TY - JOUR T1 - A New <em>O</em><sup>6</sup>-Alkylguanine-DNA Alkyltransferase Inhibitor Associated with a Nitrosourea (Cystemustine) Validates a Strategy of Melanoma-Targeted Therapy in Murine B16 and Human-Resistant M4Beu Melanoma Xenograft Models JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 171 LP - 177 DO - 10.1124/jpet.108.137737 VL - 326 IS - 1 AU - Maryse Rapp AU - Jean C. Maurizis AU - Janine Papon AU - Pierre Labarre AU - Ting-Di Wu AU - Alain Croisy AU - Jean L. Guerquin-Kern AU - Jean C. Madelmont AU - Emmanuelle Mounetou Y1 - 2008/07/01 UR - http://jpet.aspetjournals.org/content/326/1/171.abstract N2 - Chemoresistance to O6-alkylating agents is a major barrier to successful treatment of melanoma. It is mainly due to a DNA repair suicide protein, O6-alkylguanine-DNA alkyltransferase (AGT). Although AGT inactivation is a powerful clinical strategy for restoring tumor chemosensitivity, it was limited by increased toxicity to nontumoral cells resulting from a lack of tumor selectivity. Achieving enhanced chemosensitization via AGT inhibition preferably in the tumor should protect normal tissue. To this end, we have developed a strategy to target AGT inhibitors. In this study, we tested a new potential melanoma-directed AGT inhibitor [2-amino-6-(4-iodobenzyloxy)-9-[4-(diethylamino) ethylcarbamoylbenzyl] purine; IBgBZ] designed as a conjugate of O6-(4-iododbenzyl)guanine (IBg) as the AGT inactivator and a N,N-diethylaminoethylenebenzamido (BZ) moiety as the carrier to the malignant melanocytes. IBgBZ demonstrated AGT inactivation ability and potentiation of O6-alkylating agents (cystemustine, a chloroethylnitrosourea) in M4Beu highly chemoresistant human melanoma cells both in vitro and in tumor models. The biodisposition study on mice bearing B16 melanoma, the standard model for the evaluation of melanoma-directed agents, and the secondary ion mass spectrometry imaging confirmed the concentration of IBgBZ in the tumor and in particular in the intracytoplasmic melanosomes. These results validate the potential of IBgBZ as a new, more tumor-selective, AGT inhibitor in a strategy of melanoma-targeted therapy. The American Society for Pharmacology and Experimental Therapeutics ER -