Methods comprising apoptosis inhibitors for the generation of transgenic pigs

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Stem Cell Related Patent Number US6054442

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


 
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