Evaluation of Melanin-Targeted Radiotherapy in Combination with Radiosensitizing Drugs for the Treatment of Melanoma

The incidence of malignant melanoma is rising faster than that of any other cancer in the United States.An [ 131 I]-labeled benzamide -[ 131 I]MIP-1145 -selectively targets melanin, reduces melanoma tumor burden and increases survival in preclinical models.Our purpose was to determine the potential of radiosensitizers to enhance the anti-tumor efficacy of [ 131 I]MIP-1145.Melanotic (A2058) and amelanotic (A375 and SK-N-BE(2c)) cells were treated with [ 131 I]MIP-1145 as a single agent or in combination with drugs with radiosenitizing potential.Cellular uptake of [ 131 I]MIP-1145 and toxicity were assessed in monolayer culture.The interaction between radiosensitizers and [ 131 I]MIP-1145 was evaluated by combination index analysis in monolayer cultures and by delayed growth of multicellular tumor spheroids.[ 131 I]MIP-1145 was taken up by and was toxic to melanotic cells but not amelanotic cells.Combination treatments comprising [ 131 I]MIP-1145 with the topoisomerase inhibitor topotecan or the PARP-1 inhibitor AG014699 resulted in synergistic clonogenic cell kill and enhanced delay of the growth of spheroids derived from melanotic melanoma cells.The proteasome inhibitor bortezomib had no synergistic cytotoxic effect with [ 131 I]MIP-1145 and failed to enhance the delay of spheroid growth.Following combination treatment of amelanotic cells, neither synergistic clonogenic cell kill nor enhanced growth delay of spheroids was observed.