Experimental evaluation of anthracycline analogs.

This review summarizes the preclinical tests conducted to date for experimental evaluation of new anthracycline analogs. Most of the data are derived from the experience at the Istituto Nazionale Tumori, Milan, Italy, at the National Cancer Institute, Bethesda, Md, and at the Farmitalia Research Laboratories, Nerviano, Italy. In vitro cytotoxicity tests are useful for determining the doses to be used in vivo. Antitumor activity tests in mice can be divided into different stages. P388 and L1210 leukemias are generally used in primary screening; the value of adding L1210 leukemia is briefly discussed. Other experimental tumors adopted include disseminated leukemia and transplanted solid tumors. The importance of the route and schedule of treatment is stressed. Drugs should be administered iv in the case of solid tumors, and the schedule of treatment can be adjusted according to the pharmacokinetic properties of the new analog, when these are known. If possible, the parent compound and the new analog should be dissolved in the same solvents. In the toxicity tests, cardiac toxicity deserves particular attention. Until now, the only experimental model in which a number of new anthracyclines have been tested is the rat model proposed by Zbinden. A comparison between cardiotoxicity data obtained in such models and antitumor data obtained in mice shows that cardiac toxicity can be dissociated from the antitumor activity. Knowledge of pharmacokinetic properties of new analogs is of importance for selecting the schedules of treatment and for explaining selective toxic effects.