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| Title: | Methods and compositions for modulation and inhibition of telomerase in vitro |
| 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, Miguel; Austin, TX, USA Mamiya, Blain; Austin, TX, USA Windle, Bradford E.; San Antonio, TX, USA Wajima, Makoto; San Antonio, TX, USA |
| Summary: | This invention introduces methods of modulating and inhibiting telomerase activity, via a process of contacting cells with nucleoside derivatives such as 7-de:aza-2'-deoxy:guanosine. 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, and nucleotide analogs such as 7-deaza-2'-deoxyquanosine-5'-triphosphate (7-deaza-dGTP) have been found to be substrates for processive telomerase which are incorporated into the telomeric sequence. Further disclosed herein are properties by which the nucleotide subsequently affects the processivity of telomerase, converting processive telomerase to non-processive telomerase. The incorporation of such nucleotide analogs is described herein as inhibiting the formation of G-quartets by telomeric sequence. Additional methods for the conversion of cancer processive telomerase to the more benign non-processive telomerase are provided, which include partially cleaving the telomerase RNA. Additional properties and mechanisms of the nucleoside analogs are delineated herein. Further claims of the invention include telomerase modulation by the 7-deaza-nucleotides to allow the design of new telomerase inhibitors, modulators and agents for affecting telomere structure and function. 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: | US6054442 |
| Application Number: | US1996000675119 |
| Date Filed: | 03/07/1996 |
| Date Published: | 25/04/2000 |
| Assignee: | Board of Regents, The University of Texas System, Austin, TX, USA CTRC Research Foundation, San Antonio, TX, USA |