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 Hall, A. Articles by Cattan, A. R. Search for Related Content PubMed PubMed Citation Articles by Hall, A. Articles by Cattan, A. R.

Possible Role of Inhibition of Glutathione S-Transferase in the Partial Reversal of Chlorambucil Resistance by Indomethacin in a Chinese Hamster Ovary Cell Line¹

Leukaemia Research Fund Laboratory [A. H., S. J. P., A. R. C.] and Department of Clinical Oncology [C. N. R., I. D. H., A. L. H.], Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom NE2 4HH

We have reported previously the isolation and characterization of a Chinese hamster ovary cell line, designated CHO-Chl^r, which exhibits resistance to bifunctional nitrogen mustards while maintaining sensitivity to a range of other alkylating agents and chemotherapeutic drugs. This enhanced drug resistance is associated with a greater than 40-fold increase in the level of expression of an alpha class (YcYc) glutathione S-transferase (GST) as compared to the parental, CHO-K1, cell line. Here, we have purified GST from CHO-Chl^r cells and show that the nonsteroidal antiinflammatory drug indomethacin acts as an inhibitor of enzyme activity. Indomethacin at 500 µM causes no significant decrease in colony forming ability of either CHO-K1 or CHO-Chl^r cells. However, the cytotoxicity of chlorambucil is potentiated 5.5-fold in CHO-Chl^r cells, but only 2.5-fold in CHO-K1 cells following preexposure to 500 µM indomethacin. In contrast, the antiinflammatory agent acetylsalicylic acid failed to inhibit the activity of purified GST and caused no potentiation of chlorambucil toxicity, suggesting that the potentiation by indomethacin is not due to the effects of this drug on prostaglandin synthesis. These studies provide further evidence that GSTs may be involved in the development of resistance to bifunctional alkylating agents and suggest that indomethacin, or agents with similar activities, may be of value as an adjunct to chemotherapy in some patients with tumors resistant to treatment with alkylating agents.

¹ Supported by the Tyneside Leukaemia Research Fund, the North of England Cancer Research Campaign, and the Leukaemia Research Fund.

² To whom requests for reprints should be addressed, at LRF Laboratory, 4th Floor, Cookson Building, New Medical School, Framlington Place, University of Newcastle Upon Tyne, NE2 4HH, United Kingdom.

Received 5/ 9/88. Revised 2/23/89. Revised 8/18/89. Accepted 8/21/89.

This article has been cited by other articles:

				T. Nakajima, T. Takayama, K. Miyanishi, A. Nobuoka, T. Hayashi, T. Abe, J. Kato, K. Sakon, Y. Naniwa, H. Tanabe, et al. Reversal of Multiple Drug Resistance in Cholangiocarcinoma by the Glutathione S-Transferase-{pi}-Specific Inhibitor O1-Hexadecyl-{gamma}-glutamyl-S-benzylcysteinyl-D-phenylglycine Ethylester J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 861 - 869. [Abstract] [Full Text] [PDF]

				M. L. O'Brien, B. Vulevic, S. Freer, J. Boyd, H. Shen, and K. D. Tew Glutathione Peptidomimetic Drug Modulator of Multidrug Resistance-Associated Protein J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 1348 - 1355. [Abstract] [Full Text]

				Z. Zhao, K. A. Koeplinger, T. Peterson, R. A. Conradi, P. S. Burton, A. Suarato, R. L. Heinrikson, and A. G. Tomasselli Mechanism, Structure-Activity Studies, and Potential Applications of Glutathione S-Transferase-Catalyzed Cleavage of Sulfonamides Drug Metab. Dispos., September 1, 1999; 27(9): 992 - 998. [Abstract] [Full Text]