Abstract
Intracerebral (i.c.) and subcutaneous (s.c.) 9L tumours were treated simultaneously with various doses of the nitrosoureas, BCNU or CCNU, and 2.5 mmol kg-1 of misonidazole (MISO). After 24 h, tumours were removed, dissociated into single cell suspensions and the cells plated for colony formation. In both i.c. and s.c. tumours, no cell kill was observed after exposure to MISO alone, and no additional cell kill was observed when MISO was combined with either nitrosourea. If s.c. 9L tumours were clamped 30 min after i.p. injection of 2.5 mmol kg-1 MISO, then 2 h later the clamps were removed and the nitrosourea injected, an increase in cell kill was observed. This increase in cell kill was statistically significant (P less than 0.01) for each dose of BCNU administered, but not statistically significant (P greater than 0.05) for the moderate dose of CCNU administered. Clamping did not alter the colony forming efficiency of cells from untreated 9L s.c. tumours or from those treated with each drug alone. These data demonstrate that hypoxic cells are required for misonidazole to potentiate the cell-killing effects of the nitrosoureas and that s.c. 9L tumours contain no such cells.
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- Barker M., Hoshino T., Gurcay O., Wilson C. B., Nielsen S. L., Downie R., Eliason J. Development of an animal brain tumor model and its response to therapy with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res. 1973 May;33(5):976–986. [PubMed] [Google Scholar]
- 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]
- Clement J. J., Gorman M. S., Wodinsky I., Catane R., Johnson R. K. Enhancement of antitumor activity of alkylating agents by the radiation sensitizer misonidazole. Cancer Res. 1980 Nov;40(11):4165–4172. [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- Mulcahy R. T. Chemical properties of nitrosoureas: implications for interaction with misonidazole. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):599–602. doi: 10.1016/0360-3016(82)90692-7. [DOI] [PubMed] [Google Scholar]
- Mulcahy R. T., Dembs N. Time-dose relationships for simultaneous misonidazole and 1,3-bis(2-chloroethyl)-1-nitrosourea exposures in vitro. Cancer Res. 1983 Aug;43(8):3539–3543. [PubMed] [Google Scholar]
- Mulcahy R. T., Siemann D. W., Sutherland R. M. In vivo response of KHT sarcomas to combination chemotherapy with radiosensitizers and BCNU. Br J Cancer. 1981 Jan;43(1):93–99. doi: 10.1038/bjc.1981.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roizin-Towle L. A., Hall E. J. Enhanced cytotoxicity of antineoplastic agents following prolonged exposure to misonidazole. Br J Cancer. 1981 Aug;44(2):201–207. doi: 10.1038/bjc.1981.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rosenblum M. K., Knebel K. D., Vasquez D. A., Wilson C. B. Brain-tumor therapy. Quantitative analysis using a model system. J Neurosurg. 1977 Feb;46(2):145–154. doi: 10.3171/jns.1977.46.2.0145. [DOI] [PubMed] [Google Scholar]
- Rosenblum M. L., Knebel K. D., Vasquez D. A., Wilson C. B. In vivo clonogenic tumor cell kinetics following 1,3-bis(2-chloroethyl)-1-nitrosourea brain tumor therapy. Cancer Res. 1976 Oct;36(10):3718–3725. [PubMed] [Google Scholar]
- Rosenblum M. L., Knebel K. D., Wheeler K. T., Barker M., Wilson C. B. Development of an in vitro colony formation assay for the evaluation of in vivo chemotherapy of a rat brain tumor. In Vitro. 1975 Sep-Oct;11(5):264–273. doi: 10.1007/BF02615637. [DOI] [PubMed] [Google Scholar]
- Rosenblum M. L., Wheeler K. T., Wilson C. B., Barker M., Knebel K. D. In vitro evaluation of in vivo brain tumor chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res. 1975 Jun;35(6):1387–1391. [PubMed] [Google Scholar]
- Schmidek H. H., Nielsen S. L., Schiller A. L., Messer J. Morphological studies of rat brain tumors induced by N-nitrosomethylurea. J Neurosurg. 1971 Mar;34(3):335–340. doi: 10.3171/jns.1971.34.3.0335. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- Siemann D. W., Sutherland R. M. Combinations of cyclophosphamide and misonidazole in the KHT sarcoma. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):647–650. doi: 10.1016/0360-3016(82)90704-0. [DOI] [PubMed] [Google Scholar]
- Spooner D., Peacock J. H., Stephens T. C. Enhancement of cytotoxic drugs by misonidazole (MISO) in Lewis lung tumors of different sizes, and mouse bone marrow. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):643–646. doi: 10.1016/0360-3016(82)90703-9. [DOI] [PubMed] [Google Scholar]
- Stewart J. R., Gibbs F. A., Jr, Lehman C. M., Peck J. W., Egger M. J. Change in the in vivo hyperthermic response resulting from the metabolic effects of temporary vascular occlusion. Int J Radiat Oncol Biol Phys. 1983 Feb;9(2):197–201. doi: 10.1016/0360-3016(83)90099-8. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Twentyman P. R. Modification of tumour and host response to cyclophosphamide by misonidazole and by WR 2721. Br J Cancer. 1981 Jun;43(6):745–755. doi: 10.1038/bjc.1981.112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wallen C. A., Michaelson S. M., Wheeler K. T. Evidence for an unconventional radiosensitivity of rat 9L subcutaneous tumors. Radiat Res. 1980 Dec;84(3):529–541. [PubMed] [Google Scholar]
- Wheeler K. T., Jr, Kaufman K., Feldstein M. Response of a rat brain tumor to fractionated therapy with low doses of BCNU and irradiation. Int J Radiat Oncol Biol Phys. 1979 Sep;5(9):1553–1557. doi: 10.1016/0360-3016(79)90770-3. [DOI] [PubMed] [Google Scholar]
- Wheeler K. T., Wallen C. A. Is cell survival a determinant of the in situ response of 9L tumours? Br J Cancer Suppl. 1980 Apr;4:299–303. [PMC free article] [PubMed] [Google Scholar]