Interaction between chemicals and melanin : Role in the aetiology, diagnosis and treatment of melanoma

Abstract: The incidence of malignant melanoma has continually increased over the past decades and the prognosisis poor after dissemination of metastases. A conspicuous feature of melanocytes and melanoma cells is the production of melanin. Many chemicals are interacting with melanin and melanogenesis in various ways; certain substances, mainly polycyclic amines, are adsorbed on the preformed melanin, while 2-thiouracil and related thioureylenes are incorporated into nascent melanin as false precursors. The present investigations were focused on the interaction between chemicals and melanin as a possible basis for the induction of malignant melanoma as well as the diagnosis and treatment of the disease. The melanin affinity of 50 carcinogenic substances was demonstrated in vitro. The technique used is straightforward and gives basic data on substances that may be involved in melanoma induction. Inadditional autoradiographic studies, the disposition of two of these substances, known to induce melanoma in experimental animals (dimethylbenz(a)anthracene and benzo(a)pyrene), were studied in pigmented mice and the melanin affinic properties were confirmed also in vivo. It is known that enzymes capable of bioactivating chemicals are present in melanocytes, and together with the melanin affinity this combination is apparently an aetiological factor behind malignant melanoma.The thioureylenes, which are selectively incorporated into melanin during its synthesis, might be used for the diagnosis and treatment of malignant melanoma. By autoradiography it was found that 14C- and 125I-labelled 2-thiouracil are strongly retained in melanoma metastases in mice, which is encouraging for possible clinical imaging of the disease.For treatment of malignant melanoma, studies were focused on the development of boronated thioureylenes for neutron capture therapy. A simple technique for the covalent linking of decaborane to thioureylenes was utilised, and the results from studies of such adducts, e.g. decaborane-bis-5-(diethylamino)methyl-2-thiouracil, on the incorporation into melanin in vitro and in melanoma-bearing mice by neutron capture radiography clearly demonstrated specific uptake in melanin and melanoma, with concentrations in the tumours of the order suitable for possible therapy. By double-isotope radiography it was demonstrated that the melanin synthesis, the target for the incorporation, mainly takes place in melanoma cells out of the S-phase of the cell cycle.