Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics--current status and future prospects.
A key property of malignant tumours is their immortality or limitless replicative potential. Cell replication is associated with the maintenance of telomeres and in the great majority of cases, through the reactivation of the reverse transcriptase telomerase. Targeting the telomere/telomerase machinery offers a novel and potentially broad-spectrum anticancer therapeutic strategy since telomerase is constitutively overexpressed in the vast majority of human cancers. Telomeres are also critically short in most tumours compared to normal tissues. Strategies that exploit these differences include the direct targeting of components of telomerase: the protein component hTERT or RNA component hTR. Examples of such agents include the small molecule hTERT inhibitor BIBR1532 and GRN163L, a thio-phosphoramidate oligonucleotide targeting the template region of hTR as a "template antagonist". Anti-tumour effects have been observed in both cell lines and, especially for GRN163L, in xenografted human tumours in mice. Effects, however, are largely dependent upon initial telomere length, which can result in a substantial lag before antitumour activity is observed in tumours possessing relatively long telomeres. An alternative approach is to target the telomere itself (Telomere Targeting Agents, TTAs). Several classes of small molecules have been described that induce the G-rich single-stranded overhang of telomeric DNA to fold into 4-stranded G-quadruplex structures. Such folding is incompatible with telomerase function and may induce rapid telomere uncapping. These molecules have shown potent telomerase inhibition in nanomolar concentrations in vitro and the rapid induction of senescence in cancer cells. The trisubstituted acridine based TTA, BRACO19, has demonstrated single agent activity against human tumour xenografts with anti-tumour effects apparent from only 7 days of treatment. In the near future, it is expected that lead examples from both the direct telomerase targeted agents (e.g., GRN163L) and from the distinct class of those targeting telomeres (e.g., AS1410 based on BRACO19) will enter Phase I clinical trial where clinical benefit from this class of novel drugs will be determined.
Kelland
Lloyd R
LR
Antisoma Research Laboratories, St. Georges Hospital Medical School, Cranmer Terrace, London SW17 OQS, UK. lloyd@antisoma.com
D002455:Cell Division / Q000187:drug effects*; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005544:Forecasting; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012313:RNA / Q000037:antagonists & inhibitors*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000187:drug effects*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase