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. 1983 Sep;48(3):375–383. doi: 10.1038/bjc.1983.202

The effect of radiosensitizers on the pharmacokinetics of melphalan and cyclophosphamide in the mouse.

M Hinchliffe, N J McNally, M R Stratford
PMCID: PMC2011478  PMID: 6615699

Abstract

Misonidazole (MISO) has been shown to affect the pharmacokinetics of both cyclophosphamide (CY) and melphalan (MEL) in WHT mice resulting in increased plasma levels of the cytotoxic drugs. The effect is not solely due to the reduction in body temperature observed with large single doses of MISO, as a change in MEL pharmacokinetics was still observed when the mice were maintained at 37 degrees C. Inhibition of cytotoxic drug metabolism may also be a possible mechanism. Such a pharmacokinetic effect could account for part of the potentiation of MEL and CY action observed in tumours with large single doses of MISO. However, a chronic low dosing schedule of MISO did not affect the plasma half-life of either cytotoxic drug, although a significant potentiation of each drug in combination with a chronic MISO dose has been obtained in some tumours. These results suggest that potentiation of chemotherapeutic drug action by MISO in the clinical situation is unlikely to be due to changes in drug pharmacokinetics.

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Selected References

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

  1. 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]
  2. 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]
  3. Chang S. Y., Alberts D. S., Melnick L. R., Walson P. D., Salmon S. E. High-pressure liquid chromatographic analysis of melphalan in plasma. J Pharm Sci. 1978 May;67(5):679–682. doi: 10.1002/jps.2600670529. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Furner R. L., Brown R. K. L-phenylalanine mustard (L-PAM): the first 25 years. Cancer Treat Rep. 1980 Apr-May;64(4-5):559–574. [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. 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]
  9. McNally N. J., Hinchliffe M., de Ronde J. Enhancement of the action of alkylating agents by single high, or chronic low doses of misonidazole. Br J Cancer. 1983 Aug;48(2):271–278. doi: 10.1038/bjc.1983.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Peacock J. H., Stephens T. C. Influence of anaesthetics on tumour-cell kill and repopulation in B16 melanoma treated with melphalan. Br J Cancer. 1978 Dec;38(6):725–731. doi: 10.1038/bjc.1978.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Shoemaker D. D., McManus M. E., Hoerauf R., Strong J. M. Studies on the O-demethylation of misonidazole by rat liver microsomes. Cancer Treat Rep. 1982 Jun;66(6):1343–1347. [PubMed] [Google Scholar]
  12. 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]
  13. Tannock I. F. In vivo interaction of anti-cancer drugs with misonidazole or metronidazole: cyclophosphamide and BCNU. Br J Cancer. 1980 Dec;42(6):871–880. doi: 10.1038/bjc.1980.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Twentyman P., Workman P. Effect of misonidazole or metronidazole pretreatment on the response of the RIF-1 mouse sarcoma to melphalan, cyclophosphamide, chlorambucil and CCNU. Br J Cancer. 1982 Mar;45(3):447–455. doi: 10.1038/bjc.1982.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Weaver F. A., Torkelson A. R., Zygmunt W. A., Browder H. P. Tissue culture cytotoxicity assay for cyclophosphamide metabolites in rat body fluids. J Pharm Sci. 1978 Jul;67(7):1009–1012. doi: 10.1002/jps.2600670738. [DOI] [PubMed] [Google Scholar]
  17. Workman P., Brown J. M. Structure-pharmacokinetic relationships for misonidazole analogues in mice. Cancer Chemother Pharmacol. 1981;6(1):39–49. doi: 10.1007/BF00253009. [DOI] [PubMed] [Google Scholar]
  18. Workman P. Pharmacokinetics of hypoxic cell radiosensitizers: a review. Cancer Clin Trials. 1980 Fall;3(3):237–251. [PubMed] [Google Scholar]
  19. Workman P., Twentyman P. R. Structure/activity relationships for the enhancement by electron-affinic drugs of the anti-tumour effect of CCNU. Br J Cancer. 1982 Aug;46(2):249–259. doi: 10.1038/bjc.1982.190. [DOI] [PMC free article] [PubMed] [Google Scholar]

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