DNA mismatch repair and O-6-alkylguanine-DNA alkyltransferase analysis andresponse to temodal in newly diagnosed malignant glioma

Purpose: We evaluated the response to Temodal (Schering-Plough Research Ins titute, Kenilwarth, NJ) of patients with newly diagnosed malignant glioma, as well as the predictive value of quantifying tumor DNA mismatch repair ac tivity and O-6-alkylguanine-DNA alkyltransferase (AGT). Patients and Methods: Thirty-three patients with newly diagnosed glioblasto ma multiforme (GBM) and five patients with newly diagnosed anaplastic astro cytoma (AA) were treated with Temodal at a starting dose of 200 mg/m(2) dai ly for 5 consecutive days with repeat dosing every 28 days after the first daily dose. Immunochemistry for the detection of the human DNA mismatch rep air proteins MSH2 and MLH1 and the DNA repair protein AGT was performed wit h monoclonal antibodies and characterized with respect to percent positive staining. Results: Of the 33 patients with OEM, complete responses (CRs) occurred in three patients, partial responses (PRs) occurred in 14 patients, stable dis ease (SD) was seen in four patients, and 12 patients developed progressive disease (PD). Toxicity included infrequent grades 3 and 4 myelosuppression, constipation, nausea, and headache. Thirty tumors showed greater than 60% cells that stained for MSH2 and MLH1, with three CRs, 12 PRs, three SDs, an d 12 PDs. Eight tumors showed 60% or less cells that stained with antibodie s to MSH2 and/or MLH1, with 3 PRs, 3 SDs, and 2 PDs. Eleven tumors showed 2 0% or greater cells that stained with an antibody to AGT, with 1 PR, 2 SDs, and 8 PDs. Twenty-five tumors showed less than 20% cells that stained for AGT, with 3 CRs, 12 PRs, 4 SDs, and 6 PDs. Conclusion: These results suggest that Temodal has activity against newly d iagnosed GEM and AA and warrants continued evaluation of this agent. Furthe rmore, pretherapy analysis of tumor DNA mismatch repair and, particularly, AGT protein expression may identify patients in whom tumors are resistant t o Temodal. (C) 1998 by American Society of Clinical Oncology.