Telomerase as a target for anticancer therapy

Jerry W. Shay

University of Texas Southwestern Medical Center Dallas, TX 75390-9039 USA Email:

Telomerase, a cellular reverse transcriptase, is upregulated/reactivated in almost all human cancers catalyzing the synthesis and extension of repetitive (TTAGGG) telomeric DNA onto the ends of chromosomes. Normal human cells either do not express telomerase or express very low levels and thus telomeres progressively shorten with each cell division due to incomplete replication of lagging strand DNA synthesis. The correlation between telomerase activity, telomere length homeostasis, and cancer suggests that long-term tumor growth requires telomerase and that telomerase inhibitors may have utility in cancer therapeutics. Promising approaches for telomerase inhibition include the use of a mutant dominant/negative versions of the catalytic telomerase subunit (hTERT) and the use of antisense oligonucleotides directed against the template RNA component (hTR) of the telomerase holoenzyme. These telomerase inhibitors, but not chemically-related molecules, have been shown to reduce telomerase activity but not initially affect cell growth rates, lead to progressive shortening of telomeres with each cell division, and ultimately cause cells to undergo apoptosis in a time-frame dependent on initial telomere length. Other approaches that do not require a time delay for efficacy include the use of the hTERT promoter in a replication-competent adenoviral vector and the use of immunotherapy directed against telomerase-specific peptides. Only telomerase-expressing cells should be killed using these approaches. In the future, telomerase inhibitors are most likely to be used after standard treatments, as well as in combination with angiogenesis inhibitors or other cancer gene therapy approaches.

For more information, contact Shay@UTSW.SWMED.EDU

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Molecular Therapies.