New Drugs for Cancer Temozolomide by cot14472


                      New Drugs for Cancer: Temozolomide
      Amid the excitement about new strategies for cancer drug        the Massachusetts General Hospital will present impressive
discovery, particularly for molecular targeted approaches,            data on responses to another camptothecin, topotecan, in
steady progress continues in the discovery of new potential           patients with methotrexate-relapsed or refractory CNS lym-
for more traditional cytotoxic drugs. Such is the case for            phoma. This agent is now the subject of a new phase II trial at
temozolomide (TMZ), a close analog of dimethyltriazinoimi-            the Dana-Farber/Harvard Cancer Center.
dazole carboxamide (DTIC). Both drugs belong to the gener-                Comprehensive phase II testing of candidate agents in a
al class of methylating agents, and share the advantages of           broad array of tumors is still the only way to identify activity
lipid solubility, modest toxicity, and an interesting profile of      of new drugs in “orphan” diseases. Perhaps when molecular
activity against melanoma, lymphomas, and primary brain               arrays can tell us how to match drugs with tumors, the process

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tumors. However, TMZ has the added advantage of sponta-               will become less empirical. For example, there is a clear ratio-
neous chemical conversion to the active methylating metabo-           nale for testing STI-571 in gliomas [4]. This drug is an
lite, the methyldizaonium ion. Synthesized and initially tested       inhibitor of the bcr-abl kinase activated in chronic myelocytic
in the United Kingdom, TMZ has wound a tortuous path                  leukemia, and is highly active in that disease. It is also an
through clinical trials in the United States, recently achieving      effective inhibitor of a related kinase, the platelet derived
approval for relapsed anaplastic astrocytoma on the basis of          growth factor receptor, which is overexpressed in many
superior results, compared to procarbazine, in randomized             gliomas. While this kind of targeted therapy has great appeal,
phase II trials. In the accompanying article, the first of a series   there is no substitute for doing the comprehensive trials of
on new drugs in this journal, Agarwala and Kirkwood provide           the more traditional cytotoxics, as painful and tedious as that
a careful look at this potentially important drug [1], which          may be. The results may surprise us.
clearly deserves further evaluation in combination with other
drugs and with radiotherapy. The molecular basis for its activ-       REFERENCES
ity in brain tumors is not understood, although the response
                                                                        1 Agarwala SS, Kirkwood JM. Temozolomide, a novel alkylat-
rates seem high enough to warrant correlative studies with
                                                                          ing agent with activity in the central nervous system, may
molecular profiles of the important drug resistance and tumor             improve the treatment of advanced metastatic melanoma. The
biology factors.                                                          Oncologist, 2000;5:144-151.
      While we all hope for major breakthroughs from targeted
drug development, we should not ignore the important work               2 Friedman HS, Petros WP, Friedman AH et al. Irinotecan ther-
                                                                          apy in adults with recurrent or progressive malignant glioma.
on traditional cytotoxics ongoing in trials sponsored by the
                                                                          J Clin Oncol 1999;17:1516-1525.
National Cancer Institute (NCI). Friedman and colleagues,
from the NCI-sponsored New Approaches to Tumor Therapy                  3 Personal communication. Proc Am Soc Clin Oncol, 2000;19
consortium, have recently described impressive activity of                (in press).
irinotecan as second-line therapy in glioblastomas [2]. At the          4 Druker BJ, Lydon NB. Lessons learned from the development
upcoming year 2000 meeting of the American Society of                     of an Abl tyrosine kinase inhibitor for chronic myelogenous
Clinical Oncology meeting, Batchelor and associates [3] at                leukemia. J Clin Invest 2000;105:3-7.

                                                                      Bruce A. Chabner, MD
                                                                      Chief Medical Officer
                                                                      Dana-Farber/Partners Cancer Care
                                                                      Massachusetts General Hospital

The Oncologist 2000;5:xi
                         New Drugs for Cancer: Temozolomide
                                  Bruce A. Chabner
                                Oncologist 2000;5;0-1
                           DOI: 10.1634/theoncologist.5-2-0
                      This information is current as of July 9, 2010

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