Pharmac. Ther. Vol. 38, pp. 321 to 329, 1988 0163-7258/88 $0.00 + 0.50 Printed in Great Britain. All rights reserved Copyright ~ 1988 Pergamon Press plc Specialist Subject Editor: G. Powls METABOLIC INACTIVATION OF BLEOMYCIN ANALOGS BY BLEOMYCIN HYDROLASE SAID M. SEBTI and JOHN S. LAZO University of Pittsburgh School of Medicine, Department of Pharmacology, 518 Scaife Hall, Pittsburgh, PA 15261, U.S.A. 1. INTRODUCTION The bleomycins (BLMs) are a family of antitumor antibiotics first isolated by Umezawa and co-workers (Umezawa, 1966; Umezawa et al., 1979) from cultures of Streptomyces verticillus as copper-containing mixtures. Elucidation of the exact chemical structure of BLM required more than a decade. BLM A2 (Fig. 1) has now been chemically synthesized (Takita et al., 1982; Aoyagi et al., 1982). There are several hundred natural and synthetic BLM analogs now available; all have the fundamental glycopeptide structure of bleo- mycinic acid (Fig. 1). Most BLMs differ from one another at their terminal amine (R 0. For example, BLM A 2 contains a dimethylsulfonium propylamine as a terminal amine whereas BLM B2 contains an agmatine. Peplomycin contains a phenylethyl amine and liblomycin contains a bulky lipophilic terminal amine consisting of several phenyl rings interlinked with ether bonds (Fig. 1). BLM analogs with internal modifications of the BLM molecule are also available. The talisomycins, for example, contain an additional taiose sugar (R2) whereas deglyco BLMs correspond to BLM molecules that lack the two carbohydrate groups of bleomycinic acid. All BLMs contain a bithiazole moiety that confers intrinsic fluorescence. The clinical mixture used in the United States and Europe to treat human malignancies comprises 55-70% BLM A2, 25-30% BLM B2 and small quantities of a variety of other BLMs. In the Soviet Union and China, BLM A 5 is the predominant BLM found in the clinical mixture. Bleomycin is an essential component of regimens that are curative against germ-cell and testicular carcinomas and lymphomas. Bleomycin combined with vinblastine and cis-diamminedichloroplatinum has been reported to produce a greater than 70% complete response rate and disease-free survival in testicular carcinoma (Einhorn and Donohue, 1977). In Hodgkin's disease, adding doxorubicin, bleomycin, vinblastine and decarbazine (ABVD) to the more traditional mechlorethamine, vincristine, procarbazine and prednisone (MOPP) regimen has improved complete response rates to 92% and five-year disease-free survival to 84% (Bonadonna and Santoro, 1982). Bleomycin has also been added to cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy for diffuse histocytic lymphoma with success (Newcomer et al., 1982). Certain types of squamous cell carcinomas also respond to a moderate degree to bleomycin-containing regimens (Bennett and Reich, 1979). One reason for the usefulness of the BLMs may relate to their ability to complement other antitumor agents. Cultured tumor cells resistant to a variety of other antineo- plastic agents, such as vinblastine and doxorubicin, may be more responsive to BLM (Gupta, 1985). One of the most unusual and valuable features of the BLMs is a lack of significant bone marrow, hepatic or renal toxicity (Bennett and Reich, 1979). Thus, overlapping toxicity between BLM and other antineoplastic drugs is uncommon. With repeated clinical doses, however, BLM does induce pulmonary fibrosis (Blum et al., 1973; Umezawa, 1979). 321