Initial testing of VNP40101M (Cloretazine) by the pediatric preclinical testing program.
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.
Keir
Stephen T
ST
Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA.
Morton
Christopher L
CL
Billups
Catherine
C
Smith
Malcolm A
MA
Houghton
Peter J
PJ
Gururangan
Sridharan
S
D000818:Animals; D018906:Antineoplastic Agents, Alkylating; D001932:Brain Neoplasms / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005909:Glioblastoma; D005910:Glioma; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D006834:Hydrazines; D013449:Sulfonamides; C483604:laromustine; D019853:O(6)-Methylguanine-DNA Methyltransferase