Antitumor drug toxicity in tumor-free and tumor-bearing mice

Summary

This report summarizes studies of the toxicology of two antitumor drugs, l-phenylalanine mustard (l-PAM) and 5-fluorouracil (5-FU), administered singly and in combination to tumor-free and tumor-bearing mice. The purpose was to obtain data that might reveal the effect of disease on standard endpoints of drug toxicity. Young adult female B6C3F1 mice free of tumor or bearing murine mammary adenocarcinoma 16/C were treated with various dosages or combinations of l-PAM and 5-FU. All experiments included diluent control groups, and treatments were all administered IP daily for 5 days. Tumor size, body weight, hematology, clinical chemistry, and histopathology data were obtained on days 19, 21, 24, 28, 32, and 39 (day of tumor implantation = day 1; treatment on days 14–18), or on the corresponding post-treatment days in tumor-free mice. Tumor-bearing mice exhibited notable abnormalities in peripheral hematologic values and in concentrations of plasma urea nitrogen. If no drug treatment was administered, persistent reticulocytosis, granulocytosis, and uremia occurred in these mice. These abnormalities seemed to be related to tumor growth; drug treatment that produced partial regressions temporarily moderated cell counts and urea nitrogen concentrations. In general, these effects were observed in tumor-bearing mice receiving the highest doses in each experiment, suggesting that tumor-bearing mice are less sensitive than tumor-free mice to the effects of drugs on vital normal cells. Our data suggest that in the case of the particular tumor, host strain, and drugs studied here, distinct qualitative and quantitative differences in toxicity are obserbed when responses of tumor-free and tumor-bearing mice are compared.