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Increased Expression of Glutathione S-Transferase Gene in cis-Diamminedichloroplatinum(II)-resistant Variants of a Chinese Hamster Ovary Cell Line¹

Department of Biochemistry, Oita Medical School, Oita 879-56 [Y. S., M. N., M. O., K. K., M. K.]; Department of Biochemistry, Hokkaido University School of Medicine, Sapporo 060 [M. S.], and Department of Biochemistry, Faculty of Medicine, University of Tokyo, Tokyo 113 [M. M.], Japan

We have isolated cis-diamminedichloroplatinum(II) (CDDP)-resistant variants, C/CDP-1 and C/CDP-2, from a Chinese hamster ovary (CHO) cell line after a stepwise exposure to increasing concentrations of CDDP, and a CDDP-sensitive revertant, R-1, from C/CDP-2 after continuous incubation for 5 months in the absence of CDDP. C/CDP-1 and C/CDP-2 showed 7- and 10-fold higher resistance to CDDP, respectively, compared to CHO cells. C/CDP-2 was cross-resistant to carboplatin, L-phenylalanine mustard (melphalan), and CdSO₄, but not to other anticancer agents. Alkaline elution of DNA showed an increased amount of DNA interstrand cross-linking formation in CHO cells, but not in C/CDP-2 cells, when CHO and C/CDP-2 cells were cultured with CDDP. By contrast, alkaline elution of DNA showed increased formation of DNA cross-links when nuclei of C/CDP-2 cells were treated with CDDP. The activity of glutathione S-transferase (GST) of C/CDP-1 and C/CDP-2 was 4- and 6-fold higher than that of CHO cells, respectively. The cellular level of GST activity of R-1 was almost similar to that of CHO cells. Northern blotting analysis revealed that GST- mRNA in both C/CDP-1 and C/CDP-2 cell lines was increased more than 5-fold over that of CHO and R-1 cells. There is no apparent gene amplification of GST- gene in CDDP-resistant cell lines. Immunoblot assays showed a specific increase of GST- in C/CDP-1 and C/CDP-2, but no increase in GST-µ and GST-. We also compared CDDP-resistant properties of a resistant variant, P/CDP-5, derived from human prostate cancer PC-3 cell line, with those of C/CDP-1 and C/CDP-2 cells and found no increased GST activity in P/CDP-5 cells. Multiple mechanisms might be considered for acquisition of CDDP resistance in various cell lines in culture.

¹ This study was supported by a grant-in-aid from the Ministry of Education, Science and Culture of Japan.

² To whom requests for reprints should be addressed.

Received 5/24/89. Revised 9/17/89. Accepted 9/21/89.

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