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Melanin pigment displays strong photo- and radioprotective properties, suggesting that inhibition melanogenesis could increase sensitivity of melanoma to ionizing radiation. We tested this concept in human melanoma cells cultured in either Ham's F10 medium to maintain amelanotic phenotype or DMEM to induce/stimulate melanin production, respectively; N-phenylthiourea (PTU) and d-penicillamine were used as an inhibitor of melanogenesis. Melanogenic activity was evaluated by visual inspection (color of cell pellets) or by measurement of tyrosinase (dopa oxidase) activity assay. Amelanotic cells or cells with various melanin content were exposed to gamma radiation and tested for viability and colony forming capability. Gamma radiation at doses of 2–15 Gy inhibited cell viability and colony forming efficiency in dose- and time-dependent manner, but pigmented melanoma cells were significantly more resistant to gamma radiation than nonpigmented cells (p < 0.05–0.001). Both PTU and d-penicillamine inhibited strongly tyrosinase activity and melanin production in melanoma cells (p < 0.05–0.001). Furthermore, inhibition of melanogenesis by PTU or d-penicillamine resulted in enhancement of melanoma cells sensitivity to killing by gamma rays. In conclusion, the results of these cell culture experiments give support to a clinical trial of pharmacologically induced decrease in melanin synthesis to enhance the efficacy of radiotherapy in advanced melanomas. © 2008 Wiley-Liss, Inc.