The effectiveness of the anthracycline analog 4'-epidoxorubicin in the treatment of experimental tumors: a review

The current report presents the data of the Division of Cancer Treatment of the National Cancer Institute (NCI) on the antitumor activity of the anthracycline antibiotic 4′-epidoxorubicin in experimental tumor systems. Direct comparisons are made with doxorubicin in individual experiments, and the data are related to those of earlier studies in the form of a review of experimental activity, in order to assess the relative activity of 4′-epidoxorubicin and doxorubicin. The experimental test models utilized by the NCI for these studies included the leukemias P388 and L1210, B-16 melanoma, Lewis lung carcinoma, the colon tumors 26 and 38, and the mammary tumors CD8F1 and C3H16/C. The human tumors growing in xenograft in athymic mice included the models LX-1 lung tumor, CX-1 colon tumor, and MX-1 mammary tumor. Additional comparisons were made with the tumor models Gross leukemia, sarcoma 180, MSV-induced sarcoma, MS-2 tumor, and a variety of human tumors growing in athymic mice, as well as with in vivo toxicologic and in vitro cytotoxicity models. Although for 4′-epidoxorubicin there is only a minimal alteration of the configuration of the doxorubicin molecule, quantitative comparison of 4′-epidoxorubicin and doxorubicin revealed not only similarities but also differences in biological activity. Both drugs showed activity against a broad spectrum of experimental tumors, with 4′-epidoxorubicin more effective against some tumors and equally effective against others. 4′-Epidoxorubicin evidenced less toxicity than doxorubicin in both acute and chronic toxicity studies with retention of therapeutic effectiveness and showed reduced cardiotoxicity. With 4′ -epidoxorubicin there resulted a higher therapeutic index and therapeutic ratio, permitting the use of higher dosage and a greater margin of safety. The preclinical differences in therapeutic and toxicologic manifestations of 4′-epidoxorubicin, reflecting apparent alterations in pharmacologic properties and mode of action in comparison with doxorubicin, support the broad spectrum clinical trials of this already-demonstrated clinically active drug.