Melanogenesis: a realistic target for antimelanoma therapy?

Melanin is a widely-distributed pigment in the biosphere. In the human adult, the enzymatically-catalysed process of melanin generation is the exclusive prerogative of melanocytes. Melanogenesis generates a number of reactive intermediates including orthoquinones and has been recognised as a potential hazard to melanocytes. Amplification of this cytotoxic hazard to selectively damage malignant melanogenic cells has been investigated as a rational therapeutic strategy for melanoma. A number of surrogate substrates for tyrosinase have been studied, including a range of phenols and catechols. Initial attempts to use these agents for the treatment of disseminated melanoma have foundered on problems due to unfavourable pharmacokinetics, primary toxicity or pharmacological actions of the analogue substrates, and the toxicity of hepatic metabolites. Successful exploitation of the undoubted potential of the metabolic targeting strategy presented by the subversion of melanogenesis depends on the development of prodrugs with minimal primary toxicity and improved pharmacokinetics. The range of possible novel approaches is being extended by the emergent understanding of the complexities of melanogenesis which are outlined.