This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shellard, S. A. Articles by Hill, B. T. Search for Related Content PubMed PubMed Citation Articles by Shellard, S. A. Articles by Hill, B. T.

Anomalous Relationship between Cisplatin Sensitivity and the Formation and Removal of Platinum-DNA Adducts in Two Human Ovarian Carcinoma Cell Lines in Vitro¹

Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund, Lincoln's Inn Fields, London WC2A 3PX, England

Two human ovarian tumor cell lines (SK-OV-3 and TR175), established from patients previously treated with alkylating agents, but not with cisplatin, expressed >23-fold differences in cisplatin sensitivities in vitro. Cisplatin resistance in SK-OV-3 cells appeared to be associated with increased levels of glutathione and activities of glutathione reductase and glutathione peroxidase, with reduced catalase activity. No significant modification of drug uptake was noted and there was only marginally lower (16%) total platination of DNA, measured immunochemically, in these cells compared with the more sensitive TR175 cell line. SK-OV-3 cells, however, showed a significantly lower overall ability to remove drug-induced DNA damage, with an apparent inability to remove either the major DNA-DNA intrastrand cross-links in the sequence pGpG or the adducts cis-Pt(NH₃)₂d(GMP)₂, although by alkaline elution repair of DNA-DNA interstrand cross-links was demonstrated. Significantly more of these interstrand cross-links were induced in these resistant cells. These data provide evidence for the involvement of altered glutathione metabolism and increased tolerance of certain types of drug-induced DNA damage as factors associated with the resistance phenotype of SK-OV-3 cells. Paradoxically, however, although the highly cisplatin-sensitive TR175 cells had lower glutathione levels this was not reflected in significantly higher total platination of DNA, and these cells appeared to be proficient in removing all the major platinum-DNA adducts quantitated in this study. Mechanisms responsible for this relative sensitivity to cisplatin remain to be identified.

¹ This work was supported by the Imperial Cancer Research Fund, London, England.

² To whom requests for reprints should be addressed, at The ICRF Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, England.

Received 2/27/91. Accepted 6/25/91.

This article has been cited by other articles:

				H. T. Yip, R. Chopra, R. Chakrabarti, M. S. Veena, B. Ramamurthy, E. S. Srivatsan, and M. B. Wang Cisplatin-Induced Growth Arrest of Head and Neck Cancer Cells Correlates With Increased Expression of p16 and p53. Arch Otolaryngol Head Neck Surg, March 1, 2006; 132(3): 317 - 326. [Abstract] [Full Text] [PDF]

				K. A. Strait, C. T. Warnick, C. D. Ford, B. Dabbas, E. H. Hammond, and S. J. Ilstrup Histone deacetylase inhibitors induce G2-checkpoint arrest and apoptosis in cisplatinum-resistant ovarian cancer cells associated with overexpression of the Bcl-2-related protein Bad Mol. Cancer Ther., April 1, 2005; 4(4): 603 - 611. [Abstract] [Full Text] [PDF]

				B. W. Cooper, G. J. Veal, T. Radivoyevitch, M. J. Tilby, H. J. Meyerson, H. M. Lazarus, O. N. Koc, R. J. Creger, G. Pearson, G. M. Nowell, et al. A Phase I and Pharmacodynamic Study of Fludarabine, Carboplatin, and Topotecan in Patients With Relapsed, Refractory, or High-Risk Acute Leukemia Clin. Cancer Res., October 15, 2004; 10(20): 6830 - 6839. [Abstract] [Full Text] [PDF]