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 N(7)-methylguanine and N(3)-methyladenine, which are repaired by the base excision repair pathway in which PARP-1 actively participates.
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 N(7)-methylguanine and N(3)-methyladenine, which are repaired by the base excision repair pathway in which PARP-1 actively participates.
Authors: Michelle J Clarke; Evan A Mulligan; Patrick T Grogan; Ann C Mladek; Brett L Carlson; Mark A Schroeder; Nicola J Curtin; Zhenkun Lou; Paul A Decker; Wenting Wu; E Ruth Plummer; Jann N Sarkaria Journal: Mol Cancer Ther Date: 2009-01-27 Impact factor: 6.261
Authors: Reshma Jagsi; Kent A Griffith; Jennifer R Bellon; Wendy A Woodward; Janet K Horton; Alice Ho; Felix Y Feng; Corey Speers; Beth Overmoyer; Michael Sabel; Anne F Schott; Lori Pierce Journal: J Clin Oncol Date: 2018-03-20 Impact factor: 44.544
Authors: Shiv K Gupta; Sani H Kizilbash; Brett L Carlson; Ann C Mladek; Felix Boakye-Agyeman; Katrina K Bakken; Jenny L Pokorny; Mark A Schroeder; Paul A Decker; Ling Cen; Jeanette E Eckel-Passow; Gobinda Sarkar; Karla V Ballman; Joel M Reid; Robert B Jenkins; Roeland G Verhaak; Erik P Sulman; Gaspar J Kitange; Jann N Sarkaria Journal: J Natl Cancer Inst Date: 2015-11-27 Impact factor: 13.506
Authors: R A Daniel; A L Rozanska; E A Mulligan; Y Drew; H D Thomas; D J Castelbuono; Z Hostomsky; E R Plummer; D A Tweddle; A V Boddy; S C Clifford; N J Curtin Journal: Br J Cancer Date: 2010-10-26 Impact factor: 7.640