The Leeuwenhoek Lecture, 1982 - Studies of microbial products in rising to the challenge of curing cancer

Abstract

The author’s studies, with his collaborators, on antitumour antibiotics, low molecular mass immunity-enhancing compounds by microorganisms, and microbial products inhibiting the generation of cells that suppress immunity are described. Among about 50 antitumour antibiotics discovered, bleomycin has been used in cancer treatment. The complicated structures of bleomycin and its metal complexes were determined and totally synthesized. The fermentation and chemical methods for preparation of bleomycin analogues and derivatives were established, and, on the basis of action mechanisms, analogues with improved therapeutic activity were developed. Anthracycline antibiotics were also studied; aclacinomycin, effective against leukaemia, and 4´- O -tetrahydropyranyladriamycin (THP), which has strong therapeutic effects against various types of cancer, were developed. Among new antibiotics recently discovered, spergaulin is discussed. A unique screening method for finding microbial products that bind to cell surfaces was established, resulting in the discovery of bestatin, arphamenines, forphenicine, forphenicinol and ebelactones which enhance the action of cellular immunity. Bestatin has been studied in great detail, exhibiting favourable effects in randomization tests. The importance of compounds that can suppress the generation of suppressor cells is discussed. A new antitumour antibiotic, named oxanosine, and arphamenines, described above, were found to inhibit the generation of suppressor cells The contribution of antibacterial antibiotics to cancer treatment is also discussed. It is proposed that a combination treatment with chemotherapeutic agents, low molecular mass immunity-enhancing agents and compounds that inhibit the generation of suppressor cells will make a great contri­bution to cure cancer.

The Effect of Structure and Mechanism of the Hsp70 Chaperone on the Ability to Identify Chemical Modulators and Therapeutics

“…It was later found that 15-DSG, which differs from spergualin only in the absence of the C-15 hydroxyl group, exhibited eightfold more effective antitumor activity in mice (although a greater LD 50 of 35-40 mg/kg was observed) [180]. In subsequent experiments, 15-DSG displayed immunosuppressive activity at higher doses than those which induced antitumor activity [183]. Indeed, the immunosuppressant activity of 15-DSG (see below) leads to successful reversal of acute graft-versushost disease and prolonged survival following xenograft and allograft transplants [184].…”