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Role of Carrier Ligand in Platinum Resistance of Human Carcinoma Cell Lines¹

Department of Biochemistry and Biophysics and Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599

We have examined the effects of the cis-diammine and 1,2-diaminocyclohexane (dach) carrier ligands on cytotoxicity, platinum accumulation and efflux, platinum incorporation into DNA, cytotoxicity of Pt-DNA adducts, and repair of Pt-DNA adducts in the human ovarian carcinoma A2780 cell line, the human colon carcinoma HCT8 cell line, and their cis-diamminedichloroplatinum(II) (cisplatin)-resistant derivatives, A2780/DDP and HCT8/DDP. The A2780/DDP cell line was 7.7-fold resistant to cisplatin, and the HCT8/DDP cell line was 1.6-fold resistant to cisplatin compared to their parental cell lines. Both were considered as examples of acquired cisplatin resistance. The HCT8/S cell line was 4.6-fold resistant to cisplatin compared with the A2780/S cell line and was considered an example of intrinsic resistance. Decreased accumulation of cisplatin made a significant contribution to acquired cisplatin resistance in the A2780/DDP cell line, probably contributed to intrinsic resistance in the HCT8/S cell line, but made little or no contribution to acquired resistance in the HCT8/DDP cell line. Decreased cytotoxicity of Pt-DNA adducts made a major contribution to both acquired and intrinsic cisplatin resistance in all three cell lines. Increased repair activity made a significant contribution to the decreased cytotoxicity of Pt-DNA adducts in the HCT8/S cell line, a weak contribution in the A2780/DDP cell line, and no contribution in the HCT8/DDP cell line. Glutathione levels were elevated in all the cell lines with acquired and intrinsic resistance, but the increased glutathione levels were not associated with decreased incorporation of platinum into DNA. These data suggest that both decreased accumulation and increased repair contribute to cisplatin resistance to different degrees in these human carcinoma cell lines. In addition, mechanism(s) other than repair may contribute to the decreased cytotoxicity of cis-diammine-Pt-DNA adducts. Of the cells with acquired cisplatin resistance, the HCT8/DDP cell line showed no resistance to tetrachloro(trans-DL)1,2-diaminocyclohexaneplatinum(IV) (ormaplatin, formerly known as tetraplatin), while the A2780/DDP cell line was just as resistant to ormaplatin as to cisplatin. The intrinsically cisplatin-resistant HCT8/S cell line showed only partial cross-resistance to ormaplatin. The effects of the dach carrier ligand on both acquired and intrinsic resistance in these cell lines appeared to occur primarily at the level of cytotoxicity of dach-Pt adducts, but the differences in the cytotoxicity of cis-diammine-Pt and dach-Pt adducts could not be explained by differences in repair of those adducts. Thus, the effects of the dach carrier ligand on the cytotoxicity of Pt-DNA adducts in these cell lines may be due to mechanism(s) other than total adduct repair, such as the effects of the dach ligand on the formation and/or repair of interstrand cross-links or on the ability of Pt-DNA adducts to inhibit essential processes such as replication or transcription.

¹ Supported by Public Health Service Grant CA34082. W. S. was supported by a postdoctoral traineeship from the National Institute of Environmental Health Sciences (Grant 5 T32 ES07126).

² Present address: Division of Oncology and Pulmonary Drug Products, HFD-150, FDA, 17B-45, 5600 Fishers Lane, Rockville, MD 20857.

³ To whom requests for reprints should be addressed, at Department of Biochemistry and Biophysics, CB 7260, FLOB, University of North Carolina, Chapel Hill, NC 27599-7260.

Received 1/27/92. Accepted 12/ 8/92.

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