The influence of the radiosensitizer misonidazole on the effectiveness of several alkylating agents and cis-platinum against advanced solid murine tumors was investigated. Tumor regrowth delay, frequency of tumor regressions, and animal life span were used to evaluate misonidazole in combination with cyclophosphamide, l-phenylalanine mustard, 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea, aziridinylbenzoquinone, and cis-platinum. In the advanced M5076 ovarian carcinoma, misonidazole enhanced the activity of cyclophosphamide, l-phenylalanine mustard, 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea, and aziridinyl benzoquinone, but not cis-platinum. In early B16 melanoma, misonidazole plus cyclophosphamide was no more effective than cyclophosphamide alone. In advanced Lewis lung carcinoma, misonidazole enhanced the antitumor activity of cyclophosphamide but not 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea. Misonidazole, at 1000 mg/kg, increased the antitumor effectiveness of l-phenylalanine mustard and cyclophosphamide in M5076 tumors by factors of 2.2 and 1.8, but caused only a 1.2- and 1.3-fold increase in the myelotoxicity of these agents as determined by spleen colony assay of normal bone marrow. Misonidazole also increased the toxicity of cyclophosphamide and l-phenylalanine mustard in non-tumor-bearing mice but to a lesser degree than it enhanced antitumor activity. These results indicate that misonidazole is capable of enhancing the effects not only of ionizing radiation but of alkylating agents as well.
Supported by Contract NCI N01-CM-53765.