CYCLOSPORINE-A, VERAPAMIL AND S9788 REVERSE DOXORUBICIN RESISTANCE INA HUMAN MEDULLARY-THYROID CARCINOMA CELL-LINE

Multidrug resistance was investigated in TT cells, a human medullary t hyroid carcinoma (MTC) cell line and in normal thyrocytes. MDR1 mRNA w as revealed by polymerase chain reaction (PCR) analysis both in normal and neoplastic cells despite the absence of glycoprotein P (Pgp) by i mmunohistochemistry using JSB-1 monoclonal antibody. Glutathione-S-tra nsferase mRNA was undetectable by Northern blotting in TT cells. Doxor ubicin-induced cytotoxicity was evaluated in TT cells with MTT, lactic odehydrogenase (LDH), glutathione (GSH) assays and neutral red uptake. IC50 values obtained for MTT assays were higher than those obtained w ith the three other tests. Cyclosporin A (CSA) (3 mu M), verapamil (10 mu M) and S9788 (5 mu M) partially reversed the resistance to doxorub icin after a 48 h co-incubation (followed by a 24 h post-incubation fo r the S9788). Under these conditions, GSH levels were altered by verap amil and S9788, whereas CSA decreased LDH activity. CSA and verapamil had no effect on MTT assay. In conclusion this MTC cell line exhibited over-expression of the MDR1 gene and its resistance to doxorubicin ca n be partially reversed by CSA, verapamil and S9788.