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Editorial |
Chief Medical Officer, Dana-Farber/Partners Cancer Care, Massachusetts General Hospital
| See also page 144
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Amid the excitement about new strategies for cancer drug discovery, particularly for molecular targeted approaches, steady progress continues in the discovery of new potential for more traditional cytotoxic drugs. Such is the case for temozolomide (TMZ), a close analog of dimethyltriazinoimidazole carboxamide (DTIC). Both drugs belong to the general class of methylating agents, and share the advantages of lipid solubility, modest toxicity, and an interesting profile of activity against melanoma, lymphomas, and primary brain tumors. However, TMZ has the added advantage of spontaneous chemical conversion to the active methylating metabolite, the methyldizaonium ion. Synthesized and initially tested in the United Kingdom, TMZ has wound a tortuous path through clinical trials in the United States, recently achieving approval for relapsed anaplastic astrocytoma on the basis of superior results, compared to procarbazine, in randomized phase II trials. In the accompanying article, the first of a series on new drugs in this journal, Agarwala and Kirkwood provide a careful look at this potentially important drug [1], which clearly deserves further evaluation in combination with other drugs and with radiotherapy. The molecular basis for its activity in brain tumors is not understood, although the response rates seem high enough to warrant correlative studies with molecular profiles of the important drug resistance and tumor biology factors.
While we all hope for major breakthroughs from targeted drug development, we should not ignore the important work on traditional cytotoxics ongoing in trials sponsored by the National Cancer Institute (NCI). Friedman and colleagues, from the NCI-sponsored New Approaches to Tumor Therapy consortium, have recently described impressive activity of irinotecan as second-line therapy in glioblastomas [2]. At the upcoming year 2000 meeting of the American Society of Clinical Oncology meeting, Batchelor and associates [3] at the Massachusetts General Hospital will present impressive data on responses to another camptothecin, topotecan, in patients with methotrexate-relapsed or refractory CNS lymphoma. This agent is now the subject of a new phase II trial at the Dana-Farber/Harvard Cancer Center.
Comprehensive phase II testing of candidate agents in a broad array of tumors is still the only way to identify activity of new drugs in "orphan" diseases. Perhaps when molecular arrays can tell us how to match drugs with tumors, the process will become less empirical. For example, there is a clear rationale for testing STI-571 in gliomas [4]. This drug is an inhibitor of the bcr-abl kinase activated in chronic myelocytic leukemia, and is highly active in that disease. It is also an effective inhibitor of a related kinase, the platelet derived growth factor receptor, which is overexpressed in many gliomas. While this kind of targeted therapy has great appeal, there is no substitute for doing the comprehensive trials of the more traditional cytotoxics, as painful and tedious as that may be. The results may surprise us.
References
Related articles in The Oncologist:
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