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

Publication ,  Journal Article
Badruddoja, MA; Keir, ST; King, I; Zeidner, J; Vredenburgh, JJ; Muhlbaier, LH; Bigner, DD; Friedman, HS
Published in: Neuro Oncol
July 2007

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.

Duke Scholars

Published In

Neuro Oncol

DOI

ISSN

1522-8517

Publication Date

July 2007

Volume

9

Issue

3

Start / End Page

240 / 244

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Sulfonamides
  • Prodrugs
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice
  • Male
  • Hydrazines
 

Citation

APA
Chicago
ICMJE
MLA
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Badruddoja, M. A., Keir, S. T., King, I., Zeidner, J., Vredenburgh, J. J., Muhlbaier, L. H., … Friedman, H. S. (2007). Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice. Neuro Oncol, 9(3), 240–244. https://doi.org/10.1215/15228517-2007-011
Badruddoja, Michael A., Stephen T. Keir, Ivan King, Joseph Zeidner, James J. Vredenburgh, Lawrence H. Muhlbaier, Darell D. Bigner, and Henry S. Friedman. “Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice.Neuro Oncol 9, no. 3 (July 2007): 240–44. https://doi.org/10.1215/15228517-2007-011.
Badruddoja MA, Keir ST, King I, Zeidner J, Vredenburgh JJ, Muhlbaier LH, et al. Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice. Neuro Oncol. 2007 Jul;9(3):240–4.
Badruddoja, Michael A., et al. “Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice.Neuro Oncol, vol. 9, no. 3, July 2007, pp. 240–44. Pubmed, doi:10.1215/15228517-2007-011.
Badruddoja MA, Keir ST, King I, Zeidner J, Vredenburgh JJ, Muhlbaier LH, Bigner DD, Friedman HS. Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice. Neuro Oncol. 2007 Jul;9(3):240–244.
Journal cover image

Published In

Neuro Oncol

DOI

ISSN

1522-8517

Publication Date

July 2007

Volume

9

Issue

3

Start / End Page

240 / 244

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Sulfonamides
  • Prodrugs
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice
  • Male
  • Hydrazines