Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death
Open accessAbstract
The correlation between telomerase activity and human tumors has led to the hypothesis that tumor growth requires reactivation of telomerase and that telomerase inhibitors represent a class of chemotherapeutic agents. Herein, we examine the effects of inhibition of telomerase inside human cells. Peptide nucleic acid and 2′ -O- MeRNA oligomers inhibit telomerase, leading to progressive telomere shortening and causing immortal human breast epithelial cells to undergo apoptosis with increasing frequency until no cells remain. Telomere shortening is reversible: if inhibitor addition is terminated, telomeres regain their initial lengths. Our results validate telomerase as a target for the discovery of anticancer drugs and supply general insights into the properties that successful agents will require regardless of chemical type. Chemically similar oligonucleotides are in clinical trials and have well characterized pharmacokinetics, making the inhibitors we describe practical lead compounds for testing for an antitelomerase chemotherapeutic strategy.
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Written from the paper’s full text.
TL;DR
Inhibiting telomerase in immortal human cells with 2′-O-MeRNA or PNA oligonucleotides caused progressive telomere shortening, apoptosis, and eventual loss of proliferation. Telomere shortening and growth arrest were reversible when inhibitor treatment was stopped.
Key findings
- Complementary 2′-O-MeRNA inhibited >95% of telomerase activity 1 day after transfection and >70% at 3 days. HME50-5E proliferation slowed after 15–25 days, and no treated cells remained after 110 days; apoptosis rose from <5% during the first 60 days to 14% at 80 days and 56% at 100 days, versus 2–3% in controls.
- DU145 cells began slowing after 60 days and had undergone 20 fewer population doublings than mismatch-treated cells by 120 days. HME50-hTERT cells, with longer telomeres, showed no significant growth reduction over 120 days.
- Mean telomere restriction fragment length decreased from 2,000 to 1,700 bp in HME50-5E cells by 60 days, from 3,600 to 2,200 bp in DU145 cells by 76 days, and from 7,600 to 6,800 bp in HME50-hTERT cells after 75 days. A template-directed PNA inhibited >90% of telomerase activity at 1 day and shortened telomeres, whereas a nontemplate PNA inhibited only 50% and did not shorten telomeres.
- After inhibitor withdrawal at 76 days, eroded telomeres returned to approximately initial lengths within 3 weeks, and previously static HME50-5E cells regained growth within 3 weeks. No evidence for an ALT pathway was observed.
Methods
- Immortal human cell lines HME50-5E, DU145, and HME50-hTERT were transfected with 2′-O-MeRNA or PNA/DNA complexes using cationic lipids; treatment was repeated every 3–4 days for 120 days, with mismatch oligomers, lipid alone, or nontemplate PNA as controls.
- Telomerase activity was measured by TRAP, mean telomere length by telomere restriction fragment Southern analysis, apoptosis by Annexin V flow cytometry, and proliferation by cell counts/population doublings.
- Effects of matched versus mismatched or nontemplate inhibitors were compared over time to test sequence-specific, telomerase-dependent mechanisms.
Limitations
- Stated in the paper: the TRF assay does not monitor subtelomeric erosion and may underestimate total telomeric DNA loss; 5–30% of telomerase activity remained after treatment; systemic telomerase inhibition would also affect normal stem cells; the long lag before phenotypic effects complicates drug development; and no ALT pathway was observed in these cell types, leaving applicability to ALT-positive tumors uncertain.
- Evident from the text: findings are in vitro in a small number of immortal cell lines, including p53-mutant lines, with no animal or human efficacy/toxicity data; the 120-day culture experiments required stringent precautions against contamination but remain vulnerable to long-term culture artifacts.
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Claims the paper makes
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- Findingown data§ Results
By 100 days, 56% of HME50-5E cells treated with match oligomer underwent apoptosis.
“and this percentage increased to 56% after 100 days”
Quote in the paperSubstantial claim - Findingown data§ Results
Within 60 days of treatment, the mean telomere length of HME50-5E cells treated with 2'-O-MeRNA complementary to hTR was reduced from 2,000 to 1,700 bp.
“Within 60 days of treatment, the mean telomere length of HME50-5E cells treated with 2′-O-MeRNA complementary to hTR was reduced from 2,000 to 1,700 bp (Fig. 4a).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Inhibition of telomerase by 2'-O-MeRNA leads to progressive telomere shortening.
“leading to progressive telomere shortening”
- Also stated in: § Abstract · plain
“cause telomeres to shorten”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data§ Results
Growth of HME50-5E cells treated with control mismatch oligomer was not affected.
“The growth of cells treated with the control oligomer containing mismatch bases was not affected.”
Quote in the paperSubstantial claim - Findingown data§ Results
By 80 days, 14% of HME50-5E cells treated with match oligomer underwent apoptosis.
“By 80 days, however, 14% of cells treated with the match oligomer were observed to undergo apoptosis”
Quote in the paperSubstantial claim
- Findingown data§ Abstract
2'-O-MeRNA and PNA oligomers complementary to the template region of hTR inhibit telomerase.
“Peptide nucleic acid and 2′-O-MeRNA oligomers inhibit telomerase”
- Also stated in: § Abstract · plain
“We observe that 2′-O-MeRNA and peptide nucleic acid (PNA) oligomers complementary to the template region of hTR inhibit telomerase”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data§ Results
By the end of the experiment after 120 days, DU145 cells treated with complementary 2'-O-MeRNA had undergone 20 fewer population doublings than cells treated with mismatch-containing oligomer.
