DOXORUBICINE RESISTANCE MODULATION BY CYC LOSPORINE-A AND VERAPAMIL IN 5 HUMAN CELL-LINES OF MEDULLARY-THYROID CANCER

Medullary thyroid carcinoma (MTC) is frequently resistant to chemother apy. Multidrug resistance (MDR) is one of the involved mechanisms. In this work we have studied the MDRI gene expression in five MTC human c ell lines that we have isolated and we have compared this expression t o that of normal thyroid tissue. We have also tried to reverse the res istance to doxorubicin with verapamil (VRP) and ciclosporin A (CSA). M DRI ARNm expression was studied and quantified by polymerase chain rea ction (PCR) in normal and pathological thyroid tissues. The doxorubici n-induced cytotoxicity was evaluated with the 3,-4,5 dimethylthiazol-2 ,5 diphenyl tetrazolium bromide (MTT) test, the neutral red (NR) uptak e and with total glutathione (GSH) or intracellular lactate dehydrogen ase (LDH) measurements. We found an increase of MDRI ARNm in MTC as co mpared with normal tissues. Doxorubicin was cytotoxic after a 48-h coi ncubation with the cells. Three mu M CSA and 10 mu M VRP reversed the doxorubicin resistance only after a 48-h coincubation, generally follo wed with a 24 h-post-incubation. In these conditions, the GSH levels w ere decreased only by VRP in all the five cell lines. In conclusion, a chemoresistance related to the MDRI gene overexpression was found in the five human MTC lines tested. VRP and CSA reversed the resistance t o doxorubicin in all the MTC cell lines tested.