Radicals and melanomas

Abstract

The synthesis of melanin involves the oxidation of phenolic substrates by the enzyme tyrosinase. In vertebrates tyrosinase is present only in specialized cells (melanocytes), where it catalyses the oxidation of tyrosine and certain diphenolic intermediate products to quinones which polymerize to give rise to melanin. This specialized metabolic pathway provides a possible approach to the specific chemotherapy of malignant tumours of pigment cells (malignant melanoma). Certain analogues of tyrosine are oxidized by tyrosinase generating reactive orthoquinones with cytotoxic potential. One such analogue, 4-hydroxyanisole, has been investigated as a possible specific melanocytotoxic precursor. The parent compound inhibits DNA synthesis but exhibits little general toxicity, while the tyrosinase oxidation products are highly toxic to cells. The mechanism of this toxicity may involve semiquinone radicals. Encouraging initial results have been obtained from clinical pilot studies using intra-arterial infusion of hydroxyanisole in patients with localized recurrences of malignant melanoma.

Small molecule-induced ablation and subsequent regeneration of larval zebrafish melanocytes

“…One class of phenolic compounds has been previously reported to cause cytotoxicity specific to melanocytes (melanocytotoxicity) in mammals (reviewed by Riley, 1985). These compounds feature a phenolic ring with a functional group at the para position, a structure that is similar to tyrosine, the initial substrate of tyrosinase during the biochemical synthesis of melanin.…”

“…Scale bar: in B, 500 m for A-D; in F, 400 m for E,F; in G, 400 m. (H) When larvae were incubated with 4-HA from 14 to 72 hpf, the same punctate melanocyte pattern of cell death appeared (white arrowheads). (I) Illustration of the mechanism of 4-HA melanocytotoxicity (see Riley, 1985). Note that tyrosinase converts the prodrug 4-HA to a cytotoxic o-quinone.…”

Tumour-cell-endothelial interactions: free radicals are mediators of melanoma-induced endothelial cell damage

“…Our results therefore tempt us to suggest that an oxygen radical-mediated destruction of the vascular EC lining may contribute to this extraordinary metastatic potential. Compared with other neoplasms melanoma cells generate significant amounts of reactive oxygen species through their unique metabolic pathway -the biosynthesis of melanin [4,6,15,30,33,44]. The possibility that toxic damage to cells could occur from the action of these oxidation products has been previously recognized and it has been shown that melanoma-associated free-radical damage can occur in vivo [2,4,15,33].…”

“…Compared with other neoplasms melanoma cells generate significant amounts of reactive oxygen species through their unique metabolic pathway -the biosynthesis of melanin [4,6,15,30,33,44]. The possibility that toxic damage to cells could occur from the action of these oxidation products has been previously recognized and it has been shown that melanoma-associated free-radical damage can occur in vivo [2,4,15,33]. Consequently the manipulation of free radicals in this tumour has been proposed as a therapeutic targeting strategy for melanoma and both inhibitors or accelerators of free radical chain reactions have indeed been shown to inhibit growth and metastasis formation of melanomas in vivo [13,30,33,41].…”

“…The possibility that toxic damage to cells could occur from the action of these oxidation products has been previously recognized and it has been shown that melanoma-associated free-radical damage can occur in vivo [2,4,15,33]. Consequently the manipulation of free radicals in this tumour has been proposed as a therapeutic targeting strategy for melanoma and both inhibitors or accelerators of free radical chain reactions have indeed been shown to inhibit growth and metastasis formation of melanomas in vivo [13,30,33,41]. In these studies an interference with melanoma cell metabolism and proliferation as well as immunomodulatory effects have been proposed as important mechanisms to inhibit growth and metastasis.…”