Abstract
Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) which have a combined incidence of 5–8/100,000 population, represent the most common primary central nervous system tumors. The treatment outcomes even with aggressive approach including surgery, radiaton therapy and chemotherapy are dismal with median reported survival is less than 1 year. Temozolomide is a new drug which has shown promise in treating malignant gliomas and other difficult-to-treat tumors. This drug is a per os (p.o) imidazotetrazine second-generation alkylating agent which represents the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. The efficacy of temozolomide was tested in vitro studies and has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma (HGG). In addition, in clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Moreover, preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. At the present time temozolomide is approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. Temozolomide’s characteristics which make it a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types are its predictable bioavailability and minimal toxicity. An overview of the mechanism of action of temozolomide and a summary of results from more important randomized controlled clinical trials in high grade gliomas are presented here.
Highlights
Temozolomide (TMZ; TemodarTM [TemodalTM in the United Kingdom and Europe], ScheringPlough Corporation; Kenilworth, NJ) is a novel oral alkylating agent that has shown efficacy in the treatment of a variety of solid tumors, including primary malignant brain tumors [1,2,3,4,5,6,7]
We considered all meta-analysis or randomized controlled trials providing information about the effectiveness of temozolomide on treatment of malignant gliomas, its adverse profile effects, its dosage and administration, and future directions of ongoing research as eligible
Temozolomide is an effective p.o. administered anticancer agent that demonstrates a broad spectrum of activity in various solid tumors and distribution to all tissues, including the brain
Summary
Temozolomide (TMZ; TemodarTM [TemodalTM in the United Kingdom and Europe], ScheringPlough Corporation; Kenilworth, NJ) is a novel oral alkylating agent that has shown efficacy in the treatment of a variety of solid tumors, including primary malignant brain tumors [1,2,3,4,5,6,7]. TMZ has certain advantages over many existing alkylating agents because of its unique chemical structure and pharmacokinetic properties [8,9]. Because of its small molecular weight, TMZ efficiently crosses the blood brain barrier and is effective against primary brain tumors [10]. TMZ can be administered orally without dietary restrictions, and essentially 100% of the orally administered dose enters the blood flow. TMZ is associated with a low incidence of severe adverse events. Unlike nitrosoureas and other alkylating agents that chemically cross-link the DNA and are associated with severe, doselimiting, cumulative hematologic toxicity, TMZ is associated with generally mild, noncumulative myelosuppression
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