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 Meijer, C. Articles by de Vries, E. G. E. Search for Related Content PubMed PubMed Citation Articles by Meijer, C. Articles by de Vries, E. G. E.

Relationship of Cellular Glutathione to the Cytotoxicity and Resistance of Seven Platinum Compounds¹

Divisions of Medical Oncology [C. M., N. H. M., H. T-B., G. J. M., E. G. E. de V.] and Endocrinology [W. J. S.], Department of Internal Medicine, University Hospital, Oostersingel 59, 9713 EZ Groningen, the Netherlands

² To whom requests for reprints should be addressed.

The role of glutathione (GSH) in the effectiveness of and resistance to 7 platinum compounds (5 Pt(II) and 2 Pt(IV) drugs] was evaluated in a 8.6-fold cisplatin (CDDP)-resistant human small cell lung cancer cell line (GLC₄/CDDP), the parent GLC₄ line, a 3.7-fold CDDP-resistant human embryonal carcinoma cell line (Tera-CP), and the parent Tera line (NTera2/D1). Resistance factors for both CDDP-resistant cell lines were determined after continuous incubation (4 days) with CDDP.

Continuous incubation with the other studied platinum drugs revealed complete cross-resistance for carboplatin (CBDCA) and zeniplatin but less for enloplatin (ENLO) and iproplatin in both models. Tetraplatin and lobaplatin showed, respectively, partial and complete cross-resistance in GLC₄/CDDP but no cross-resistance in Tera-CP.

GSH level, but not glutathione S-transferase activity, of the 4 cell lines correlated with platinum drug concentrations inhibiting cell survival by 50% after continuous incubation (r = 0.86, P < 0.05). GSH depletion by DL-buthionine-S,R-sulfoximine (BSO) increased sensitivity, as measured after a 4-h exposure to the drugs, of GLC₄/CDDP for CDDP 2.0-fold, for CBDCA 1.7-fold, for zeniplatin 1.7-fold, and almost to the level of the sensitive GLC₄ for ENLO, whereas no effect was observed for lobaplatin and the Pt(IV) compounds iproplatin and tetraplatin. BSO-modulating effect was higher in the sensitive GLC₄ line for most compounds; therefore reduction of resistance could be achieved only for CDDP and ENLO. In contrast to GLC₄, no modulation occurred in Tera. In Tera-CP BSO increased sensitivity for CDDP 1.5-fold, for CBDCA 1.9-fold, and for zeniplatin 1.2-fold; no effect was observed for ENLO, lobaplatin, and the Pt(IV) compounds.

Reduction of CDDP resistance by BSO was known to occur with identical cellular platinum levels and higher Pt-DNA binding in GLC₄/CDDP. However, pretreatment with BSO followed by 4 h ENLO incubation increased cellular platinum levels in both GLC₄ and GLC₄/CDDP while Pt-DNA binding remained unchanged.

In conclusion, GSH reflected sensitivity to platinum-containing drugs. However, since the involvement of GSH differed between the models and the various platinum drugs, the effect of modulation with BSO was unpredictable.

¹ This study was partly presented at the 82nd Annual Meeting of the American Association for Cancer Research, Houston, TX, May 15–18, 1991, and partly supported by Grants GUKC 90-18 and 91-09 from the Dutch Cancer Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/22/92. Accepted 10/ 2/92.

This article has been cited by other articles:

				A. Yoshida, H. Takemura, H. Inoue, T. Miyashita, and T. Ueda Inhibition of Glutathione Synthesis Overcomes Bcl-2-Mediated Topoisomerase Inhibitor Resistance and Induces Nonapoptotic Cell Death via Mitochondrial-Independent Pathway Cancer Res., June 1, 2006; 66(11): 5772 - 5780. [Abstract] [Full Text] [PDF]

				P. Yang, J. O. Ebbert, Z. Sun, and R. M. Weinshilboum Role of the Glutathione Metabolic Pathway in Lung Cancer Treatment and Prognosis: A Review J. Clin. Oncol., April 10, 2006; 24(11): 1761 - 1769. [Abstract] [Full Text] [PDF]

				P. F. Smith, B. M. Booker, P. Creaven, R. Perez, and L. Pendyala Pharmacokinetics and Pharmacodynamics of Mesna-Mediated Plasma Cysteine Depletion J. Clin. Pharmacol., December 1, 2003; 43(12): 1324 - 1328. [Abstract] [Full Text] [PDF]

				B. Yang, N. Keshelava, C. P. Anderson, and C. P. Reynolds Antagonism of Buthionine Sulfoximine Cytotoxicity for Human Neuroblastoma Cell Lines by Hypoxia Is Reversed by the Bioreductive Agent Tirapazamine Cancer Res., April 1, 2003; 63(7): 1520 - 1526. [Abstract] [Full Text] [PDF]

				R. Furumai, A. Matsuyama, N. Kobashi, K.-H. Lee, M. Nishiyama, H. Nakajima, A. Tanaka, Y. Komatsu, N. Nishino, M. Yoshida, et al. FK228 (Depsipeptide) as a Natural Prodrug That Inhibits Class I Histone Deacetylases Cancer Res., September 1, 2002; 62(17): 4916 - 4921. [Abstract] [Full Text] [PDF]

				H. B. Deng, H. K. Parekh, K.-C. Chow, and H. Simpkins Increased Expression of Dihydrodiol Dehydrogenase Induces Resistance to Cisplatin in Human Ovarian Carcinoma Cells J. Biol. Chem., April 19, 2002; 277(17): 15035 - 15043. [Abstract] [Full Text] [PDF]

				K. Zhang, M. Chew, E. B. Yang, K. P. Wong, and P. Mack Modulation of Cisplatin Cytotoxicity and Cisplatin-Induced DNA Cross-Links in HepG2 Cells by Regulation of Glutathione-Related Mechanisms Mol. Pharmacol., April 1, 2001; 59(4): 837 - 843. [Abstract] [Full Text]

				L. Pendyala, P. J. Creaven, G. Schwartz, N. J. Meropol, W. Bolanowska-Higdon, J. Zdanowicz, M. Murphy, and R. Perez Intravenous Ifosfamide/Mesna Is Associated with Depletion of Plasma Thiols without Depletion of Leukocyte Glutathione Clin. Cancer Res., April 1, 2000; 6(4): 1314 - 1321. [Abstract] [Full Text]

				J. Welink, E. Boven, J. B. Vermorken, H. E. Gall, and W. J. F. van der Vijgh Pharmacokinetics and Pharmacodynamics of Lobaplatin (D-19466) in Patients with Advanced Solid Tumors, Including Patients with Impaired Renal or Liver Function Clin. Cancer Res., September 1, 1999; 5(9): 2349 - 2358. [Abstract] [Full Text] [PDF]