Colvin Om

DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma

PURPOSE We evaluated the response to Temodal (Schering-Plough Research Institute, Kenilworth, NJ) of patients with newly diagnosed malignant glioma, as well as the predictive value of quantifying tumor DNA mismatch repair activity and O6-alkylguanine-DNA alkyltransferase (AGT). PATIENTS AND METHODS Thirty-three patients with newly diagnosed glioblastoma multiforme (GBM) and five patients with newly diagnosed anaplastic astrocytoma (AA) were treated with Temodal at a starting dose of 200 mg/m2 daily for 5 consecutive days with repeat dosing every 28 days after the first daily dose. Immunochemistry for the detection of the human DNA mismatch repair proteins MSH2 and MLH1 and the DNA repair protein AGT was performed with monoclonal antibodies and characterized with respect to percent positive staining. RESULTS Of the 33 patients with GBM, complete responses (CRs) occurred in three patients, partial responses (PRs) occurred in 14 patients, stable disease (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, and 12 PDs. Eight tumors showed 60% or less cells that stained with antibodies to MSH2 and/or MLH1, with 3 PRs, 3 SDs, and 2 PDs. Eleven tumors showed 20% 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 diagnosed GBM and AA and warrants continued evaluation of this agent. Furthermore, pretherapy analysis of tumor DNA mismatch repair and, particularly, AGT protein expression may identify patients in whom tumors are resistant to Temodal.

Phase II treatment of medulloblastoma and pineoblastoma with melphalan: clinical therapy based on experimental models of human medulloblastoma.

We conducted a phase II study of intravenous (IV) melphalan in the treatment of children with recurrent medulloblastoma and in the initial treatment of children with poor-prognosis medulloblastoma and pineoblastoma. There was one complete response (CR) and two partial responses (PRs) among the 12 children with recurrent medulloblastoma. There were three PRs in the four patients initially treated with melphalan for poor-prognosis medulloblastoma or pineoblastoma. Toxicity was limited to severe myelosuppression with marked neutropenia and thrombocytopenia. These results support our laboratory studies demonstrating melphalan activity in human medulloblastoma, suggest that similar activity may be demonstrated against pineoblastoma, and support further trials with this agent (administered prior to radiotherapy) in the treatment of patients with newly diagnosed poor-prognosis medulloblastoma.

Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats

The current study was designed to evaluate the toxicity and activity of Spartaject™ Busulfan, a microcrystalline preparation of busulfan, following its intrathecal administration into a nude rat model of human neoplastic meningitis. Animals were treated through permanent indwelling subarachnoid catheters. Human glioma D-456 MG growing in the subarachnoid space was treated with 8.1 µmol of intrathecal Spartaject™ Busulfan. Single-dose therapy was also subsequently compared with 4 doses of 8.1 and 2.0 µmol busulfan, respectively, against D-456 MG neoplastic meningitis. Additional experiments evaluated a saline control versus 8.1 µmol×1, 6.2 µmol×4 and 4.1 µmol×4, respectively, against D-456 MG. A single dose of 8.1 µmol of intrathecal Spartaject™ Busulfan resulted in an increase in median survival of 61.7% compared with the saline control. In experiment 2, all busulfan treatments showed increases in median survival of 142.8% (8.1 µmol×1), 52.3% (2.0 µmol×4), and 23% (8.1 µmol×4) (p<0.001 for all groups) compared with the saline control. These results suggest that a narrow therapeutic dose range for both toxicity and activity has been defined for intrathecal busulfan in the treatment of human neoplastic meningitis in athymic nude rats. Although busulfan has only limited activity against solid tumors, the high doses achievable in the CSF following intrathecal administration coupled with the steep dose–response relationships of alkylating agents, provide rationale for further evaluation of this agent.