Enhancement of antitumor activity of alkylating agents by the radiation sensitizer misonidazole.
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, aziridinyl-benzoquinone, 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.
D000477:Alkylating Agents / Q000008:administration & dosage*; D000818:Animals; D001388:Aziridines / Q000008:administration & dosage; D016227:Benzoquinones; D053138:Cyclohexenes; D003520:Cyclophosphamide / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D005260:Female; D008558:Melphalan / Q000008:administration & dosage; D051379:Mice; D008920:Misonidazole / Q000008:administration & dosage*; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009593:Nitroimidazoles / Q000008:administration & dosage*; D011809:Quinones / Q000008:administration & dosage; D012673:Semustine / Q000008:administration & dosage
D000477:Alkylating Agents; D001388:Aziridines; D016227:Benzoquinones; D053138:Cyclohexenes; D009593:Nitroimidazoles; D011809:Quinones; D012673:Semustine; C006052:2,5-bis(1-aziridinyl)-3,6-bis(2-methoxyethoxy)-4-benzoquinone; D008920:Misonidazole; D003520:Cyclophosphamide; D008558:Melphalan