Antitumor effects of L-glutamic acid dihydroxyanilides against experimental melanoma.
L-glutamic acid, gamma-(p-hydroxyanilide), is a naturally occurring metabolic inhibitor found in mushrooms and shown to be active against B-16 melanoma in vivo. We have prepared and evaluated 2 analogs, the 3,4- and 2,5-dihydroxy derivatives, since these might represent more immediate precursors to the putative biologically active quinone. Both dihydroxy derivatives were more toxic than the parent phenol. The 2,5-dihydroxy derivative was significantly more cytotoxic with a 5-fold decrease in IC50 for both human and B-16 melanoma cells in vitro. In the presence of mushroom tyrosinase, both derivatives were potent inhibitors of isolated DNA polymerase with essentially complete inhibition occurring at concentrations of 10(-5) M. The 3,4-dihydroxy derivative exerted inhibitory effects primarily upon thymidine incorporation into melanoma cells in vitro while the 2,5-dihydroxy derivative also inhibited uridine and leucine incorporation. There was no significant antitumor activity observed in the B-16 system, a fact which might be attributed to the increased toxicity of the compounds.
D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D004259:DNA-Directed DNA Polymerase / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005971:Glutamates / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D014442:Monophenol Monooxygenase / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000188:drug therapy; D012878:Skin Neoplasms / Q000188:drug therapy*
D000813:Anilides; D005971:Glutamates; D014442:Monophenol Monooxygenase; D004259:DNA-Directed DNA Polymerase