The basic requirement for an anti-cancer drug to be effective with minimal side effects is target-specific, i.e. "working on cancer cell only"
It is known that a key characteristic of malignant cancer cells is their immortality or limitless replication potential. And, it has been observed that cell replication is associated with the maintenance of telomeres. And in most cases, the maintenance of telomeres is through the reactivation of the reverse transcriptase telomerase. Because of need of this activity, telomerase is usually and constitutively over-expressed in most cancer cells. Comparing to the normal cells, telomeres are also critically short in most cancer cells. Consequently, researchers use these differences including the direct targeting of the telomere/telomerase machinery components for the anticancer therapeutic strategy. As mentioned before, the basic components of telomerase targeted by the anti-cancer drugs are the protein component hTERT or RNA component hTR.
Examples of such agents are GRN163L and BRACO19. BRAC019 is a telomere targeting-agent (TTA), to target the telomere itself. GRN163L is a thio-phosphoramidate oligonucleotide targeting the template region of hTR as a "template antagonist. Anti-tumour effects have been observed for GRN163L, in xenografted human tumours in mice. However, its effects are largely dependent upon initial telomere length. [1]
Researchers from University of Texas Southwestern Medical Center found that a lipid-modified N3'-->P5' thio-phosphoramidate oligonucleotide (GRN163L) inhibits telomerase more potently than its parental nonconjugated thio-phosphoramidate sequence (GRN163). [2] In another study, German researchers compared the potential of GRN163 and GRN163L for the treatment of human hepatoma xenografts (Hep3B and Huh7) in nude mice. The study indicated that both GRN163 and GRN163L inhibited telomerase activity and tumor cell growth in a dose-dependent manner in vitro and in vivo. However, the potency and efficacy of GRN163L, was superior to GRN163. [3]
A recent study has shown that GRN163L stopped the spread of cancer into the lungs of the mice. Thus, it might be able to prevent metastasis in other tumors. Currently, the innovator company, Geron, considers its application in chronic lymphocytic leukemia.
[1] Kelland LR Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics--current status and future prospects. Eur J Cancer. 2005 May;41(7):971-9. [2] Herbert BS et al, Lipid modification of GRN163, an N3'-->P5' thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene. 2005 Aug 4;24(33):5262-8. [3] Djojosubroto MW et al, Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma. Hepatology. 2005 Aug 19; [4] New Molecule Stops Cancer's Spread, HealthDay, September 2, 2005