© Copyright 2008 by the Society for Neuro-Oncology
Received July 3, 2008
Basic and Translational Investigations
|
Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts
Gaspar J. Kitange 1,
Brett L. Carlson 1,
Mark A. Schroeder 1,
Patrick T. Grogan 1,
Jeff D. Lamont 2,
Paul A. Decker 3,
Wenting Wu 3,
C. David James 4,
Jann N. Sarkaria 1*
1 Department of Radiation Oncology, Mayo Clinic, Rochester, MN
2 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN
3 Department of Biostatistics, Mayo Clinic, Rochester, MN
4 Department of Neurosurgery, University of California San Francisco, CA
* To whom correspondence should be addressed. E-mail: sarkaria.jann{at}mayo.edu.
 |
Abstract |
|---|
Temozolomide (TMZ)-based therapy is the standard of care for patients with glioblastoma multiforme (GBM), and resistance to this drug in GBM is modulated by the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT). Expression of MGMT is silenced by promoter methylation in approximately half of GBM and clinical studies have shown that elevated MGMT protein levels or lack of MGMT promoter methylation is associated with TMZ resistance in some, but not all GBM tumors. The relationship between MGMT protein expression and tumor response to TMZ was evaluated in 4 GBM xenograft lines that had been established from patient specimens and maintained by serial subcutaneous passaging in nude mice. Three MGMT unmethylated tumors all displayed elevated basal MGMT protein expression, but only 2 of these were resistant to TMZ therapy (GBM43 and 44), while the other (GBM14) displayed a level of TMZ sensitivity that was similar in extent to that seen in a single MGMT hypermethylated line (GBM12). In tissue culture and animal studies, TMZ treatment resulted in robust and prolonged induction of MGMT expression in the resistant GBM43 and GBM44 xenograft lines, while MGMT induction was blunted and abbreviated in GBM14. Consistent with a functional significance of MGMT induction, treatment of GBM43 with a protracted low dose TMZ regimen was significantly less effective than a shorter high-dose regimen, while survival for GBM14 was improved with the protracted dosing regimen. In conclusion, MGMT expression is dynamically regulated in some MGMT non-methylated tumors, and in these tumors, protracted dosing regimens may not be effective.
Key Words:
Glioblastoma xenografts, MGMT induction, temozolomide, promoter methylation
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
