Enhancement of melphalan-induced tumour cell killing by misonidazole: an interaction of competing mechanisms.
In the present studies we have used the RIF-1 tumour in C3H mice to try to identify the mechanism(s) responsible for the enhancement of melphalan (L-PAM) induced tumour cell killing by the 2-nitroimidazole misonidazole (MISO). Most of this work was done with a single large dose of MISO (750 mg kg-1) given 30 min before injection of L-PAM. We found no effect of MISO on the repair of L-PAM-induced potentially lethal damage (PLD) as measured using an in vitro clonogenic survival assay. However, we identified three interrelated and competing processes which affect tumour cell killing by L-PAM subsequent to MISO injection. First, MISO reduces the clearance rate of L-PAM from the blood, an effect which enhances the cell killing by L-PAM. Second, MISO reduces the body temperature which produces a significant reduction in L-PAM cytotoxicity. Third, there is an enhancement of L-PAM cell killing by MISO over and above these two competing processes which is probably a result of the same mechanism by which cells in vitro are sensitized to L-PAM by pre-exposure to MISO under hypoxic conditions.
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D007700:Kinetics; D008558:Melphalan / Q000097:blood / Q000627:therapeutic use*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000097:blood / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors
D009593:Nitroimidazoles; D008920:Misonidazole; D008558:Melphalan