Telomerase inhibition, oligonucleotides, and clinical trials

Corey, David R.

doi:10.1038/sj.onc.1205063

Cited by 97 publications

(56 citation statements)

References 33 publications

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“…7 In the current study, intratumoral GRN163 treatment of myeloma and lymphoma xenografts with short telomeres reduced tumor volumes by 40% to 50% compared with controls and was as effective as doxorubicin monotherapy in xenograft models. Although a potential limitation of oligonucleotide therapies is bioavailability to tumor tissues, 46 our results demonstrated that daily intraperitoneal GRN163 treatment decreased telomerase levels in flank xenografts (by up to 92% of control tumors) and reduced myeloma tumor growth (Figure 8). In addition, sublethally irradiated NOD/SCID mice with tumor xenografts treated with systemic daily intraperitoneal GRN163 (up to 50 mg/kg per day) exhibited no significant adverse effects compared with PBS-treated mice.…”

Section: Discussionmentioning

confidence: 65%

“…45 Telomerase is an ideal target for oligonucleotide therapy because the critical RNA template of the ribonucleoprotein essential for telomeric elongation is exposed and accessible to competitive binding by nucleic acids. 12,46 Previous testing of a reverse transcriptase telomerase inhibitor in murine xenograft models with rapidly proliferating or bulky tumors has been limited by the death of the host animal from malignant disease before the onset of growth inhibition. However, in those experiments, the telomerase inhibitor (BIBR1532) failed to induce apoptosis or cell death in vitro even after prolonged treatment.…”

Section: Discussionmentioning

confidence: 99%

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Telomerase inhibition with an oligonucleotide telomerase template antagonist: in vitro and in vivo studies in multiple myeloma and lymphoma

Wang

Chin

et al. 2004

Blood

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The effects of telomerase inhibition with an oligonucleotide N3 3 P5 thiophosphoramidate (GRN163) complementary to the telomerase template region were examined on human multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) cell lines, primary MM cells, and tumor xenografts. GRN163 treatment reduced telomerase levels in all cells and induced more rapid telomeric shortening. Continuous GRN163 treatment for 7 to 14 days resulted in proliferative arrest, morphologic changes, and apoptosis characteristic of cell crisis in tumor cell lines with short (1.7-5.4 kb) but not long (9-11 kb) telomeres. Intratumoral administration of GRN163 also inhibited the growth of MM and NHL xenografts established from cell lines with short telomeres (Hs602 lymphoma, 2.7 kb; CAG myeloma, 2.7 kb) and increased tumor apoptosis. However, GRN163 therapy of NHL xenografts established from cells with long telomeres (11.0 kb) had equivocal effects on tumor growth and did not induce apoptosis during this time frame. Systemic daily intraperitoneal administration of GRN163 in myeloma xenografts with short telomere lengths also decreased tumor telomerase levels and reduced tumor volumes. These data demonstrate that telomerase is important for the replication of mature B-cell neoplasia by stabilizing short telomeres, and they suggest that telomerase inhibition represents a novel therapeutic approach to MM and NHL. IntroductionThe preservation of telomeres, DNA-protein structures located at the ends of eukaryotic chromosomes, is essential to the immortalization process. In most normal somatic cells, telomeric DNA is progressively lost with each cell division until a critically short telomere length is obtained, and telomeres lose the ability to protect linear chromosomal ends. The resultant telomeric dysfunction induces cell "crisis" with chromosomal instability, end-to-end chromosome fusions, activation of DNA checkpoint responses, apoptosis, and cell death. 1 Human telomerase is a complex ribonucleoprotein reverse transcriptase composed of an RNA template (hTR) and a catalytic protein subunit (hTERT), which is responsible for synthesizing d-(TTAGGG) n telomeric repeats at chromosomal ends. Stabilizing telomeric DNA through telomerase up-regulation or activating alternative mechanisms of telomere maintenance is essential if cells are to survive and proliferate indefinitely. 2 Telomerase activity (TA) is not found in most normal somatic cells, which lack hTERT, but it has been detected in high levels in 85% to 90% of human cancers. 1 Although telomerase is not an oncogene, 3 transfecting hTERT into normal epithelial or endothelial cells transformed with the simian virus 40 large T-antigen and the N-ras oncogene allows cells to bypass crisis and ultimately to achieve malignancy, confirming the role of telomerase in cellular immortalization and tumorigenesis. 1 Telomerase inhibition by numerous strategies, including dominant-negative telomerase mutants, 4,5 small-molecular-weight compounds, 6 reversetranscriptase inhibitors, 7 G-quadruplex interactive...

