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  • Title: DNA repair enzyme, O6-methylguanine DNA methyltransferase, modulates cytotoxicity of camptothecin-derived topoisomerase I inhibitors.
    Author: Kuo CC, Liu JF, Chang JY.
    Journal: J Pharmacol Exp Ther; 2006 Feb; 316(2):946-54. PubMed ID: 16258022.
    Abstract:
    Two camptothecin-resistant cell lines, CPT30 and KB100, were established and characterized previously in our laboratory. Because enhanced sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and decreased expression of O(6)-methylguanine-DNA methyltransferase (MGMT) protein were observed in these lines, we hypothesized that MGMT may be a determinant of cytotoxicity associated with camptothecin-derived DNA topoisomerase I inhibitors (CPTs). We used the Tet-On system to induce expression of MGMT in Chinese hamster ovary (CHO) cells and RNA interference to knock down MGMT expression in human nasopharyngeal carcinoma HONE-1 cells in order to identify any correlations between MGMT expression and CPTs cytotoxicity. CHO-derived Tet-On-inducible cells (S12+) showed MGMT overexpression and statistically significant more resistance to BCNU, camptothecin, 7-ethyl-10-hydrocamptothecin (SN38), and topotecan than parental CHO cells (p < 0.05), but there was less resistance to CPTs than to BCNU. Knockdown of MGMT expression with small interfering RNA in HONE-1 cells conferred increased sensitivity to BCNU and CPTs compared with mock control. Furthermore, alteration of MGMT expression coincides with CPT-induced cell death and poly(ADP-ribose) polymerase cleavage. There were no differences in protein levels and catalytic activity of topoisomerase I between MGMT-proficient and MGMT-deficient cells from the Tet-On-inducible and small interfering RNA (siRNA) systems. Resistance to CPTs coincided with decreased amounts of protein-linked DNA breaks generated by CPTs in MGMT-proficient cells and vice versa in MGMT-deficient cells. Our data indicate that MGMT can modulate cytotoxicity of CPT-derived topoisomerase I inhibitors.
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