[Antitumor drugs and potentiators aiming circumvention of drug resistance].
We have been studying the resistance mechanisms of various antitumor drugs and screening substances from natural and synthetic products which overcome resistance. In this paper, we described compounds mainly obtained from our screening systems. I. Circumvention of multidrug resistance (MDR). Lactoquinomycin was discovered from the culture broth of a strain of Streptomyces sp. and it showed preferential growth inhibition against multidrug-resistant L5178 Y cells. The mechanism of action of lactoquinomycin was studied. Another novel antibiotic, resorthiomycin, exhibited not only preferential inhibition against MDR tumor cells but also augmentation of cytotoxicity of several antitumor drugs. As synthetic potentiators, dipyridamole, cepharanthine, AHC-52 and analogs of dihydropyridines were described; all of them were thought to interact with a P-glycoprotein and inhibit active efflux of drugs from tumor cells. SDB-ethylenediamine was unique because it overcame MDR and also potentiates a wide range of antitumor drugs including 5-FU and bleomycin. II. E-64 was found to inhibit the activity of a bleomycin-inactivating enzyme. It potentiated the activity of peplomycin in vitro and in vivo. III. Cadeguomycin was discovered from the culture filtrate of a Streptomyces sp. and it potentiated Ara-C by inhibition of the activity of dCMP deaminase, an Ara-C-inactivating enzyme.
Institute of Applied Microbiology, University of Tokyo.
H
H
Suzuki
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000473:pathology; D003561:Cytarabine / Q000494:pharmacology; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D007942:Leukemia, Experimental / Q000473:pathology; D051379:Mice; D017663:Peplomycin
D000970:Antineoplastic Agents; D003561:Cytarabine; D001761:Bleomycin; D017663:Peplomycin