Effect of partition coefficient on the ability of nitroimidazoles to enhance the cytotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.
The ability of three nitroimidazoles [SR-2508, misonidazole (MISO), and benznidazole] with differing octanol-water partition coefficients to enhance the cytotoxicity of the nitrosourea 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was evaluated in two mouse tumors (the KHT sarcoma and the SCC VII/St carcinoma). These results were compared with the effect on two normal tissues (bone marrow CFU-S and testis spermatogonia). When given as a large single dose, benznidazole was more effective than MISO in enhancing the cytotoxicity of CCNU to both tumors. SR-2508 had no effect. The advantage of benznidazole over MISO was lost, however, because benznidazole gave more toxicity in the normal tissues than MISO. In experiments where the nitroimidazoles were administered by multiple small injections to maintain a blood plasma level between 50 and 100 micrograms/ml, benznidazole was also more effective than MISO in enhancing CCNU cytotoxicity in the tumors. In each case, enhancement was rather less than that obtained with large single injections. Again, however, benznidazole did not produce a consistently greater therapeutic gain than MISO because it also enhanced normal tissue toxicity while MISO did not. SR-2508 was ineffective in both tumors and normal tissues. We conclude that neither SR-2508 nor benznidazole are superior to MISO in combination with CCNU.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D007274:Injections, Intraperitoneal; D008130:Lomustine / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000473:pathology; D009593:Nitroimidazoles / Q000097:blood / Q000494:pharmacology*; D009607:Nitrosourea Compounds / Q000008:administration & dosage*; D012995:Solubility; D013093:Spermatogonia / Q000187:drug effects / Q000473:pathology
D009593:Nitroimidazoles; D009607:Nitrosourea Compounds; D008130:Lomustine