title: Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice.
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.
authors.affiliation: Center for Neurosciences, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Badruddoja
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Ivan
authors.initials: I
authors.lastname: King
authors.forename: Joseph
authors.initials: J
authors.lastname: Zeidner
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Muhlbaier
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011355:Prodrugs / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D006834:Hydrazines; D011355:Prodrugs; D013449:Sulfonamides; C483604:laromustine