Temozolomide: Mechanisms of Action, Repair and Resistance

• DOI: 10.2174/1874467211205010102
• Publication Date: 2011-12-29T14:22:05Z
• Authors: Jihong Zhang; Malcolm F.G. Stevens; Tracey D. Bradshaw
• Keywords: Temozolomide; O-6-methylguanine-DNA methyltransferase

Glioblastoma multiforme is the most common aggressive adult primary tumour of central nervous system. Treatment includes surgery, radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. TMZ an alkylating agent prodrug, delivering a methyl group to purine bases DNA (O6-guanine; N7-guanine N3-adenine). The cytotoxic lesion, O6-methylguanine (O6-MeG) can be removed by methylguanine methyltransferase (MGMT; direct repair) in tumours expressing this protein, or tolerated mismatch repair-deficient (MMR-) tumours. Thus MGMT MMR deficiency confers resistance TMZ. Inherent- acquired present major obstacles successful treatment. Strategies devised thwart enhance response TMZ, including inhibition repair mechanisms which contribute resistance, are under clinical evaluation. Depletion prior chemotherapy prevents O6-MeG repair; thus, pseudosubstrates O6-benzylguanine lomeguatrib able sensitise Disruption base excision (BER) results persistence potentially lethal N7- N3- lesions contributing significantly cytoxicity particularly when adducts repaired tolerated. Several small molecule inhibitors poly(ADP-ribose)polymerase-1 (PARP-1), critical BER protein yielding promising clinically, both combination with as single patients whose possess homologous recombination defects. Another validated, but yet preclinical target, mandatory abasic (AP) endonuclease-1 (APE-1); tests, APE-1 potentiates activity. An alternative strategy synthesis molecule, evoking irrepairable O6-G lesion. Preliminary efforts achieve goal described.