Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice

¹ Center for Neurosciences, University of Arizona, Tucson, AZ 85721, USA
² Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
³ Vion Pharmaceuticals, New Haven, CT 06511, USA
⁴ Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
⁵ Department of Biostatistics/Bioinformatics, Duke University Medical Center, Durham, NC 27710, and Vion Pharmaceuticals, New Haven, CT 06511, USA
⁶ Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC 27710, USA
⁷ Departments of Surgery, Pathology, and Pediatrics, Duke University Medical Center, Durham, NC 27710, USA

^* To whom correspondence should be addressed. E-mail: fried003{at}mc.duke.edu.

	Abstract

VNP40101M, or 1,2-bis(methylsulfonyl)-1-(2-choloroethyl)-2-(methylamino)carbonylhydrazine (Cloretazine), is a bifunctional prodrug that belongs to a class of DNA-modifying agents--the sulfonylhydrazines--that has been synthesized and been shown to have activity against a wide spectrum of xenografts. The current study was designed to assess the activity of VNP40101M administered at a dose of 18 mg/kg daily for five days against a panel of human adult and pediatric CNS tumors growing subcutaneously or intracranially in athymic nude mice. The results demonstrated statistically significant (p < 0.05) growth delays of 15.0, 8.3, 51.0, 60+, 60+, and 60+ days in subcutaneous xenografts derived from childhood glioblastoma multiforme (D-456 MG), childhood ependymoma (D-528 EP and D-612 EP), childhood medulloblastoma (D-425 MED), and adult malignant glioma (D-245 MG and D-54 MG), respectively, with corresponding tumor regressions in 10 of 10, 4 of 10, 8 of 10, 9 of 10, 9 of 10, and 10 of 10 treated mice, respectively. Delayed toxicity was seen more than 60 days after treatment, with 23 deaths in 100 treated animals, despite a median weight loss of only 0.06%. In mice bearing intracranial D-245 MG xenografts, treatment with VNP40101M at a dose of 18 mg/kg daily for five days produced a 50% increase in median survival compared with controls. Additional experiments conducted against subcutaneous D-245 MG xenografts by using reduced doses of 13.5 or 9.0 mg/kg daily for five days demonstrated tumor growth delays of 82.2 and 53.5 days, with corresponding tumor regressions in 8 of 9 and 9 of 10 treated mice, respectively (all values, p < 0.001), with one toxic death. These findings suggest that VNP40101M is active in the treatment of a wide range of human central nervous system tumors and warrants translation to the clinic.

Key Words: alkyltransferase, Cloretazine, glioblastoma multiforme, O⁶-alkylguanine-DNA nitrosoureas, xenografts

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