Inhibition of telomerase activity in renal cell carcinoma cells by doxorubicin and anti-Fas monoclonal antibody.

Telomerase, the ribonucleoprotein enzyme that maintains the telomeres of eukaryotic chromosomes, is an attractive target for a mechanism-based therapeutic approach as its activation has been associated with unlimited proliferation in most types of cancer cells. Here, we investigated the effect of chemotherapeutic or immunotherapeutic agents and anti-Fas monoclonal antibody (mAb) on telomerase activity in renal cell carcinoma (RCC) cells. Primary RCC cells were surgically obtained from 24 patients with RCC. Telomerase activity and cytotoxicity were determined by the telomeric repeat amplification protocol and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, respectively. Telomerase activity was positive in 20 (83.3%) of the 24 primary RCC cell cultures. Treatment of ACHN human RCC cells with anti-Fas mAb in combination with vinblastine, interferon-α or interferon-γ did not affect telomerase activity. However, a combination of anti-Fas mAb and doxorubicin resulted in marked down-regulation of telomerase activity in conjunction with a synergistic cytotoxicity. This inhibitory effect on telomerase activity was also observed in 16 telomerase-positive primary RCC cell cultures. These findings suggest that telomerase may be a promising molecular target for combination therapy using biological response modifiers and doxorubicin for RCC.