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X-ray Repair Cross-Complementing Gene I Protein Plays an Important Role in Camptothecin Resistance

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520

X-ray repair cross-complementing gene I protein (XRCC1) in complex with DNA polymerase ß, DNA ligase III, and poly(ADP-ribose) polymerase is important in the base excision repair process. Previously, we isolated camptothecin (CPT)-resistant cell lines (KB100 and KB300) from the human epidermoid carcinoma cell line KB by exposure to CPT. From these CPT-resistant cell lines, their revertants (KB100^rev and KB300^rev), which lost most of their CPT-resistant phenotype during passage in the absence of CPT, were established. In this study, we found the expression levels of XRCC1 protein in KB100 and KB300 were 5-fold more than in their respective revertant cell lines, whereas there was no difference in the expression of XRCC1-associated proteins such as DNA polymerase ß, DNA ligase III, poly(ADP-ribose) polymerase, and apurinic/apyrimidinic endonuclease. The degree of CPT resistance was relatively correlated with the XRCC1 protein amount. We also found XRCC1 gene amplification in CPT-resistant KB100 and KB300 cell lines. To confirm a correlation between overexpression of XRCC1 and CPT resistance, we transfected the XRCC1 gene into KB100^rev and obtained two different transfected cell lines (clones 14 and 16). The expression levels of XRCC1 in the transfected cell lines were higher than in KB100^rev but lower than in KB100 with no difference in XRCC1-associated protein expression levels. Resistance to CPT in transfected cell lines was 2–2.5-fold higher than in KB100^rev in regard to growth inhibition and 4-fold higher with respect to clonogenicity. Transfected cell lines also showed increased resistance to other topoisomerase I poisons. However, the cytotoxicity of VP-16 and cisplatin was similar in both the transfected cells and KB100^rev. Similar to our CPT-resistant cell lines, the resistance of transfected cell lines was reversed by treatment with 3-aminobenzamide. These results indicate that CPT resistance in our cells could be partly attributable to the overexpression of XRCC1.

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