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. 1984 Dec;50(6):801–808. doi: 10.1038/bjc.1984.259

Effect of misonidazole pretreatment on nitrogen mustard-induced DNA cross-linking in mouse tissues in vivo.

D Murray, R E Meyn
PMCID: PMC1977012  PMID: 6498077

Abstract

In the present study we have used the alkaline elution technique to study the effect of misonidazole (MISO) on the initial amount of DNA cross-linking in various normal and neoplastic tissues of C3H mice treated with nitrogen mustard (HN2) in vivo. Tissue samples for analysis of the cross-links were prepared 1 h after injection with HN2 to minimize the effect of subsequent repair processes on the yield of lesions. For mice receiving HN2 alone, the greatest level of cross-linking was found in spleen and jejunum, with the liver showing the lowest level. In animals that had been pretreated with MISO (1 mg g-1, i.p.) for 0.5 h prior to injection with HN2, the amount of cross-linking in the spleen and jejunum was not affected by MISO; however, in all other tissues that were examined, cross-linking was enhanced by MISO to a varying extent depending on the specific tissue. The greatest enhancement was observed in the liver (X 6) and kidney (X 3.1), both of these tissues showing a greater enhancement than either of the two fibrosarcomas. The potentiation of HN2 cross-linking in a particular tissue correlated well with two cellular processes that are known to be nitroreduction-dependent in vitro, namely, the degree of MISO-induced GSH depletion and the binding of MISO to cellular macromolecules. Thus, the potentiation of cross-linking in normal tissues such as liver and kidney, and by inference in tumours, may be intimately related to the generation and/or accumulation of nitro-reduced MISO metabolites in those tissues.

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Selected References

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  1. Biaglow J. E. Cellular electron transfer and radical mechanisms for drug metabolism. Radiat Res. 1981 May;86(2):212–242. [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. Bump E. A., Taylor Y. C., Brown J. M. Role of glutathione in the hypoxic cell cytotoxicity of misonidazole. Cancer Res. 1983 Mar;43(3):997–1002. [PubMed] [Google Scholar]
  4. Cesarone C. F., Bolognesi C., Santi L. Improved microfluorometric DNA determination in biological material using 33258 Hoechst. Anal Biochem. 1979 Nov 15;100(1):188–197. doi: 10.1016/0003-2697(79)90131-3. [DOI] [PubMed] [Google Scholar]
  5. Chin J. B., Rauth A. M. The metabolism and pharmacokinetics of the hypoxic cell radiosensitizer and cytotoxic agent, misonidazole, in C3H mice. Radiat Res. 1981 May;86(2):341–357. [PubMed] [Google Scholar]
  6. 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]
  7. Ewig R. A., Kohn K. W. DNA damage and repair in mouse leukemia L1210 cells treated with nitrogen mustard, 1,3-bis(2-chloroethyl)-1-nitrosourea, and other nitrosoureas. Cancer Res. 1977 Jul;37(7 Pt 1):2114–2122. [PubMed] [Google Scholar]
  8. Garrecht B. M., Chapman J. D. The labelling of EMT-6 tumours in BALB/C mice with 14C-misonidazole. Br J Radiol. 1983 Oct;56(670):745–753. doi: 10.1259/0007-1285-56-670-745. [DOI] [PubMed] [Google Scholar]
  9. Grdina D. J., Basic I., Guzzino S., Mason K. A. Radiation response of cell populations irradiated in situ and separated from a fibrosarcoma. Radiat Res. 1976 Jun;66(3):634–643. [PubMed] [Google Scholar]
  10. 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]
  11. Hissin P. J., Hilf R. A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem. 1976 Jul;74(1):214–226. doi: 10.1016/0003-2697(76)90326-2. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. Meyn R. E., Jenkins W. T. Variation in normal and tumor tissue sensitivity of mice to ionizing radiation-induced DNA strand breaks in vivo. Cancer Res. 1983 Dec;43(12 Pt 1):5668–5673. [PubMed] [Google Scholar]
  15. Millar B. C. Hypoxic cell radiosensitizers as potential adjuvants to conventional chemotherapy for the treatment of cancer. Biochem Pharmacol. 1982 Aug 1;31(15):2439–2445. doi: 10.1016/0006-2952(82)90051-x. [DOI] [PubMed] [Google Scholar]
  16. Miller G. G., Ngan-Lee J., Chapman J. D. Intracellular localization of radioactively labeled misonidazole in EMT-6-tumor cells in vitro. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):741–744. doi: 10.1016/0360-3016(82)90725-8. [DOI] [PubMed] [Google Scholar]
  17. Murray D., Meyn R. E. Enhancement of the DNA cross-linking activity of melphalan by misonidazole in vivo. Br J Cancer. 1983 Feb;47(2):195–203. doi: 10.1038/bjc.1983.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Murray D., Meyn R. E. Enhancement of the DNA cross-linking activity of nitrogen mustard by misonidazole and diethyl maleate in a mouse fibrosarcoma tumor in vivo. Cancer Res. 1984 Jan;44(1):91–96. [PubMed] [Google Scholar]
  19. Ross W. E., Ewig R. A., Kohn K. W. Differences between melphalan and nitrogen mustard in the formation and removal of DNA cross-links. Cancer Res. 1978 Jun;38(6):1502–1506. [PubMed] [Google Scholar]
  20. 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]
  21. Stone H. B., Milas L. Modification of radiation responses of murine tumors by misonidazole (Ro 07-0582), host immune capability, and Corynebacterium parvum. J Natl Cancer Inst. 1978 Apr;60(4):887–893. doi: 10.1093/jnci/60.4.887. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Suit H. D., Suchato C. Hyperbaric oxygen and radiotherapy of a fibrosarcoma and of a squamous-cell carcinoma of C3H mice. Radiology. 1967 Oct;89(4):713–719. doi: 10.1148/89.4.713. [DOI] [PubMed] [Google Scholar]
  24. Taylor Y. C., Bump E. A., Brown J. M. Studies on the mechanism of chemosensitization by misonidazole in vitro. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):705–708. doi: 10.1016/0360-3016(82)90717-9. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Twentyman P. R. Growth delay in small EMT6 spheroids induced by cytotoxic drugs and its modification by misonidazole pretreatment under hypoxic conditions. Br J Cancer. 1982 Apr;45(4):565–570. doi: 10.1038/bjc.1982.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Twentyman P. R. In vitro pre-incubation with misonidazole under hypoxic conditions--effect on drug response of EMT6 spheroids. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):607–609. doi: 10.1016/0360-3016(82)90694-0. [DOI] [PubMed] [Google Scholar]
  28. Varghese A. J., Whitmore G. F. Binding to cellular macromolecules as a possible mechanism for the cytotoxicity of misonidazole. Cancer Res. 1980 Jul;40(7):2165–2169. [PubMed] [Google Scholar]
  29. Wheeler K. T., Wallen C. A., Wolf K. L., Siemann D. W. Hypoxic cells and in situ chemopotentiation of the nitrosoureas by misonidazole. Br J Cancer. 1984 Jun;49(6):787–793. doi: 10.1038/bjc.1984.122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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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