In vitro studies of 2,4-dihydroxyphenylalanine, a prodrug targeted against malignant melanoma cells.
We have evaluated the chemotherapeutic potential of 2,4-dihydroxyphenylalanine, a targeted prodrug that can be hydroxylated by tyrosinase (monophenol monooxygenase, EC 1.14.18.1) within melanoma cells to form the cellular toxin 2,4,5-trihydroxyphenylalanine (6-hydroxydopa). 2,4-Dihydroxyphenylalanine proved to be cytotoxic to both B-16 and Cloudman melanoma cells in vitro. The immediate effects of 2,4-dihydroxyphenylalanine included inhibition of DNA, RNA, and protein syntheses. In contrast, no decrease in macromolecular synthesis or viability was seen against cultures of MJY-alpha mammary tumor or L-1210 leukemia, two cell types that do not contain tyrosinase. Within the melanoma cultures, greater cytotoxicity was seen against melanotic (tyrosinase-containing) cells than against amelanotic (tyrosinase-lacking) cells. The cytotoxicity of 2,4-dihydroxyphenylalanine was blocked by 1-phenylthiourea, an inhibitor of tyrosinase. These results show that 2,4-dihydroxyphenylalanine is toxic to melanoma cells and that activation of 2,4-dihydroxyphenylalanine requires the presence of tyrosinase.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use*; D007939:Leukemia L1210 / Q000188:drug therapy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism
C001388:6-hydroxydopa; D004295:Dihydroxyphenylalanine; D014442:Monophenol Monooxygenase