Factors influencing the chemosensitization of melphalan by misonidazole.
The effect of melphalan alone or combined with various schedules of misonidazole (MISO) has been tested on a murine fibrosarcoma. The tumoricidal effect has been determined using the growth delay assay. Large single doses (500-1000 mgkg-1) of MISO enhanced the anti-tumour effect of melphalan, especially at high melphalan doses. This was accompanied by a drop in body and tumour temperature and an increase in the melphalan half-life. The MISO-induced hypothermia was prevented in one experiment by keeping the mice in an ambient temperature of 35 degrees C for 3 h. This reduced the exposure to melphalan but did not diminish the cytotoxic effect of the drug combination. Chronic administration of MISO for an 8 h period gave no enhancement of melphalan damage, whether melphalan was given half-way through or at the end of the period of dosing. It seems that a threshold tumour concentration of MISO, in excess of 70 micrograms g-1, is needed for enhancement of melphalan cytotoxicity; prolonged exposures to very low doses are ineffective.
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D008558:Melphalan / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D008920:Misonidazole / Q000378:metabolism / Q000627:therapeutic use*; D009593:Nitroimidazoles / Q000627:therapeutic use*; D013696:Temperature
D009593:Nitroimidazoles; D008920:Misonidazole; D008558:Melphalan