ROLE OF GLUTATHIONE, GLUTATHIONE S-TRANSFERASES AND MULTIDRUG RESISTANCE-RELATED PROTEINS IN CISPLATIN SENSITIVITY OF HEAD AND NECK-CANCER CELL-LINES

Resistance to chemotherapy is a major problem in the treatment of pati ents with head and neck squamous cell carcinoma (HNSCC), Important fac tors involved are drug detoxification by glutathione (GSH) and reduced drug accumulation due to active transport out of the cell by so-calle d 'multidrug resistance-related proteins'. We have studied a panel of eight HNSCC cell lines showing differences in sensitivity to the anti- cancer drug cisplatin. Our previous studies indicated that the IC50 va lues were inversely correlated with the intracellular accumulation of platinum (Pt). In the present study, cellular GSH levels were found no t to be related to the IC50 values. The expression levels of the enzym es glutathione S-transferase (GST) alpha, mu and pi, the multidrug res istance-related proteins P-glycoprotein (P-gp). multidrug resistance-a ssociated protein (MAP) and the lung resistance protein (LRP) were det ermined semiquantitatively by means of immunocytochemistry, The levels of the GSTs. P-gp and LRP were not found to be correlated with the IC 50 values of the HNSCC cell lines. Surprisingly, however, an inverse c orrelation was found between MRP levels and IC50 values. The MRP expre ssion levels were in agreement with the results of the MRP functional assay. based on the transport of calcein across the cell membrane as p erformed for two of the cell lines. Further studies should prove wheth er other pump mechanisms or DNA repair are involved in the cisplatin a ccumulation and the subsequent HNSCC cell growth inhibition.