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| Title: | Methods for modulation and inhibition of telomerase |
| Inventors: | Chen, Shih-Fong; San Antonio, TX, USA Maine, Ira; San Antonio, TX, USA Kerwin, Sean M.; Round Rock, TX, USA Fletcher, Terace M.; San Antonio, TX, USA Salazar, Miquel; Austin, TX, USA Mamiya, Blain; Austin, TX, USA Wajima, Makoto; San Antonio, TX, USA Windle, Bradford E.; San Antonio, TX, USA |
| Summary: | Described herein are methods of reducing the proliferative capacity of a cell via modulation and inhibition of telomerase activity. Central to the invention is the discovery that normal human stem cells produce a regulated non-processive telomerase activity, while cancer cells produce a processive telomerase activity. Furthermore, nucleotide analogs, such as 7-deaza-2'-deoxyquanosine-5'-triphosphate (7-deaza-dGTP) were found to be substrates for processive telomerase and incorporated into telomeric sequences. Described herein are means by which the incorporation of this nucleotide subsequently affects the processivity of telomerase, converting processive telomerase to non-processive telomerase, and inhibiting the formation of G-quartets by telomeric sequence. Further disclosed are methods for converting cancer processive telomerase to the more benign non-processive telomerase, such as by partially cleaving the telomerase RNA. Claims of the invention include nucleoside analogs which were found to be capable of a variety of activities including the mediation of allosteric-like inhibition of telomerase, premature termination and shortening of telomeric DNA, destabilization of telomeric structure and function and eventually cell death. Therapeutic applications in the treatment of cancer are included. |
| Abstract: | It was found that normal human stem cells produce a regulated non-processive telomerase activity, while cancer cells produce a processive telomerase activity. Nucleotide analogs, such as 7-deaza-2'-deoxyquanosine-5'-triphosphate (7-deaza-dGTP) were found to be substrates for processive telomerase and incorporated into telomeric sequence. The incorporation of this nucleotide subsequently affected the processivity of telomerase, converting processive telomerase to non-processive telomerase. The incorporation of this nucleotide analogs was also found to inhibit formation of G-quartets by telomeric sequence. Other methods for converting cancer processive telomerase to the more benign non-processive telomerase include partially cleaving the telomerase RNA. The nucleoside analogs were found to be capable of a variety of activities including mediating allosteric-like inhibition of telomerase, premature termination and shortening of telomeric DNA, destabilization of telomeric structure and function and eventually cell death. Understanding the mechanisms of telomerase modulation by the 7-deaza-nucleotides has allowed the design of new telomerase inhibitors, modulators and agents for affecting telomere structure and function. These discoveries have application in the treatment of cancer. |
| US Patent Website: | Click Here for Full Text of Patent |
| Title Number: | US6593306 |
| Application Number: | US1999000467932 |
| Date Filed: | 21/12/1999 |
| Date Published: | 15/07/2003 |
| Assignee: | Board of Regents, The University of Texas System, Austin, TX, USA CTRC Research Foundation, San Antonio, TX, USA |