Recent Approaches to Improve the Antitumor Efficacy of Temozolomide

Author(s): Lucio Tentori, Grazia Graziani.

Journal Name: Current Medicinal Chemistry

Volume 16 , Issue 2 , 2009

Abstract:

Temozolomide (TMZ) is an oral anticancer agent approved for the treatment of newly diagnosed glioblastoma in combination with radiotherapy. Moreover, TMZ has shown comparable efficacy with respect to dacarbazine, the reference drug for metastatic melanoma. Due to its favorable toxicity and pharmacokinetic profile, TMZ is under clinical investigation for brain metastasis from solid tumors and refractory leukemias. TMZ interacts with DNA generating a wide spectrum of methyl adducts mainly represented by N-methylpurines. However, its antitumor activity has been mainly attributed to O6-methylguanine, since tumor cell sensitivity inversely correlates with the levels of O6-alkylguanine DNA alkyltransferase and requires an intact mismatch repair system. Therefore, an increasing number of studies have been performed in order to identify patients who will benefit from TMZ treatment on the basis of their molecular/genetic profile. Unfortunately, resistance to the methylating agent occurs relatively often and strongly affects the rate and durability of the clinical response in cancer patients. Thus, different approaches have been developed to abrogate resistance or to increase the efficacy of TMZ and for many of them investigation is still underway. Herein, we provide an overview on the recent findings of preclinical and clinical studies on TMZ in combination with inhibitors of DNA repair, chemotherapeutic drugs with different mechanisms of action or radiotherapy, anti-angiogenic agents and other biological modulators.

Keywords: Temozolomide, poly(ADP-ribose) polymerase, chemotherapy, cancer, drug resistance, DNA repair

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Article Details

VOLUME: 16
ISSUE: 2
Year: 2009
Page: [245 - 257]
Pages: 13
DOI: 10.2174/092986709787002718
Price: $58

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