Temozolomide and treatment of malignant glioma

Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) occu r more frequently than other types of primary central nervous system tumors , having a combined incidence of 5-8/100,000 population. Even with aggressi ve treatment using surgery, radiation, and chemotherapy, median reported su rvival is less than 1 year. Temozolomide, a new drug, has shown promise in treating malignant gliomas a nd other difficult-to-treat tumors. Temozolomide, a p.o. imidazotetrazine s econd-generation alkylating agent, is the leading compound in a new class o f chemotherapeutic agents that enter the cerebrospinal fluid and do not req uire hepatic metabolism for activation. In vitro, temozolomide has demonstr ated schedule-dependent antitumor activity against highly resistant maligna ncies, including high-grade glioma, In clinical studies, temozolomide consi stently demonstrates reproducible linear pharmacokinetics with approximatel y 100% p,o, bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O-6-alkylguanine alkyltransferase to overcome resistance to chemot herapy in malignant glioma and malignant metastatic melanoma, Temozolomide has recently been 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. Predictable bioavailability and minimal toxicity m ake temozolomide a candidate for a wide range of clinical testing to evalua te the potential of combination treatments in different tumor types. An ove rview of the mechanism of action of temozolomide and a summary of results f rom clinical trials in malignant glioma are presented here.