Recent elucidation of regulatory mechanisms of eu- and pheomelanogenesis has led us towards an exciting new era of melanogenesis control. I will chiefly address our progress on inhibitory control of melanogenesis from the macromolecular level to human skin colour. In the past, the exploration and search for skin depigmenting agents has been focussed on and initiated from substances which can suppress isolated tyrosinase in vitro. Now, as I have classified below, many new melanogenic inhibitors have been discovered which, in spite of their non-suppressive effect on isolated naked tyrosinase, suppress melanin formation in the living pigment cell in vitro as well as in the natural world. I will also discuss a recently found unique disorder: unilateral suppression of mixed melanogenesis.

Human melanoma regression by single thermal neutron capture therapy (NCT) using melanoma-seeking 10B compounds has been achieved. Since 1972, the aim of my team has been to synthesize tumor-seeking 10B-compounds possessing selective affinity for specific metabolic activity of the target cancer cells. Once the melanoma takes up these 10B compounds, thermal neutrons, which cause insignificant cell damage, are easily absorbed by nonradioactive 10B, inducing the 10B(n, alpha)7Li reaction and releasing the high LET particles to 14 mu melanoma cell diameter, destroying the tumor without damaging surrounding tissue. Radiobiological and preclinical studies culminated in the first successful human NCT treatment, with no recurrence of the treated melanoma since July, 1987.

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As pigment cells undergo melanoma genesis, accentuated melanogenesis concurrently occurs in principle. Subsequent to the understanding of intrinsic factors controlling both processes, we found our selective melanoma neutron capture therapy (NCT) using 10B-dopa (melanin substrate) analogue, 10B1-p-boronophenylalanine (10B1-BPA), followed by 10B(n, alpha)7Li reaction, induced by essentially harmless thermal neutrons, which releases energy of 2.33 MeV to 14 mu, the diameter of melanoma cells. In vitro/in vivo radiobiological analysis revealed the highly enhanced melanoma killing effect of 10B1-BPA. Chemical and prompt gamma ray spectrometry assays of 10B accumulated within melanoma cells after 10B1-BPA administration in vitro and in vivo show high affinity, e.g., 10B melanoma/blood ratio of 11.5. After successfully eradicating melanoma transplanted into hamsters with NCT, we advanced to preclinical studies using spontaneously occurring melanoma in Duroc pig skin. We cured three melanoma cases, 4.6 to 12 cm in diameter, by single neutron capture treatment. Complete disappearance of melanoma was obtained without substantial side effects. Acute and subacute toxicity as well as pharmacodynamics of 10B1-BPA have been studied in relation to therapeutic dosage requirements. Clinical radiation dosimetry using human phantom has been carried out. Further preclinical studies using human melanoma transplanted into nude mouse have been a useful model for obtaining optimal results for each melanoma type. We recently treated the first human melanoma patient with our NCT, using essentially the method for Duroc pig melanoma, and obtained similar regression time course leading to cure.

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Omission of L-glutamine (GIn) from the culture medium decreases tyrosinase activity and increases y-GTP activity in cultured melanotic B-16 melanoma cells; inclusion of this amino acid in the medium shows the reverse effects, Its absence, however, decreases the y-GTP activity in non-pigmented cells like HeLa cells, fibroblasts and amelanotic melanoma cells and its presence induces a dose dependent increase in this enzyme activity in these cells. The decrease of y-GTP activity in the melanotic melanoma cells by GIn is attributed to increased production of dopa and its derivatives by these cells, as evidenced by our results. Our data also indicate the inhibitory effects of dopa and several other dopa derivatives known to be produced by the melanoma cells on isolated bovine kidney y-GTP.