laromustine and Glioblastoma

Cloretazine (VNP40101M) is a newly synthesized alkylating agent belonging to a novel class of alkylating agents called 1,2-bis(sulfonyl)hydrazines. Agents that belong to this class do not produce vinylating and chloroethylating species, and hence this class of alkylating agents is thought to have minimal systemic toxicity. Cloretazine produces two short-lived active species: 1,2-bis(methylsulfonyl)-1-(2-chloroethyl) hydrazine (a chloroethylating species) and a thiophilic carbamoylating methylisocyanate species. The chloroethylating species preferentially produces lesions at the O(6) position of guanine. The methylisocyanate species may inhibit O(6)-alkylguanine-DNA alkyltransferase, an important mechanism of resistance against alkylating agents. The purpose of this study was to determine the efficacy and tolerability of Cloretazine in patients with recurrent glioblastoma multiforme. The basis for the determination of efficacy was the proportion of patients alive without evidence of disease progression six months after initiation of treatment. Patients with recurrent glioblastoma multiforme received Cloretazine (300 mg/m(2)) intravenously every six weeks. Radiographic response, survival data, and toxicity were assessed. Thirty-two patients were enrolled. Median age was 56 years; 24 patients (75%) were men. At six months, two patients were alive and progression free, so the six-month progression-free survival (PFS) was 6%. The median PFS was 6.3 weeks. There were no objective radiographic responses. Twelve patients had stable disease for at least one cycle, but only two patients received more than three cycles. Nine patients experienced grade 4 thrombocytopenia and three patients experienced grade 4 neutropenia. Cloretazine administered every six weeks was relatively well tolerated, although this schedule has insignificant activity for patients with recurrent glioblastoma multiforme.

Topics: Adult; Aged; Brain Neoplasms; Disease Progression; Female; Glioblastoma; Humans; Hydrazines; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Sulfonamides; Survival Rate; Time Factors; Treatment Outcome

VNP40101M is a novel alkylating agent that yields two reactive compounds (a chloroethylating species and methylisocyanate) and has demonstrated activity against a wide spectrum of tumor xenografts. VNP40101M was tested against an in vivo panel of five pediatric brain tumor xenografts at a dose of 18 mg/kg/day administered for 5 days. O-6-methylguanine-DNA methyltransferase (MGMT) levels of xenografts were assessed by Western blot analysis. Only one xenograft (GBM2), which lacked detectable MGMT expression, demonstrated an objective response to VNP40101M. VNP4010M antitumor activity was observed only in the absence of MGMT expression, with resistance to VNP4010M seen even with low MGMT expression.

Topics: Animals; Antineoplastic Agents, Alkylating; Brain Neoplasms; Drug Evaluation, Preclinical; Female; Glioblastoma; Glioma; Hydrazines; Mice; Mice, Inbred Strains; O(6)-Methylguanine-DNA Methyltransferase; Sulfonamides; Transplantation, Heterologous; Treatment Outcome