thrall DE: Phase I evaluation of carboplatin at 37 and 42°C in tumor bearing dogs. Proc North American Hyperthermia Group, Abst Bd-9, 1989

  53. Schilsky RL, O'Laughlin K, Ratain MJ: Phase I clinical and pharmacological study of thymidine (NSC 21548) and cis-diamminedichloroplatinum (II) in patients with advanced cancer. Cancer Res 46: 4184–4188, 1986

    Google Scholar 

  54. Rankin PW, Jacobson EL, Benjamin RC, Moss J, Jacobson MK: Quantitative studies of inhibitors of ADP-ribosylation in vitro and in vivo. J Biol Chem 264: 4312–4317,1989

    Google Scholar 

  55. Cohen JD, Schmitt CL, Robins HI, Javid MJ: The interaction of hyperthermia (HT), thymidine (TdR), and ionizing irradiation (XRT) in lymphoid neoplasms. Proc Radiation Research Society: Abst Af-13, 1989

  56. Cohen JD, Robins HI, Schmitt CL: Interactions of hyperthermia (HT) and thymidine (TdR) with carboplatin (CBDCA) or ionizing irradiation (XRT) in glioblastoma cells. Proc Radiation Research Society: Abst Af-14, 1989

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Cohen, J.D., Robins, H.I. & Javid, M.J. Sensitization of C6 glioma to carboplatin cytotoxicity by hyperthermia and thymidine. J Neuro-Oncol 9, 1–8 (1990). https://doi.org/10.1007/BF00167062

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