A new O6-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

The Journal of Pharmacology and Experimental Therapeutics
Maryse RappE Mounetou

Abstract

Chemoresistance to O(6)-alkylating agents is a major barrier to successful treatment of melanoma. It is mainly due to a DNA repair suicide protein, O(6)-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 O(6)-(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 O(6)-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, ...Continue Reading

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Citations

Dec 29, 2010·Analytical and Bioanalytical Chemistry·Maria Careri, Alessandro Mangia
Apr 30, 2008·Nutrition and Cancer·Xavier DurandoPhilippe Chollet
Jun 6, 2014·ACS Medicinal Chemistry Letters·Radhia El AissiEmmanuel Moreau
May 3, 2011·European Journal of Medicinal Chemistry·Pierre DaumarMarie-Josèphe Galmier
Nov 5, 2014·Organic & Biomolecular Chemistry·Mathieu AndréEmmanuelle Mounetou
Aug 21, 2013·Organic & Biomolecular Chemistry·Mathieu AndréEmmanuelle Mounetou

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