Intrinsic drug resistance in a human medullary thyroid carcinoma cell line: association with overexpression of mdrl gene and low proliferation fraction.

Medullary thyroid carcinoma (MTC) is a cancer that is relatively insensitive to clinical chemotherapy. Our previous studies have demonstrated that an established human MTC cell line, TT, seems to possess an intrinsic resistance phenotype when tested for its chemosensitivity to multiple antineoplastic agents. We now report our investigation on the potential mechanisms responsible for the chemoresistance of TT cells. Northern analysis showed an increased level of multidrug resistance gene (mdrl) mRNA in TT and in an inherently drug-resistant colon carcinoma cell line, LoVo, when compared with CEM, a drug-sensitive leukemic lymphoblastic cell line; the latter two cell lines were included here as a control. Verapamil (10 microM) partially reversed resistance to doxorubicin in TT and LoVo cells, but had no effect on doxorubicin cytotoxicity to CEM cells. Expression of glutathione-S-transferase-pi (GST pi) gene was undetectable in TT, whereas, under similar conditions, GST pi mRNA was detectable in LoVo. Growth kinetics studies revealed that doubling times of the 3 cell lines in exponential growth were 95, 37, and 24 h for TT, LoVo and CEM, respectively. Flow-cytometric analysis showed that the percentage of TT population is S phase was 49% and 33% of the LoVo and CEM cell populations, respectively, while the G1/G0 fraction of TT was about 63% and 61% higher than that of LoVo and CEM, respectively. Our data suggest that the intrinsic chemoresistance in TT cells may be attributed to the combined factors of overexpression of the mdrl gene, a slower growth rate and a smaller proliferation fraction, although other factors or mechanisms that are yet to be investigated may also act in concert to contribute to the resistance phenotype of TT.