Current Status of PEP Bleomycin Studies in Japan

Abstract

Bleomycin is an antitumor antibiotic produced by an actinomyces, Streptomyces verticillus, isolated from soil by Umezawa et al. [19] in 1962, and occurs as a complex of basic, water-soluble polypeptides made up of 13 bleomycins different in terminal amine, with bleomycin A₂ as the chief component. In 1965, Ichikawa et al. [4] made its clinical application, proving it to be effective in treating squamous cell carcinoma. The drug was later shown to be effective against malignant lymphoma as well. In the meantime, the characteristic adverse reactions to this drug have been revealed, indicating that the drug, unlike the other carcinostatics introduced to date, is accompanied by less adverse effects on the hematopoietic organs, while it may give rise to pulmonary fibrosis, which has recently been accepted as occurring with a frequency of 5%—10% [8,11]. Such situations have led to a desire for the introduction of a new bleomycin (BLM) that is no less effective than the currently available bleomycin, but which is accompanied by lower incidences of adverse reactions. About 300 new derivatives of BLM, having the same basal BLM structure but different terminal amines, were screened, and pepleomyein (experimental code: NK 631), which was found in animal experiments to be close to the above-mentioned target properties, was chosen [5, 9, 12, 15, 17, 18]. Its chemical structure is shown in Fig. 1. It occurs as a single compound differing from the present BLM in the terminal amine of moiety VII.

We are greatly indebted to the assistance given by the Pepleomycin Research Project ot Japan, Dermatological Section (Dr. A. Kukita, at the University of Tokyo, Tokyo; Dr. M. Tashiro, at Kagoshima University, Kagoshima; Dr. Y. Miura, at Hokkaido University, Sapporo; Dr. T. Arao, at Kumamoto University, Kumamoto; Dr. H. Urabe, at Kyushu University, Fukuoka, and Dr. M. Matsunaka, at Wakayama Medical College, Wakayama)