In vitro studies of 2,4-dihydroxyphenylalanine, a prodrug targeted against malignant melanoma cells.

Abstract

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.

• Authors: M E Morrison, M J Yagi, G Cohen
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 82 Issue 9 Pg. 2960-4 (May 1985) ISSN: 0027-8424 [Print] United States
• PMID: 3921968 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 6-hydroxydopa
• Dihydroxyphenylalanine
• Monophenol Monooxygenase

Topics

• Animals
• Cell Survival (drug effects)
• Cells, Cultured
• Dihydroxyphenylalanine (analogs & derivatives, metabolism, therapeutic use)
• Leukemia L1210 (drug therapy)
• Mammary Neoplasms, Experimental (drug therapy)
• Melanoma (drug therapy, metabolism)
• Mice
• Monophenol Monooxygenase (metabolism)