GLUTATHIONE CONTENT BUT NOT GAMMA-GLUTAMYL CYSTEINE SYNTHETASE MESSENGER-RNA EXPRESSION PREDICTS CISPLATIN RESISTANCE IN HEAD AND NECK-CANCER CELL-LINES

Purpose: To correlate cellular glutathione content and gamma-glutamyl cysteine synthetase (gamma GCS) mRNA expression with cisplatin sensiti vity in a panel of seven head and neck squamous cancer cell lines. Met hods: Cisplatin IC50 was determined for each cell line using a sodium tetreazolium (XTT) assay. Cellular glutathione content was measured by using a previously reported enzymic method. gamma GCS mRNA expression was measured using an RNase protection assay. Results: Total cellular glutathione was an excellent predictor of cisplatin sensitivity in th is series of cell lines. The IC50 for cisplatin in the cell line with the highest glutathione concentration was approximately 90 times highe r than in the cell line with the lowest glutathione concentration. Reg ression analysis showed a highly statistically significant positive co rrelation between cisplatin IC50 and cellular glutathione (coefficient of determination R-2 = 0.81, P = 0.0012). Somewhat surprisingly, in c ontrast to previous studies in ovarian cancer, gamma GCS mRNA expressi on in these cell lines was not significantly predictive of either tota l cellular glutathione or cisplatin sensitivity (R-2 = 0.005, P = 0.84 ). As expected, treatment of resistant cell lines with buthionine sulf oximine resulted in decreased cellular glutathione and enhanced cispla tin sensitivity. Conclusions: Our results suggest that glutathione may be an important determinant of cisplatin sensitivity in clinical head and neck cancer. Since cisplatin is the most active chemotherapy drug for the treatment of this disease, this correlation may have importan t clinical relevance. The lack of correlation between glutathione leve l and gamma GCS expression suggests that salvage or alternate syntheti c pathways may be critical in these cells.