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Enhanced Host Cell Reactivation of Damaged Plasmid DNA in HeLa Cells Resistant to cis-Diamminedichloroplatinum(II)¹

Tumor Biology Laboratory, Departments of Biochemistry and Medicine, Chang Gung Medical College, Taoyuan, Taiwan 33332 [C. C-K. C, Y-L. L, P-W. C], and Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529 [S. L-C], Republic of China

Human HeLa cells resistant to cisplatin were established by stepwise selection. The selected cells showed a 15- to 20-fold cisplatin resistance (CPR) at the dose level resulting in 50% inhibition. These cells were cross-resistant to mitomycin C, melphalan, and ethyl methanesulfonate but not to Adriamycin, colchicine, or vinblastine. The expression of cisplatin-damaged plasmid DNA carrying the bacterial chloramphenicol acetyltransferase (CAT) gene after its transfection into CPR cells was enhanced by 3-fold. This did not correlate with the degree of CPR. However, the development of the CPR phenotype paralleled the enhanced CAT activity. The addition of aphidicolin (an inhibitor of DNA -polymerase) to CPR cells effectively diminished the enhanced CAT activity and CPR. These studies have identified an enhanced host cell reactivation of the damaged plasmid in the acquisition of CPR, suggesting that DNA repair is a potential mechanism for the development of CPR phenotype in human cells.

¹ This work was supported in part by grants from Chang Gung Medical College (CMRP 256) and National Science Council, Republic of China (NSC78-0412-B182-16).

² To whom requests for reprints should be addressed.

³ Present address: Department of Biomedical Sciences, University of California, Berkeley, CA 94720.

Received 6/19/90. Accepted 10/26/90.

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