Telomere defence mechanisms have been recommended as potential targets for new anti-cancer interventions (Folini and Zaffaroni, 2005), as unlimited proliferative possibility has been identified as one of the six hallmarks of cancer. The selective reactivation of telomerase largely in human tumours, the ability to obstruct its expression or function is being actively explored. This includes the use of various approaches aimed, firstly to prevent the enzyme's catalytic activity; secondly to obstruct the expression of its components (i.e. hTR, hTERT); or thirdly to influence the signalling pathways accountable for the post-translational modifications of the enzyme (Cairney and Keith, 2008).
Nucleoside analogs were amongst the earliest drugs tested for suppressing telomerase activity, these work as chain terminators during nucleotide polymerisation. In numerous tumours in vitro and in vivo models there are induced anti-proliferative and anti-tumour effects when various nucleostide analogs effectively impede telomerase activity and produce telomere shortening, relying on the concentration and extent of exposure (Damm et al., 2001). Non-competitive inhibitor, BIBR1532 has also been shown to impede telomerase (Zimmermann and Marten, 2007; Kelland, 2005). BIBR1532 is one of the most efficacious telomerase inhibitors discovered so far and it attaches to a site in the telomerase which is different from those for deoxyribonucleotides and the DNA primer. BIBR1532 treated in human cancer cells of different histological origin leads to progression of telomere shortening and prevention of cell proliferation, independent of p53 gene status. Furthermore, in nude mice there is a marked decrease in the tumourigenic potential following xenotran...
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... in phase I/II clinical trials using GRN163L (Shay and Keith, 2008; Tabori et al., 2007).
Various research has shown that antisense molecules (including ribozymes, siRNAs and peptide nucleic acids) directed to down-regulating hTERT expression are capable of bringing about short-term anti-proliferative effects and apoptosis, which cannot be clarified by the typical model based on telomere shortening (Shay and Wright, 2002). A feature of the control of cell proliferation other than telomere length (“fast pathway”, Fig. 4) might therefore be affected upon interference with hTERT (Folini et al., 2009). Initiation of telomere dysfunctions and a DNA damage response at the telomere level during pathways separate of the telomere lengthening activity of the enzyme; this occur due to early anti-proliferative effects initiated by hTERT knockdown (Folini et al., 2009).