MODULATION OF CISPLATIN CYTOTOXICITY BY SULFASALAZINE

The efficacy of cisplatin [cis-diamminedichloroplatinum (II); DDP] is hampered by acquired or de novo resistance of malignant cells to its c ytotoxic effects. We have previously reported that cisplatin resistanc e parallels glutathione S-transferase (GST) activity in several human small-cell lung cancer cell lines. In the presently described studies, we used sulphasalazine, an inhibitor of GSTs, to evaluate the relativ e role of GSTs in mediating cisplatin resistance in two human small-ce ll lung cancer cell lines, NCI H-69 and H-2496. The H-69 cell line, wh ich contained relatively higher GST activity than the H-2496 cell line (317+/-7 vs 9+/-1 mU mg(-1) protein respectively), also displayed a g reater degree of cisplatin resistance (IC50 values of 25.0+/-3.9 vs 4. 5+/-1.0 mu M respectively). Western blot and Northern blot analyses of purified GSTs revealed the expression of only the pi-class GST in bot h cell lines. Sulphasalazine inhibited the purified GSTs (IC50 of 10 m u M for H-69 and 12 mu M for H-2496) from both lines in a competitive manner with similar K-i values (6.5 and 7.9 mu M for the H-69 and H-24 96 cell lines respectively). Cytotoxicity studies revealed that sulpha salazine increased the cytotoxicity of cisplatin towards both cell lin es. Isobologram analysis showed that sulphasalazine synergistically en hanced the cytotoxicity of cisplatin towards both cell lines, the magn itude of synergy being remarkably higher in H-69 cells than in H-2496 cells. Our studies indicate that clinically achievable concentrations of sulphasalazine may be useful in modulating cisplatin resistance in malignancies with increased GST-pi content.