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

Center for Neurosciences, University of Arizona, Tucson, AZ 85721 (M.A.B.); Departments of Surgery (S.T.K., J.Z., D.D.B., H.S.F.), Medicine (J.J.V.), Pathology (D.D.B., H.S.F.), Pediatrics (H.S.F.), and Biostatistics/Bioinformatics (L.H.M.), Duke University Medical Center, Durham, NC 27710; and Vion Pharmaceuticals, New Haven, CT 06511 (I.K., L.H.M.); USA

Address correspondence to Henry S. Friedman, Preston Robert Tisch Brain Tumor Center at Duke, Room 047 Baker House, South Hospital, Trent Drive, Duke University Medical Center, Durham, NC 27710, USA (fried003{at}mc.duke.edu).

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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