PT  - JOURNAL ARTICLE
AU  - Curtin, Nicola J.
AU  - Wang, Lan-Zhen
AU  - Yiakouvaki, Anthie
AU  - Kyle, Suzanne
AU  - Arris, Christine A.
AU  - Canan-Koch, Stacie
AU  - Webber, Stephen E.
AU  - Durkacz, Barbara W.
AU  - Calvert, Hilary A.
AU  - Hostomsky, Zdenek
AU  - Newell, David R.
TI  - Novel Poly(ADP-ribose) Polymerase-1 Inhibitor, AG14361, Restores Sensitivity to Temozolomide in Mismatch Repair-Deficient Cells
AID  - 10.1158/1078-0432.CCR-1144-3
DP  - 2004 Feb 01
TA  - Clinical Cancer Research
PG  - 881--889
VI  - 10
IP  - 3
4099  - http://clincancerres.aacrjournals.org/content/10/3/881.short
4100  - http://clincancerres.aacrjournals.org/content/10/3/881.full
SO  - Clin Cancer Res2004 Feb 01; 10
AB  - Purpose: Mismatch repair (MMR) deficiency confers resistance to temozolomide, a clinically active DNA-methylating agent. The purpose of the current study was to investigate the reversal mechanism of temozolomide resistance by the potent novel poly(ADP-ribose) polymerase (PARP)-1 inhibitor, AG14361, in MMR-proficient and -deficient cells. Experimental Design: The effects of AG14361, in comparison with the methylguanine DNA methyltransferase inhibitor, benzylguanine, on temozolomide-induced growth inhibition were investigated in matched pairs of MMR-proficient (HCT-Ch3, A2780, and CP70-ch3) and -deficient (HCT116, CP70, and CP70-ch2) cells. Results: AG14361 enhanced temozolomide activity in all MMR-proficient cells (1.5–3.3-fold) but was more effective in MMR-deficient cells (3.7–5.2-fold potentiation), overcoming temozolomide resistance. In contrast, benzylguanine only increased the efficacy of temozolomide in MMR-proficient cells but was ineffective in MMR-deficient cells. The differential effect of AG14361 in MMR-deficient cells was not attributable to differences in PARP-1 activity or differences in its inhibition by AG14361, nor was it attributable to differences in DNA strand breaks induced by temozolomide plus AG14361. MMR-deficient cells are resistant to cisplatin, but AG14361 did not sensitize any cells to cisplatin. PARP-1 inhibitors potentiate topotecan-induced growth inhibition, but AG14361 did not potentiate topotecan in MMR-deficient cells more than in MMR-proficient cells. Conclusions: MMR defects are relatively common in sporadic tumors and cancer syndromes. PARP-1 inhibition represents a novel way of selectively targeting such tumors. The underlying mechanism is probably a shift of the cytotoxic locus of temozolomide to N7-methylguanine and N3-methyladenine, which are repaired by the base excision repair pathway in which PARP-1 actively participates.