QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.137737v1 326/1/171    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rapp, M. Articles by Mounetou, E. Search for Related Content PubMed PubMed Citation Articles by Rapp, M. Articles by Mounetou, E.

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 484, Clermont-Ferrand Cedex, France (M.R., J.C.Mau., J.P., P.L., J.C.Mad., E.M.); Université Clermont-Ferrand 1, Clermont-Ferrand Cedex, France (E.M.); Institut Curie, Laboratoire de Microscopie Ionique, Orsay, France (T.-D.W., A.C., J.L.G.-K.); and INSERM Unité 759, Orsay, France (T.-D.W., A.C., J.L.G.-K.)

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.

Address correspondence to: Dr. Emmanuelle Mounetou, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 484, BP 184, F-63005 Clermont-Ferrand Cedex, France. E-mail: mounetou{at}inserm484.u-clermont.fr