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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, SUA |
| Summary: | Described herein are methods for the modulation and inhibition of telomerase activity via a process of contacting cells with nucleoside derivatives such as 7-deaza-2'-deoxyguanosine. 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, wherein nucleotide analogs such as 7-deaza-2'-deoxyquanosine-5'-triphosphate (7-deaza-dGTP) have been found to act as substrates for processive telomerase and are incorporated into the telomeric sequence, which subsequently affects the processivity of telomerase, converting processive telomerase to non-processive telomerase. Further elucidated herein are mechanisms by which the incorporation of such nucleotide analogs was also found to inhibit the formation of G-quartets by telomeric sequence. Also disclosed are additional methods for converting cancer processive telomerase to the more benign non-processive telomerase by partially cleaving the telomerase RNA. Therapeutic applications in the treatment of cancer are included. This invention represents a continuation of other applications filed by the same assignee and inventors. |
| 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-deazanucleotides 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: | US6004939 |
| Application Number: | US1997000879457 |
| Date Filed: | 20/06/1997 |
| Date Published: | 21/12/1999 |
| Assignee: | CTRC Research Foundation Board of Regents, San Antonio, TX, USA |