Cystemustine

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.

In this study, we have assessed the efficacy of a nitrosourea, cystemustine, in treating patients with recurrent high grade glioma with overall survival analysis as primary end-point. Forty-eight patients with recurrent high grade glioma (24 glioblastomas, 17 astrocytomas and 5 oligodendrogliomas) were treated every 2 weeks with 60 mg/m2 cystemustine by a 15 min-infusion. The median number of treatment cycles was 4 (range 1-17). The median overall survival was 8.3 months (range 1-97) and the 6- and 12-month overall survival rates were 55.3% (95% CI, 41.3-68.6%) and 29.8% (95% CI, 18.6-44.0%), respectively. The objective response rate was 18.8% (95% CI, 7.7-29.9%), and 54.2% of patients had stable disease (95% CI, 40.1-68.3%). Multivariate analysis showed that WHO performance status, histology and response to cystemustine were significant prognostic factors for survival of patients with recurrent glioma. In conclusion, cystemustine has encouraging activity for patients with recurrent high grade glioma.