An approach to the selective chemotherapy of malignant melanoma is suggested. Melanoma cells contain the copper-enzyme, tyrosinase, which converts tyrosine to L-dopa. We plan to utilize tyrosinase to convert the tyrosinase derivative, """"""""6-hydroxytyrosine"""""""" (2,4-dihydroxyphenylalanine) into the cellular toxin, """"""""6-hydroxy-dopa"""""""" (2,4,5-trihydroxyphenylalanine). The transformation of non-toxic precursor to toxic product within melanoma cells should result in the destruction of melanoma cells, without harm to other tissues. Alternate approaches are available through the conversion of other tyrosine or tyramine analogs to known toxic products, as described in the body of the application. The mechanisms of action of these cellular toxins entail their rapid and continuous generation of superoxide and hydroxyl radicals, which lead to the demise of the cells in which the toxins are accumulated. Portions of the nervous system (viz., catecholamine synthesizing neurons) contain a different enzyme, tyrosine hydroxylase (a pteridine-dependent enzyme), which normally converts tyrosine to dopa; however, the nervous system can be protected. In preliminary experiments, we have demonstrated the conversion of 6-hydroxy-tyrosine to 6-hydroxy-dopa and 6-hydroxy-tyramine to 6-hydroxy-dopamine by partially purified tyrosinase. In addition, preliminary studies with melanoma B-16 in cell culture showed that 6-hydroxytyrosine was toxic to the cells. Lastly, no acute toxicity was noted after injection of 100 mg./kg. of 6-hydroxy-tyrosine into mice. Hence, the feasibility of this approach has been established. We seek to expand the biochemical and cell culture studies, and to initiate experiments with melanoma-bearing mice. Evidence for formation of the expected cell toxins will be sought; changes in cell viability in culture and in vivo will be assessed; potential damage to the nervous system will be monitored. If successful, this project could pave the way toward the selective chemotherapy of malignant melanoma in human subjects.
| Orosz, D; Cohen, G (1987) Decarboxylation of DL-2,4-dihydroxyphenylalanine (2,4-DOPA) to 2,4-dihydroxyphenylethylamine in mouse striatal slices. Eur J Pharmacol 136:441-4 |
| Morrison, M E; Yagi, M J; Cohen, G (1985) In vitro studies of 2,4-dihydroxyphenylalanine, a prodrug targeted against malignant melanoma cells. Proc Natl Acad Sci U S A 82:2960-4 |
