title: 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.
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, 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 484, BP 184, F-63005 Clermont-Ferrand Cedex, France.
authors.forename: Maryse
authors.initials: M
authors.lastname: Rapp
authors.forename: Jean C
authors.initials: JC
authors.lastname: Maurizis
authors.forename: Janine
authors.initials: J
authors.lastname: Papon
authors.forename: Pierre
authors.initials: P
authors.lastname: Labarre
authors.forename: Ting-Di
authors.initials: TD
authors.lastname: Wu
authors.forename: Alain
authors.initials: A
authors.lastname: Croisy
authors.forename: Jean L
authors.initials: JL
authors.lastname: Guerquin-Kern
authors.forename: Jean C
authors.initials: JC
authors.lastname: Madelmont
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Mounetou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology*; D051379:Mice; D009607:Nitrosourea Compounds / Q000008:administration & dosage*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015203:Reproducibility of Results; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D004791:Enzyme Inhibitors; D009607:Nitrosourea Compounds; C051263:N'-(2-chloroethyl)-N-(2-(methylsulfonyl)ethyl)-N'-nitrosourea; D019853:O(6)-Methylguanine-DNA Methyltransferase