RELATIONSHIP OF CELLULAR GLUTATHIONE TO THE CYTOTOXICITY AND RESISTANCE OF 7 PLATINUM COMPOUNDS

C MEIJER*, NH MULDER, H TIMMERBOSSCHA, WJ SLUITER, GJ MEERSMA, EGE DEVRIES

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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-SR-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/CCDP. 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.

Original languageEnglish
Pages (from-to)6885-6889
Number of pages5
JournalCancer Research
Volume52
Issue number24
Publication statusPublished - 15-Dec-1992

Keywords

  • ACQUIRED-RESISTANCE
  • L1210 CELLS
  • CARCINOMA-CELLS
  • CARRIER-LIGAND
  • S-TRANSFERASE
  • CISPLATIN
  • CIS-DIAMMINEDICHLOROPLATINUM(II)
  • LINES
  • INVITRO
  • MECHANISMS

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