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,
radiation 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 O(6)-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.