Temozolomide: Mechanisms of Action, Repair and Resistance

Nov 30, 2011Current molecular pharmacology

How Temozolomide Works, How Cells Repair Its Damage, and How Resistance Develops

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Glioblastoma multiforme, the most common aggressive adult primary brain tumor, exhibits treatment resistance linked to DNA repair mechanisms.

Treatment with temozolomide (TMZ) may be ineffective in tumors expressing methylguanine methyltransferase (MGMT) or those that are mismatch repair-deficient.
Inhibition of MGMT prior to chemotherapy could enhance sensitivity of tumors to TMZ by preventing repair of cytotoxic DNA lesions.
Disruption of base excision repair (BER) may lead to the accumulation of harmful DNA lesions, contributing to the effectiveness of TMZ.
Small molecule inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1), which is involved in BER, are showing promising clinical results in combination with TMZ.
In preclinical studies, inhibition of abasic endonuclease-1 (APE-1) has been found to enhance the activity of TMZ.

AI simplified

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

Full Text

Full text is available at the source.

View full text ↗

Temozolomide: Mechanisms of Action, Repair and Resistance

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief