SELECTIVE INCORPORATION OF THE PROTOTYPE MELANOMA SEEKER THIOUREA INTO NASCENT MELANIN - A CHEMICAL INSIGHT

The mechanism of selective incorporation of thiourea into melanotic me lanoma was investigated by model experiments in which the effect of th e compound was examined at various stages of melanogenesis in vitro. U p to 50% inhibition of dopachrome formation was observed in the tyrosi nase-dopa reaction in the presence of thiourea at a 2:1 molar ratio wi th respect to the substrate. Under these conditions, a major product w as formed which was isolated and identified as a 1:1 dopa-thiourea add uct (adduct I). Subsequent stages of the oxidation were characterized by the development of a yellow chromophore (lambda(max) 440- 460 nm), virtually identical to that obtained by separate oxidation of the addu ct I. A less remarkable effect of thiourea was observed on the oxidati ve polymerization of 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole -2-carboxylic acid (DHICA) which was apparent on spectrophotometric an d high pressure liquid chromatography (HPLC) analysis. Radiolabelling experiments with C-14-thiourea showed that the label was initially inc orporated into the adduct I, while in the subsequent stages of the oxi dation it was associated with pigmented materials which escaped direct analysis. Incorporation of labelled thiourea into dopa-melanins was f ound to be significantly higher than incorporation into synthetic pigm ents from indole precursors. These results provide a chemical basis fo r the interpretation of the selective accumulation of thiourea in thos e melanoma areas with high rates of melanin synthesis seen in autoradi ographic experiments.