EFFECT OF PARTITION-COEFFICIENT ON THE ABILITY OF NITROIMIDAZOLES TO ENHANCE THE CYTO-TOXICITY OF 1-(2-CHLOROETHYL)-3-CYCLOHEXYL-1-NITROSOUREA

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (5) , 1961-1965
Abstract
The ability of 3 nitroimidazoles (SR-2508 [N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide], misonidazole (MISO) and benznidazole [all radiosensitizers] with differing octanol-water partition coefficients to enhance the cytotoxicity of the nitrosourea 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was evaluated in 2 mouse tumors (the KHT sarcoma and the SCC VII/St carcinoma). These results were compared with the effect on 2 normal tissues (bone marrow CFU-S [pluripotential stem cells] 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 50-100 .mu.g/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. Neither SR-2508 nor benznidazole are apparently superior to MISO in combination with CCNU.