Misonidazole Cytotoxicity in Vivo: A Comparison of Large Single Doses with Smaller Doses and Extended Contact of the Drug with Tumor Cells

Abstract

Experiments were performed to determine the kinetics and magnitude of misonidazole cytotoxicity in EMT6/Ro tumors using an in vivo-in vitro clonogenicity assay. A comparison was made between the cytotoxic effects of large single doses with smaller doses of misonidazole administered ip and those produced on extended contact of the drug with tumor cells using a continuous iv drug infusion system. After a single ip dose of 1 mg/g, cytotoxicity was maximum at 18 to 24 h; by 72 h the clonogenic cells per tumor had returned to control levels. The maximum cytotoxicity was greater (a decrease of 10 times) if the animals were kept at 37/sup 0/C compared with ambient conditions (a decrease of 4.5 times) where the body temperature would decrease due to the drug. A dose-response curve performed with the animals at 37/sup 0/C showed no significant cytotoxicity at 18 h after single ip doses of 0.5 mg/g or less. Other experiments were carried out at 37/sup 0/C using a drug continuous infusion system. Two profiles were studied: (a) continuous constant rate infusion over 3 days of constant serum and tumor levels of both 100 and 200 ..mu..g/ml and (b) continuous variable rate infusion where the maximum serummore » levels reached 80 or 200 ..mu..g/ml after 2 to 4 h and decayed with a half-life of 12 h as in humans. Significant cytotoxicity was obtained under both of these conditions. Maximum cytotoxicity occurred at about 24 h in both types of experiments and amounted to decreases of clonogenic tumor cells of 4.5 and 7 times for 100 and 200 ..mu..g/ml, respectively, after constant rate infusion and 2 to 4 times for 80 and 200 ..mu..g/ml, respectively, after variable rate infusion. Because of the relatively rapid recovery in the number of clonogenic tumor cells by 72 h, the cytotoxic effects were not reflected as changes in tumor size even when the animals were maintained at 37/sup 0/C.« less