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. 1984 Sep;50(3):305–316. doi: 10.1038/bjc.1984.177

Enhancement of melphalan-induced tumour cell killing by misonidazole: an interaction of competing mechanisms.

M R Horsman, J W Evans, J M Brown
PMCID: PMC1976784  PMID: 6466544

Abstract

In the present studies we have used the RIF-1 tumour in C3H mice to try to identify the mechanism(s) responsible for the enhancement of melphalan (L-PAM) induced tumour cell killing by the 2-nitroimidazole misonidazole (MISO). Most of this work was done with a single large dose of MISO (750 mg kg-1) given 30 min before injection of L-PAM. We found no effect of MISO on the repair of L-PAM-induced potentially lethal damage (PLD) as measured using an in vitro clonogenic survival assay. However, we identified three interrelated and competing processes which affect tumour cell killing by L-PAM subsequent to MISO injection. First, MISO reduces the clearance rate of L-PAM from the blood, an effect which enhances the cell killing by L-PAM. Second, MISO reduces the body temperature which produces a significant reduction in L-PAM cytotoxicity. Third, there is an enhancement of L-PAM cell killing by MISO over and above these two competing processes which is probably a result of the same mechanism by which cells in vitro are sensitized to L-PAM by pre-exposure to MISO under hypoxic conditions.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Begleiter A., Lam H. Y., Grover J., Froese E., Goldenberg G. J. Evidence for active transport of melphalan by two amino acid carriers in L5178Y lymphoblasts in vitro. Cancer Res. 1979 Feb;39(2 Pt 1):353–359. [PubMed] [Google Scholar]
  2. Brown J. M., Hirst D. G. Effect of clinical levels of misonidazole on the response of tumour and normal tissues in the mouse to alkylating agents. Br J Cancer. 1982 May;45(5):700–708. doi: 10.1038/bjc.1982.111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown J. M. The mechanisms of cytotoxicity and chemosensitization by misonidazole and other nitroimidazoles. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):675–682. doi: 10.1016/0360-3016(82)90711-8. [DOI] [PubMed] [Google Scholar]
  4. Clutterbuck R. D., Millar J. L., McElwain T. J. Misonidazole enhancement of the action of BCNU and melphalan against human melanoma xenografts. Am J Clin Oncol. 1982 Feb;5(1):73–78. [PubMed] [Google Scholar]
  5. Coleman C. N., Friedman M. K., Jacobs C., Halsey J., Ignoffo R., Leibel S., Hirst V. K., Gribble M., Carter S. K., Phillips T. L. Phase I trial of intravenous L-phenylalanine mustard plus the sensitizer misonidazole. Cancer Res. 1983 Oct;43(10):5022–5025. [PubMed] [Google Scholar]
  6. Evans T. L., Chang S. Y., Alberts D. S., Sipes I. G., Brendel K. In vitro degradation of L-phenylalanine mustard (L-PAM). Cancer Chemother Pharmacol. 1982;8(2):175–178. doi: 10.1007/BF00255479. [DOI] [PubMed] [Google Scholar]
  7. Furner R. L., Mellett L. B., Brown R. K., Duncan G. A method for the measurement of L-phenylalanine mustard in the mouse and dog by high-pressure liquid chromatography. Drug Metab Dispos. 1976 Nov-Dec;4(6):577–583. [PubMed] [Google Scholar]
  8. Hinchliffe M., McNally N. J., Stratford M. R. The effect of radiosensitizers on the pharmacokinetics of melphalan and cyclophosphamide in the mouse. Br J Cancer. 1983 Sep;48(3):375–383. doi: 10.1038/bjc.1983.202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Law M. P., Hirst D. G., Brown J. M. Enhancing effect of misonidazole on the response of the RIF-1 tumour to cyclophosphamide. Br J Cancer. 1981 Aug;44(2):208–218. doi: 10.1038/bjc.1981.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lee F. Y., Workman P. Modification of CCNU pharmacokinetics by misonidazole--a major mechanism of chemosensitization in mice. Br J Cancer. 1983 May;47(5):659–669. doi: 10.1038/bjc.1983.104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Martin W. M., McNally N. J., De Ronde J. Enhancement of the effect of cytotoxic drugs by radiosensitizers. Br J Cancer. 1981 Jun;43(6):756–766. doi: 10.1038/bjc.1981.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. McNally N. J. Enhancement of chemotherapy agents. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):593–598. doi: 10.1016/0360-3016(82)90691-5. [DOI] [PubMed] [Google Scholar]
