Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts

Oct 28, 2008Neuro-oncology

Higher MGMT levels are linked to resistance to temozolomide in brain tumor models

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Abstract

Approximately 50% of glioblastoma multiforme tumors have O(6)-methylguanine-DNA methyltransferase (MGMT) silenced by promoter methylation.

Elevated MGMT protein levels or lack of MGMT promoter methylation is associated with resistance to temozolomide in some glioblastoma tumors.
Among four glioblastoma xenograft lines studied, three tumors with unmethylated MGMT exhibited elevated MGMT protein expression.
Only two of the unmethylated tumors (GBM43 and GBM44) showed resistance to temozolomide, while one (GBM14) remained sensitive.
Temozolomide treatment caused a significant increase in MGMT expression in resistant tumors GBM43 and GBM44, but not in GBM14.
A prolonged low-dose temozolomide regimen was less effective for GBM43 compared to a shorter high-dose regimen, whereas GBM14 benefited from prolonged dosing.

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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 O(6)-methylguanine-DNA methyltransferase (MGMT). Expression of MGMT is silenced by promoter methylation in approximately half of GBM tumors, 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. In this study, the relationship between MGMT protein expression and tumor response to TMZ was evaluated in four GBM xenograft lines that had been established from patient specimens and maintained by serial subcutaneous passaging in nude mice. Three MGMT unmethylated tumors displayed elevated basal MGMT protein expression, but only two of these were resistant to TMZ therapy (tumors GBM43 and GBM44), 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 nonmethylated tumors, and in these tumors, protracted dosing regimens may not be effective.

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Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts

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