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Initial testing of VNP40101M (Cloretazine) by the pediatric preclinical testing program
Stephen T Keir1, Christopher L Morton, Catherine Billups
1Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA.
Pediatric Blood & Cancer
|May 22, 2008
Summary
VNP40101M shows activity against pediatric brain tumors, but only when O-6-methylguanine-DNA methyltransferase (MGMT) is not present. Resistance to this novel alkylating agent occurs with even low levels of MGMT.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- VNP40101M is a novel alkylating agent with demonstrated antitumor activity.
- Pediatric brain tumors remain a significant challenge in oncology.
- O-6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein implicated in chemoresistance.
Purpose of the Study:
- To evaluate the in vivo efficacy of VNP40101M against a panel of pediatric brain tumor xenografts.
- To investigate the role of MGMT expression in mediating response or resistance to VNP40101M.
Main Methods:
- In vivo testing of VNP40101M (18 mg/kg/day for 5 days) in five pediatric brain tumor xenografts.
- Assessment of MGMT levels in xenografts using Western blot analysis.
Main Results:
- Only one xenograft, GBM2, which lacked detectable MGMT expression, showed an objective response to VNP40101M.
- Antitumor activity of VNP40101M was observed exclusively in MGMT-negative xenografts.
- Resistance to VNP40101M was observed even with low levels of MGMT expression.
Conclusions:
- MGMT expression is a critical determinant of response to VNP40101M in pediatric brain tumors.
- VNP40101M demonstrates potential as a therapeutic agent for pediatric brain tumors that lack MGMT expression.
- MGMT status should be considered when evaluating VNP40101M for clinical application in pediatric brain cancer.
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