Evaluation of antitumor drug side effects in small animals

Abstract

This is an initial report on the development of screening tests for side effects of antitumor drugs, with small amounts of compound and short time intervals. These tests are based on acute dosing of mice and various blood or serum measurements: (a) total white blood cell count for leukopenia; (b) BUN for kidney toxicity; (c) SGPT for liver toxicity; and (d) creatine phosphokinase MB isozyme (CPK-MB) for cardiotoxicity. A correlation with the toxicity observed in other species is developed by establishing the effect of a prototype compound for each toxicity and tests of one or more compounds expected to lack such toxicity. On the basis of the limited number of compounds studied all four tests, although varying in sensitivity, seem to correlate with the results of tests in other species and with known effects in man. Final validation of these acute tests, especially the CPK-MB, will require both further study of histopathologic effects and correlation with results from clinical trials of an extended list of agents.

Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine.

“…To expand our morphological observation that NAC did not prevent doxorubicin hepatotoxicity, we examined the effect of thiol pretreatment on the elevation of serum GPT level which follows treatment with doxorubicin in the mouse (22). 24 h after receiving physiological saline, the serum GPT level in our experimental animals was 11.73+0.82 IU/liter (mean+ 1 SE).…”

“…The effect of NAC on the hepatotoxicity of doxorubicin was examined by determination of serum glutamic-pyruvic transaminase levels. It has recently been shown that treatment with doxorubicin in the dosage range used for our studies produces a significant rise in glutamic-pyruvic transaminase (GPT) levels 24 h after drug administration (22). Thus, we examined the effect of NAC on alterations in GPT levels produced by doxorubicin.…”

Antitumor activity and toxicity in animals of N-7[2-(4-nitrophenyidithio) ethyl] mitomycin C (BMY-25067)

“…Murine hematology studies were performed using methods which have been described elsewhere [4,13,14]. Briefly, BD2F 1 mice in groups of 50-70 per experiment were bled from the retro-orbital plexus and the individual pretreatment total and differential WBC counts determined.…”