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Telomerase inhibition with an oligonucleotide telomerase template antagonist: in vitro and in vivo studies in multiple myeloma and lymphoma

Wang

Chin

et al. 2004

Blood

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“…Therefore, tumours that overexpress TRF2-like Burkitt's lymphoma, might be more resistant to telomerase-inhibition therapy. This hypothesis has to be tested in cell culture models using the currently available specific telomerase inhibitors in cell lines that overexpress, for example, TRF2 or hPif1 (Damm et al, 2001;Corey, 2002).…”

Section: Discussionmentioning

confidence: 99%

Telomerase activity in B-cell non-Hodgkin lymphomas is regulated by hTERT transcription and correlated with telomere-binding protein expression but uncoupled from proliferation

Klapper¹,

Krams²,

Qian

et al. 2003

Br J Cancer

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Telomere maintenance is a prerequisite for immortalisation, and in most malignant cells is carried out by telomerase, an enzyme that synthesises new telomeric repeats on the chromosome ends. In normal or reactive tissues with a high regenerative capacity, telomerase is regulated according to the telomere loss that occurs during proliferation. To evaluate the interaction of proliferation and telomerase activity in malignant lymphomas, we quantified telomerase expression in different non-Hodgkin lymphomas in comparison to normal or reactive lymph nodes. Surprisingly, the activity levels were the same in most of the lymphomas analysed as compared to reactive lymph nodes. Significantly higher activity was detected only in Burkitt's lymphoma. Telomerase activity correlated well with hTERT and c-myc expression, but was independent of proliferation. To evaluate interactions of telomere-binding protein expression on telomerase expression in non-Hodgkin lymphoma, the mRNA levels of TRF1, TRF2, tankyrase and hPif1 were assessed by real-time RT -PCR. We demonstrate here that the magnitude of telomerase upregulation does not necessarily reflect the requirement of telomere compensation caused by proliferation. Telomerase regulation in non-Hodgkin lymphomas is therefore uncoupled from proliferative stimuli found in reactive lymphoid tissue. We suggest that the upregulation of specific telomere-binding proteins like TRF2 may contribute to telomere maintenance in malignant lymphoma.

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“…The specific expression of telomerase in most cancers raises the potential application of targeting telomerase for cancer therapy. Various strategies of telomerase-based therapeutics have been explored in the past decade including: vaccines targeting hTERT peptides for immunotherapy [7,8], gene-therapy using hTERT-promoter driven expression of suicide genes [9,10], and inhibition of telomerase activity [11][12][13]. The benefits and disadvantages of these different approaches have been reviewed [11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Potent inhibition of human telomerase by U-73122

et al. 2006

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SummaryTelomerase activity is repressed in normal human somatic cells, but is activated in most cancers, suggesting that telomerase may be an important target for cancer therapy. In this study, we report that U-73122, an amphiphilic alkylating agent that is commonly used as an inhibitor for phospholipase C, is also a potent and selective inhibitor of human telomerase. The inhibition of telomerase by U-73122 was attributed primarily to the pyrrole-2,5-dione group, since its structural analog U-73343 did not inhibit telomerase. In confirmation, we observed that telomerase was inhibited by N-ethylmaleimide, but not N-ethylsuccinimide. The IC 50 value of U-73122 for the in vitro inhibition of telomerase activity is 0.2 lM, which is comparable to or slightly more sensitive than that for phospholipase C. The inhibitory action of U-73122 on telomerase appears to be rather selective since the presence of externally added proteins did not protect the inhibition and the IC 50 values for the other enzymes tested in this study were at least an order of magnitude higher than that for telomerase. Furthermore, we demonstrate that U-73122 can inhibit telomerase in hematopoietic cancer cells. The potent and selective inhibition of telomerase by U-73122 raises the potential exploitation of this drug and other alkylating agents as telomerase inhibitor.

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Telomerase inhibition, oligonucleotides, and clinical trials

Cited by 97 publications

References 33 publications

Telomerase inhibition with an oligonucleotide telomerase template antagonist: in vitro and in vivo studies in multiple myeloma and lymphoma

Telomerase inhibition with an oligonucleotide telomerase template antagonist: in vitro and in vivo studies in multiple myeloma and lymphoma

Telomerase activity in B-cell non-Hodgkin lymphomas is regulated by hTERT transcription and correlated with telomere-binding protein expression but uncoupled from proliferation

Potent inhibition of human telomerase by U-73122

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