EFFECT OF S9788 ON THE EFFICIENCY OF DOXORUBICIN IN-VIVO AND IN-VITROIN MEDULLARY-THYROID CARCINOMA XENOGRAFT

In medullary carcinoma of the thyroid (MTC), drug resistance remains t he major obstacle to effective chemotherapy, In this work, we studied the effect of S9788 on doxorubicin (DOX) efficiency in a MTC cell line (TT cells) injected in nude mice, After two passages, TT cells were i njected in 40 nude mice divided into four groups [controls and groups receiving DOX alone (10 mg/kg), S9788 alone (50 mg/kg) or both DOX + S 9788], The weight of the mice, tumoral volume (TV), doubling time (DT) of the tumor and survival time of mice were evaluated in each group. In addition, the efficiency of DOX with or without S9788 was assessed by the inhibition of tumoral growth and specific growth delay. In vitr o, glycoprotein P 170 (P-gp) was detected on tissular sections and on tumoral cells by immunocytochemistry or flow cytometry with several mo noclonal antibodies: JSB1, MRK 16, C219 and UIC2. In vivo the weight o f the mice decreased slightly with DOX and dropped dramatically with D OX+S9788, The DT of the tumors increased with DOX over controls (22.5 +/- 8.5/12.7 +/- 3.9 days) and showed a higher value with DOX + S9788 (29.2 +/- 11.4 days), Inhibition of tumoral growth, 89% with DOX, fell to 47.6% with DOX+S9788. Specific growth delay increased with the dou ble treatment (130 versus 75% with DOX alone). In vitro, P-gp was not detected on tissular sections and cells whatever the method and the an tibody used, In conclusion, S9788 potentiates the efficiency of DOX tr eatment in vivo. The absence of P-gp may result from the absence of tr anslation of the MDR1 gene, The reversal effect of S9788 may involve a nother resistance mechanism such as the MDR Sister of MRP.