University of Texas System

Ctrc Research Foundation

Other

Ctrc Research Foundation Board of Regents

Terace M Fletcher

Shih-Fong Chen

Bradford E Windle

Ira Maine

Sean Michael Kerwin

Blain Mamiya

Makoto Wajima

Miquel Salazar

Miguel Salazar

Ming Qiu

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&prime;-deoxyquanosine-5&prime;-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.

Methods for modulation and inhibition of telomerase

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.

Methods and compositions for modulation and inhibition of telomerase in

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.

Improved telomerase activity assays are provided in which a ligation sequential reaction (LSR) or BrdUTP are used to identify a telomerase specific product. These assays are useful in diagnosing various cancers and determining the clinical prospects for cancer patients. In addition, the assays can be used to screen for substances that interfere with telomerase activity.

Rapid and sensitive assays for detecting and distinguishing between

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San Antonio, TX, United States of America

Terace M Fletcher