Telomerase Therapeutics: Telomeres Recognized as a DNA

Introduction On the basis of a consolidation of a number of principles that underpin our current understanding of the transformation of normal human cells to malignant tumors, more mechanistic and rationale approaches to cancer therapeutics are emerging. Cancer cell immortality (limitless replicative potential) is one of the hallmarks of cancer (1). The topic of telomeres and telomerase as it relates to cell immortalization and advances in targeting this almost universal characteristic of cancer for drug development forms the central theme for this commentary. The ability of cancer cells to divide indefinitely is attributable to the activation of the ribonucleoprotein enzyme, telomerase. The most well-understood function of telomerase is to act as a cellular reverse transcriptase to synthesize telomeric (TTAGGG) repeats on the end of chromosomes to compensate for the progressive telomeric shortening that occurs each time a cell divides. All replicating cells lose some telomeric repeats with each division attributable to both the end replication problem as well as processing events that are attributable to yet unidentified nucleases. Before 1994, most research efforts on telomeres and telomerase were conducted by biochemists and molecular biologists using model organisms such as yeast and protozoa. With the discovery that telomerase is repressed in most normal human tissues but expressed in 90% of human tumors (2, 3), cancer biologists have initiated experiments to determine whether inhibition of telomerase has use in cancer therapeutics. The logic for pharmacological inhibitors of telomerase is that this approach would have the potential to be more cancer specific and perhaps with fewer cytotoxic side effects compared with currently approved therapies. Telomerase inhibitors might not only directly stop the growth and kill cancer cells but also might work effectively in combination with conventional cancer treatments such as surgery, chemotherapy, and radiation therapy to delay or prevent tumor regrowth (Fig. 1). Many novel approaches targeting telomeres and telomerase have been described (Table 1). Those agents that target only telomeres are likely to have nonspecific toxicities on normal cells, whereas those that target telomeres through inhibition of telomerase would be predicted to have fewer side effects (Refs. 4–10 for reviews). The current study by Kraemer et al. (11) tested AS-ODNs complementary to the catalytic subunit of telomerase (hTERT) for their effectiveness in influencing cell growth in a bladder cancer cell line, EJ28. Although the mechanism of action of these AS-ODNs would have been predicted to inhibit telomerase activity, it would also have been expected they would have taken time to progressively shorten the telomeres of EJ28 cells before causing a growth arrest of the cells. Interestingly, the present study showed dramatic short-term effects of 5 of the 23 AS-ODN tested on the EJ28 cells leading to rapid cell death of the tumor cells. Certainly, one possibility to explain this is that the inhibition of hTERT mRNA was causing an effect on telomere state as opposed to telomere loss. Alternatively, because telomere dynamics were not examined in the present study, it is conceivable that the EJ28 cells have at least some critically short telomeres, and upon hTERT inhibition, a rapid DNA damage-signaling pathway is activated leading to a rapid cell death. This raises a central issue in the telomerase therapeutic field: the amount of time or divisions required to observe efficacy of telomerase inhibitors.