Ivette F. Emery, Chiara Battelli, Li Cai and Daniel M. Hayes
Background: The status of DNA repair systems impacts the sensitivity of tumors to chemotherapeutics. The anti-neoplastic activity of temozolomide, an alkylating agent, is affected by the enzyme O6-Methylguanine-DNA methyltransferase (MGMT), and by the mismatch repair system (MMR). Lack of MGMT makes a tumor susceptible to temozolomide provided MMR is functional. A non-functional MMR renders the tumor resistant to alkylating agents. We assayed MGMT and MMR in order to estimate the proportion of patients affected by NSCLC who may derive benefit from temozolomide, an alkylating agent not currently used in lung cancer. Method: MGMT and MMR were assayed by promoter methylation testing and by microsatellite instability testing, respectively, on 96 paraffin-embedded NSCLC samples. Methylation testing, which detects gene silencing, was conducted by methylation-specific PCR of the MGMT promoter. MSI testing, which detects a non-functional MMR, was conducted by multiplex PCR of six microsatellite regions. Results: Ninety three samples yielded interpretable results. Eighty of those (83%) had no defects detected in either MGMT or MMR. Nine samples (10%) had methylation of the MGMT promoter and four samples (4%) had microsatellite instability. The defects were not overlapping. Conclusions: Our results indicate that approximately 10% of NSCLC may be susceptible to alkylating agents, and that in the remaining population, only 4% will be resistant to these agents. Our understanding of the molecular characteristics of NSCLC suggests that alkylating agents, such as temozolomide, alone or in combination with MGMT inhibitors, may be viable option to treat selected NSCLC patients.
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