  13. Roizin-Towle L., Hall E. J. Studies with bleomycin and misonidazole on aerated and hypoxic cells. Br J Cancer. 1978 Feb;37(2):254–260. doi: 10.1038/bjc.1978.34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Sheldon P. W., Batten E. L. Potentiation in vivo of melphalan activity by nitroimidazole compounds. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):635–637. doi: 10.1016/0360-3016(82)90701-5. [DOI] [PubMed] [Google Scholar]
  15. Siemann D. W., Mulcahy R. T. Cell survival recovery kinetics in the KHT sarcoma following treatment with five alkylating agents and misonidazole. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):619–622. doi: 10.1016/0360-3016(82)90697-6. [DOI] [PubMed] [Google Scholar]
  16. Siemann D. W. Potentiation of chemotherapy by hypoxic cell radiation sensitizers--a review. Int J Radiat Oncol Biol Phys. 1982 Jun;8(6):1029–1034. doi: 10.1016/0360-3016(82)90172-9. [DOI] [PubMed] [Google Scholar]
  17. Stephens T. C., Courtenay V. D., Mills J., Peacock J. H., Rose C. M., Spooner D. Enhanced cell killing in lewis lung carcinoma and a human pancreatic-carcinoma xenograft by the combination of cytotoxic drugs and misonidazole. Br J Cancer. 1981 Apr;43(4):451–457. doi: 10.1038/bjc.1981.66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Stratford I. J., Adams G. E., Horsman M. R., Kandaiya S., Rajaratnam S., Smith E., Williamson C. The interaction of misonidazole with radiation, chemotherapeutic agents, or heat: a preliminary report. Cancer Clin Trials. 1980 Fall;3(3):231–236. [PubMed] [Google Scholar]
  19. Taylor Y. C., Evans J. W., Brown J. M. Mechanism of sensitization of Chinese hamster ovary cells to melphalan by hypoxic treatment with misonidazole. Cancer Res. 1983 Jul;43(7):3175–3181. [PubMed] [Google Scholar]
  20. Twentyman P. R., Brown J. M., Gray J. W., Franko A. J., Scoles M. A., Kallman R. F. A new mouse tumor model system (RIF-1) for comparison of end-point studies. J Natl Cancer Inst. 1980 Mar;64(3):595–604. [PubMed] [Google Scholar]
  21. Twentyman P. R., Kallman R. F., Brown J. M. The effect of time between X-irradiation and chemotherapy on the growth of three solid mouse tumors--I. Adriamycin. Int J Radiat Oncol Biol Phys. 1979 Aug;5(8):1255–1260. doi: 10.1016/0360-3016(79)90649-7. [DOI] [PubMed] [Google Scholar]
  22. Twentyman P. R., Workman P. An investigation of the possibility of chemosensitization by clinically achievable concentrations of misonidazole. Br J Cancer. 1983 Feb;47(2):187–194. doi: 10.1038/bjc.1983.26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Workman P., Little C. J., Marten T. R., Dale A. D., Ruane R. J., Flockhart I. R., Bleehen N. M. Estimation of the hypoxic cell-sensitiser misonidazole and its O-demethylated metabolite in biological materials by reversed-phase high-performance liquid chromatography. J Chromatogr. 1978 May 1;145(3):507–512. doi: 10.1016/s0378-4347(00)81386-9. [DOI] [PubMed] [Google Scholar]
  24. Workman P., Twentyman P. R., Lee F. Y., Walton M. I. Drug metabolism and chemosensitization. Nitroimidazoles as inhibitors of drug metabolism. Biochem Pharmacol. 1983 Mar 1;32(5):857–864. doi: 10.1016/0006-2952(83)90588-9. [DOI] [PubMed] [Google Scholar]

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