Central nervous system (CNS) neoplasms which either arise in the brain or metastasize from an extraneural primary site, are highly malignant tumors refractory to all conventional therapy. Similarly, patients with neoplastic meningitis from virtually any tumor such as melanoma, sarcoma or breast carcinoma do poorly, with mean survival following leptomeningeal spread measured in months. The major impediment to successful treatment is de novo or acquired resistance to chemotherapy. Temozolomide is an imidazole tetrazinone similar to dacarbazine, requiring conversion to the active methylating agent MTIC. Methylating agents, including temozolomide, produce cytotoxicity due to a lethal cycle of mismatch repair following cellular misrecognition of O(6)-methylguanine. Recent preclinical and clinical studies have confirmed the activity of temoxolomide in the treatment of malignant glioma. Unfortunately, the majority of patients ultimately display resistance to temozolomide. The two primary mechanisms of resistance to temozolomide and other alkylating agents are the enzyme O(6)-alkylguanine-DNA alkyltransferase (AGT) and a deficiency in the DNA mismatch repair pathway. Of these two mechanisms, AGT plays a primary role in resistance to temozolomide by removing the alkyl groups from the O(6) position of guanine, in effect reversing the cytotoxic lesion of temozolomide. The sensitivity of tumor cell lines to temozolomide and the alkylating agent BCNU can be correlated with AGT levels. Regional therapy of CNS parenchymal or leptomeningeal neoplasms with intratumoral or intrathecal administration respectively, offers the potential benefit of enhancing delivery to the target neoplasm while minimizing delivery and hence toxicity to systemic organs. We have previously demonstrated the activity and modest toxicity of intrathecal temozolomide in the treatment of athymic rats bearing subarachnoid AGT-human malignant gliom xenografts. We have extended these results and demonstrated the activity and safety of temozolomide delivered by intracerebral microinfusion in the treatment of malignant gliomas intracranially in athymic nude rats.
The specific aims of this proposal are: 1. To define the role of intratumoral O(6)-BG and other AGT inhibitors in enhancing systemic or intratumoral temozolomide therapy of malignant glioma; 2. To define the role of intrathecal AGT inhibitors in enhancing system or intrathecal temozolomide therapy of neoplastic meningitis.
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| Goudar, Ranjit K; Shi, Qing; Hjelmeland, Mark D et al. (2005) Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther 4:101-12 |
