TY - JOUR T1 - Involvement of the Mismatch Repair System in Temozolomide-Induced Apoptosis JF - Molecular Pharmacology JO - Mol Pharmacol SP - 334 LP - 341 DO - 10.1124/mol.54.2.334 VL - 54 IS - 2 AU - Stefania D’Atri AU - Lucio Tentori AU - Pedro Miguel Lacal AU - Grazia Graziani AU - Elena Pagani AU - Elena Benincasa AU - Giovanna Zambruno AU - Enzo Bonmassar AU - Josef Jiricny Y1 - 1998/08/01 UR - http://molpharm.aspetjournals.org/content/54/2/334.abstract N2 - Postreplicative mismatch repair plays a major role in mediating the cytotoxicity of agents generatingO 6-methylguanine in DNA. We previously showed that a methylating antitumor triazene compound, temozolomide, induces apoptosis and that the persistence ofO 6-methylguanine in DNA is required to trigger the process. We wanted to test whether the latter apoptotic signal is dependent on a functional mismatch repair system. To this end, we used two human lymphoblastoid cell lines (i.e., the mismatch repair-proficient TK6 line and its mismatch repair-deficient subline MT1) that are both deficient inO 6-methylguanine repair. Temozolomide treatment of TK6 cells brought about efficient cell growth inhibition, G2/M arrest, and apoptosis, as indicated by the results of cytofluorimetric analysis of 5-bromo-2′-deoxyuridine incorporation and DNA content and evaluation of DNA fragmentation. The drug treatment resulted also in the induction of p53 and p21/waf-1 protein expression. In contrast, MT1 cells were highly resistant to the drug and no p53 and p21/waf-1 induction was observed. Importantly, we could show that MT1 cells are not deficient in the p53-dependent apoptosis pathway; treatment with etoposide, a topoisomerase II inhibitor, resulted in p53 and p21/waf-1 protein expression and apoptosis in both cell lines. In conclusion, we demonstrate the existence of a link between a functional mismatch repair system and the trigger of apoptosis in cells exposed to clinically relevant concentrations of temozolomide. The results also suggest that p53 induction in response toO 6-guanine methylation involves the mismatch repair system. ER -