Therapeutic Effects Of Antisense-hTERTcDNA On Ovarian Cancer Mediated By Retroviral Vector In Vivo

Telomerase is absent in most normal tissues, but isabnormally reactivated in all major cancer types. Telomerase enables tumor cells to maintain telomere length, allowing indefinite replicative capacity. Albeit not sufficient in itself to induce neoplasia, telomerase is believed to be necessary for cancer cells to grow without limit. The presence of telomerase has been detectedin virtually all cancer types including the most prevalent cancers of the prostate, breast, lung, colon, bladder, uterus, ovary, and pancreas as well as in lymphomas, leukemias, and melanomas. In addition, data from cancer patients indicate that telomerase levels correlate with clinical outcome in neuroblastomas, leukemias, and prostate, gastric, and breast cancers. Studies using an anti-sense to the human telomerase RNA component demonstrate that telomerase in human tumor lines can be blocked ex vivo. In these experiments, telomerase inhibition led to telomere shortening and cancer cell death, validating telomerase as a target for anticancer genetic therapy. Telomerase is a uniquely appealing target for drug discovery because its dichotomic expression in normal versus cancer cells suggests that no serious side effects would result from a treatment abrogating telomerase activity. A variety of approaches to telomerase inhibition are being investigated and are discussed.To study the biological activity of an anti-sense to the human telomerase RNA component mediated by virus vector, which was used to therapy ovarian tumor. We constuct and characterize a recombinant retrovirus vector with full length hTERT antisense cDNA. The vectorwas introduced into ES-2 by lipofectamine-mediated gene transfection. The proliferation and the telomerase activity of the transformant cells were retarded. The hTERT gene expression and the telomerase activity of the transformant cells were all decreased. The transformant cells show partial reversion of the malignant phenotype. PT 67 was also transfected with the recombinant vector and a producer cell were generated. The retrovirus containing supernatant effectively inhibited the growth of human ovarian tumor xenografts in mouse models( s. c. tumor model and Ascitic fluids model), and enhanced the mouse survival time.