Telomerases

Telomeres are specialized structures at the termini of eukaryotic chromosomes. [Pg.764]

Telomerase is normally active during embryogenesis, but is repressed in most somatic cells before or shortly after birth. Germline cells, activated lymphocytes, and other immortal cells show no shortening of telomere length and possess telomerase activity. Thus tumor cells should also show telomerase activity that can act as a specific marker of transformation. [Pg.764]

Telomerase activity has been detected in more than 80% of cancers, including lung, breast, pancreatic, bladder, and many other cancers however, it does not seem to be necessary for cancer development. Its activity does, however, correlate with tumor progression and prognosis. [Pg.764]

The detection of telomerase activity or hTERT mRNA in excretion, secretion, brushings, and washings has been evaluated. In pancreatic, secretion samples, which contain freshly exfoliated cells, detection of telomerase activity was encouraging for cancer detection. Telomerase activity was also found to be useful in distinguishing between adenoma and carcinoma in intraductal papillary-mucinous tumors, which can sometimes be difficult to diagnose. In bronchial brushing samples, the clinical sensitivity of cancer detection is below 70% and false-positive results are commonly encountered because of contamination witli lymphocytes, which contain measurable telomerase activity. The measurement of telomerase is also expected to become a useful [Pg.764]

The TRAP (telomeric repeat amplification protocol) assay is a widely used method for detection of telomerase activity. This technique measures the telomerase activity present in cell extracts. Briefly, cellular extract containing telomerase activity is incubated with a telomeric substrate (a short strand of DNA onto which the telomerase wiU. attach the telomeric repeats) followed by polymerase chain reaction (PCR) amplification of the elongated telomere. Detection of the PCR product is by a number of methods, including gel electrophoresis, radiometric detection, ELISA, and real-time PCR detection. [Pg.765]

ITowever, most normal somatic cells lack telomerase. Consequently, upon every cycle of cell division when the cell replicates its DNA, about 50-nucleotide portions are lost from the end of each telomere. Thus, over time, the telomeres of somatic cells in animals become shorter and shorter, eventually leading to chromosome instability and cell death. This phenomenon has led some scientists to espouse a telomere theory of aging that implicates telomere shortening as the principal factor in cell, tissue, and even organism aging. Interestingly, cancer cells appear immortal because they continue to reproduce indefinitely. A survey of 20 different tumor types by Geron Corporation of Menlo Park, California, revealed that all contained telomerase activity. [Pg.382]

Telomerase Ribonucleoprotein Suppression of telomerase activity inhibition of cell proliferation change in morphology induction of apoptosis... [Pg.187]

Norton J.C., Piatyszek M.A., Wright W. E., Shay J.W., Corey D.R. Inhibition of human telomerase activity by peptide nucleic acids. Nature Biotechnol. 1996 14 615-618. [Pg.172]

Hamilton S. E., Simmons C.G., Kathir-iya I.S., Corey D.R. Cellular delivery of peptide nucleic acids and inhibition of human telomerase. Chem. Biol. 1999 6 343-351. [Pg.172]

Shammas M.A., Simmons C.G., Corey D.R., Reis R.J.S. Telomerase inhibition by peptide nucleic acids reverses immortality of transformed human cells. Oncogene 1999 18 6191-6200... [Pg.173]

Villa R., Folini M., Lualdi S., Veronese S., Daidone M.C., Zaffaroni N. Inhibition of telomerase activity by a cell-penetrating peptide nucleic acid construct in human melanoma cells. FEB.S. Lett. 2000 473 241-248. [Pg.176]

NAASANI I, SEIMIYA H and TSURUO T (1998) Telomerase inhibition, telomere shortening, and senescence of cancer cells by tea catechins , Biochem Biophys Res Commun, 249 (2), 391-6. [Pg.155]

Telomerase Tyrosinase inhibitor Sildenafil Serotonin antagonist... [Pg.75]

Guyen B et al. (2004) Synthesis and evaluation of analogues of 10H-indolo[3,2-b] quinoline as G-quadruplex stabilising ligands and potential inhibitors of the enzyme telomerase. Org Biomol Chem 2(7) 981-988... [Pg.94]

Hahn WC et al. (1999) Inhibition of telomerase limits the growth of human cancer cells. Nat Med 5(10) 1164-1170... [Pg.94]

Herbert B et al. (1999) Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc Natl Acad Sci USA 96(25) 14276-14281... [Pg.94]

Chen Z, Koeneman KS, Corey DR (2003) Consequences of telomerase inhibition and combination treatments for the proliferation of cancer cells. Cancer Res 63(18) 5917-... [Pg.94]

Rezler EM, Bearss DJ, Hurley LH (2002) Telomeres and telomerases as drug targets. Curr Opin Pharmacol 2(4) 415-423... [Pg.94]

Mergny JL et al. (2002) Natural and pharmacological regulation of telomerase. Nucleic Acids Res 30(4) 839-865... [Pg.94]

Perry PJ et al. (1998) Human telomerase inhibition by regioisomeric disubstituted amidoanthracene-9,10-diones. J Med Chem 41(24) 4873-4884... [Pg.94]

Shi DF et al. (2001) Quadruplex-interactive agents as telomerase inhibitors synthesis of porphyrins and structure-activity relationship for the inhibition of telomerase. J Med Chem 44(26) 4509-4523... [Pg.94]

Heald RA et al. (2002) Antitumor polycyclic acridines. 8.(1) Synthesis and telomerase-inhibitory activity of methylated pentacyclic acridinium salts. J Med Chem 45(3) 590-597... [Pg.94]

Mergny JL et al. (2001) Telomerase inhibitors based on quadruplex ligands selected by a fluorescence assay. Proc Natl Acad Sci USA 98(6) 3062-3067... [Pg.95]

Shin-ya K et al. (2001) Telomestatin, a novel telomerase inhibitor from Streptomyces anulatus. J Am Chem Soc 123(6) 1262-1263... [Pg.95]

Kim MY et al. (2002) Telomestatin, a potent telomerase inhibitor that interacts quite speciflcally with the human telomeric intramolecular g-quadruplex. J Am Chem Soc 124(10) 2098-2099... [Pg.95]

Harrison RJ et al. (1999) Human telomerase inhibition by substituted acridine derivatives. Bioorg Med Chem Lett 9(17) 2463-2468... [Pg.95]

Fedoroff OY et al. (1998) NMR-based model of a telomerase-inhibiting compoimd bound to G-quadruplex DNA. Biochemistry 37(36) 12367-12374... [Pg.95]

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