Authors: Tentori, Lucio; Graziani, Grazia

Source: Current Medicinal Chemistry, Volume 16, Number 2, January 2009 , pp. 245-257(13)

Publisher: Bentham Science Publishers

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

Document Type: Research article

DOI: http://dx.doi.org/10.2174/092986709787002718

Affiliations: 1: Department of Neuroscience, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy.

Publication date: 2009-01-01

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• Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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