Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1983 Jul;48(1):17–26. doi: 10.1038/bjc.1983.152

Chemosensitization by lipophilic nitroimidazoles.

P R Twentyman, P Workman
PMCID: PMC2011422  PMID: 6871076

Abstract

We have carried out experiments to determine the response of tumours and normal tissues in the C3H mouse to the combination of lipophilic nitroimidazoles and CCNU, cyclophosphamide or melphalan. The nitroimidazoles studied were Ro 07-1902 (1902) and benznidazole (Ro 07-1051, BENZO). Maximum enhancement of CCNU response in the KHT sarcoma by 2.5 mmol kg-1 1902 or 0.3 mmol kg-1 BENZO occurred at low doses of CCNU where dose modifying factors (DMF) of 2.5-3.0 and 1.5-2.0 respectively were found. The DMFs for depression of white cell count at day 3 were 1.6 and 1.2 respectively whilst the DMFs for LD50/30 were 1.5 and 1.3. There appears, therefore, to be a therapeutic gain at low doses of CCNU of about the same magnitude as produced by 2.5 mmol kg-1 misonidazole. The production of this gain at relatively low doses of BENZO is of possible clinical significance. Some sensitization of the KHT tumour to CCNU by 0.3 mmol kg-1 BENZO was maintained even with an interval of 25 h between BENZO and CCNU injection. A multiple injection regime of BENZO administration designed to maintain plasma concentrations for prolonged periods was, however, no more effective than a single dose. The response of the RIF-1 sarcoma to cyclophosphamide was not enhanced by the lipophilic sensitizers at the doses previously stated. Considerable enhancement of tumour response to melphalan (DMF 2.0) was produced by both lipophilic sensitizers. Enhancement of acute LD50 was similar in magnitude but no large enhancement by BENZO of melphalan induced white blood cell depression was observed. The evidence regarding the therapeutic potential of this combination is, therefore, equivocal.

Full text

PDF
17

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. Hirst D. G., Brown J. M., Hazlehurst J. L. Enhancement of CCNU cytotoxicity by misonidazole: possible therapeutic gain. Br J Cancer. 1982 Jul;46(1):109–116. doi: 10.1038/bjc.1982.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Kallman R. F., Silini G., Van Putten L. M. Factors influencing the quantitative estimation of the in vivo survival of cells from solid tumors. J Natl Cancer Inst. 1967 Sep;39(3):539–549. [PubMed] [Google Scholar]
  4. 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]
  5. Raaflaub J. Multiple-dose kinetics of the trypanosomicide benznidazole in man. Arzneimittelforschung. 1980;30(12):2192–2194. [PubMed] [Google Scholar]
  6. 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]
  7. Siemann D. W. In vivo combination of misonidazole and the chemotherapeutic agent CCNU. Br J Cancer. 1981 Mar;43(3):367–377. doi: 10.1038/bjc.1981.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Siemann D. W., Morrissey S., Wolf K. In vivo potentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea by the radiation sensitizer benznidazole. Cancer Res. 1983 Mar;43(3):1010–1013. [PubMed] [Google Scholar]
  9. Siemann D. W. Response of murine tumours to combinations of CCNU with misonidazole and other radiation sensitizers. Br J Cancer. 1982 Feb;45(2):272–281. doi: 10.1038/bjc.1982.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. 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]
  15. Workman P. Pharmacokinetics of hypoxic cell radiosensitizers: a review. Cancer Clin Trials. 1980 Fall;3(3):237–251. [PubMed] [Google Scholar]
  16. 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]
  17. 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]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES