DNA Repair Enzymes and Platinum Drug Resistance in Tumors

Abstract

Tumor resistance to platinum drugs is a major cause of treatment failure. Enzymes involved in DNA repair, especially the nucleotide excision repair enzymes ERCC1 and XPF, contribute to platinum drug resistance. Conversely, the clinical hypersensitivity of testicular cancer appears to be in part attributable to reduced levels of ERCC1and XPA. A large study of patients with non-small cell lung cancer demonstrated that undetectable levels of ERCC1 protein in tumors correlated with a signifi cant survival benefi t from cisplatin-based chemotherapy. Reduced ERCC1 levels in patients as a consequence of a genetic polymorphism in ERCC1 (codon 118) has been associated with platinum sensitivity.Loss of DNA mismatch repair may also contribute to acquired tumor resistance to cisplatin and carboplatin in ovarian cancer patients (but not to oxaliplatin). DNA polymerases beta and eta may also contribute to increased platinum drug tolerance. In the clinic, platinum resistance through DNA repair may be circumvented using co-administration of demethylating agents (such as decitabine to reactivate DNA mismatch repair) or by the use of ERCC1/XPF inhibitors or polymerase beta or eta inhibitors (all still to be discovered and developed). Breast cancer patients harbouring either BRCA mutations or HER-2 positive tumors may also benefi t from cisplatin-based therapy through mechanisms involving DNA repair inhibition.

Acquired resistance to miriplatin in rat hepatoma AH109A/MP10 is associated with increased Bcl-2 expression, leading to defects in inducing apoptosis

“…Nucleotide excision repair proteins have been shown to contribute to platinum resistance. Both ERCC1 and XPF, which accelerated the removal of platinum-DNA adducts (14), were not reduced in AH109A/MP10 cells compared to parental cells. Loss of mismatch repair proteins is also associated with cisplatin resistance, and DNA polymerases involved in translesion synthesis (or replicative bypass) may contribute to the tolerance to antitumor platinum complex (14).…”

“…Both ERCC1 and XPF, which accelerated the removal of platinum-DNA adducts (14), were not reduced in AH109A/MP10 cells compared to parental cells. Loss of mismatch repair proteins is also associated with cisplatin resistance, and DNA polymerases involved in translesion synthesis (or replicative bypass) may contribute to the tolerance to antitumor platinum complex (14). There was no apparent change in the expression level of MSH2, MSH6, PMS2, MLH1, DNA polymerase ß, or DNA polymerase Ë between the two cells.…”

“…Therefore, intrinsic or acquired resistance to antitumor agents is considered to be one of the limitations for successful TACE. Acquired resistance to antitumor platinum complexes has been extensively studied and found to be multifactorial, consisting of decreased drug accumulation mediated by overexpression of transporters, increased detoxification by glutathione or metallothionein, and increased tolerance/repair of DNA damage (13,14,17). The miriplatin-resistant rat hepatoma subline AH109A/MP10 established in this study was selectively resistant to DPC and oxaliplatin, which contained DACH as a carrier ligand, but not to other antitumor platinum complexes, such as cisplatin, carboplatin, and nedaplatin, which shared cis-diammine carrier ligands.…”