Inhibition of telomerase activity and cell proliferation by a reverse transcriptase inhibitor in gynaecological cancer cell lines

Telomerase is a ribonucleoprotein which has a RNA template to bind and exte nd telomere ends, so prolonging the life of tumour cells. The aim of this s tudy was to determine whether transcriptase function of telomerase could be inhibited by the reverse transcriptase inhibitors (RTI); azydothymidine (A ZT), dideoxyinosine (ddI) and AZT-5' triphosphate(AZT-TP). We examined thei r effects on the proliferation of cancer cells and the antitumour effects o f cisplatin in vitro. The three agents did not cause major changes in telom erase activity or telomere length in MCAS cells. However, in HEC-1 cells ch anges in telomerase activity and telomere length were observed that were de pendent on the RTI concentration and duration of exposure. ddI and AZT-TP r educed telomerase activity and shortened the length of the telomere. In the presence of RTI, the antitumour effects of cisplatin were enhanced. This w as particularly evident in HEC-1 cells where there was a marked reduction i n cell proliferation, appearance of morphological changes and senescent-lik e cells in the presence of ddI or AZT-TP. In MCAS cells, TP53 expression wa s increased by ddI and AZT-TP, while p21 expression was unchanged. In HEC-1 cells the expression of both TP53 and P21 was increased by ddI. Continuous administration of RTI enhanced the cell growth inhibition of cisplatin. RT I also inhibited the proliferation of some cells. (C) 1999 Elsevier Science Ltd. All rights reserved.