“By the end of the experiment (after 120 days), these cells had undergone 20 fewer population doublings than had cells treated with mismatch-containing oligomer.”
Quote in the paperSubstantial claim - Findingown data§ Results
HME50-5E cells treated with lipid alone or mismatch 2'-O-MeRNA underwent apoptosis at a rate of 2-3% throughout the entire experiment.
“By contrast, cells treated with lipid alone or the 2′-O-MeRNA oligomer containing mismatched bases underwent apoptosis at a rate of 2–3% throughout the entire experiment.”
Quote in the paperSubstantial claim - Findingown data§ Results
HME50-hTERT cells have a much longer mean TRF length (7.6 kilobases) than either HME50-5E or DU145 cells.
“HME50-hTERT cells have a much longer mean TRF length (7.6 kilobases) than either HME50-5E or DU145 cells”
Quote in the paperSubstantial claim - Findingnone given§ Abstract
Telomere shortening is reversible: if inhibitor addition is terminated, telomeres regain their initial lengths.
“Telomere shortening is reversible: if inhibitor addition is terminated, telomeres regain their initial lengths.”
Quote in the paperNot a substantial claim - Findingown data§ Abstract
Extended treatment with 2'-O-MeRNA causes immortal human breast epithelial cells to undergo apoptosis with increasing frequency until no cells remain.
“causing immortal human breast epithelial cells to undergo apoptosis with increasing frequency until no cells remain.”
Quote in the paperSubstantial claim - Findingown data§ Results
During the first 60 days after initial transfection, less than 5% of HME50-5E cells treated with fully complementary 2'-O-MeRNA underwent apoptosis.
“During the first 60 days after initial transfection, less than 5% of cells treated with the fully complementary 2′-O-MeRNA underwent apoptosis.”
Quote in the paperNot a substantial claim - Findingown data§ Results
No significant reduction in growth rates of HME50-hTERT cells was observed during the 120-day treatment period.
“we observed no significant reduction in their growth rates during the 120-day treatment period (Fig. 2c).”
Quote in the paperSubstantial claim - Findingown data§ Results
After 76 days of treatment, the mean TRF length of DU145 cells treated with 2'-O-MeRNA complementary to the template region of hTR decreased from 3,600 bp to 2,200 bp.
“with the mean TRF length of cells treated with the 2′-O-MeRNA complementary to the template region of hTR decreasing from 3,600 bp to 2,200 bp (Fig. 4b).”
Quote in the paperSubstantial claim - Findingown data§ Results
The complementary 2'-O-MeRNA oligomer blocked more than 95% of telomerase activity 1 day after transfection.
“the complementary 2′-O-MeRNA oligomer blocked more than 95% of telomerase activity 1 day after transfection”
Quote in the paperSubstantial claim - Findingown data§ Results
Addition of complementary 2'-O-MeRNA to DU145 cells caused proliferation to begin to slow after 60 days.
“Addition of complementary 2′-O-MeRNA to DU145 cells caused proliferation of cells to begin to slow after 60 days (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data§ Results
HME50-5E cells have a mean TRF length of 2,000 bp.
“HME50-5E cells have a mean terminal restriction fragment (TRF) length of 2,000 bp”
Quote in the paperSubstantial claim - Findingown data§ Results
DU145 cells possess a mean TRF length of 3,600 bp.
“whereas DU145 cells possess a mean length of 3,600 bp.”
Quote in the paperSubstantial claim - Findingown data§ Results
After 15-25 days, proliferation of HME50-5E cells treated with complementary 2'-O-MeRNA began to slow.
“After 15–25 days, proliferation of HME50-5E cells treated with the complementary oligomer began to slow”
Quote in the paperSubstantial claim - Findingown data§ Results
More than 70% of telomerase activity was inhibited 3 days after transfection with complementary 2'-O-MeRNA.
“and more than 70% of activity was inhibited 3 days after transfection (Fig. 1).”
Quote in the paperSubstantial claim - Findingown data§ Results
Addition of a PNA complementary to the hTR template to DU145 cells inhibited over 90% of telomerase activity after 1 day.
“Addition of a PNA that was complementary to the hTR template to DU145 cells inhibited over 90% of telomerase activity after 1 day (Fig. 1b)”
Quote in the paperSubstantial claim - Findingown data§ Results
After 110 days, no HME50-5E cells treated with complementary 2'-O-MeRNA remained.
“and after 110 days, no treated cells remained (Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data§ Results
A PNA directed to a nontemplate region of hTR inhibited only 50% of telomerase activity after 1 day.
“A PNA directed to a nontemplate region of hTR inhibited only 50% of telomerase activity after 1 day”
Quote in the paperNot a substantial claim - Findingown data§ Results
Addition of a PNA complementary to the hTR template to DU145 cells caused telomere shortening similar to that caused by addition of complementary 2′-O-MeRNA.
“and caused telomere shortening similar to that caused by addition of complementary 2′-O-MeRNA (Fig. 4b).”
Quote in the paperSubstantial claim - Findingown data§ Results
After stopping inhibitor addition for 3 weeks, eroded telomeres of DU145 cells treated with fully complementary oligomers returned to approximately their initial lengths.
“After 3 weeks, we noted that the eroded telomeres of cells treated with fully complementary oligomers had returned to approximately their initial lengths (Fig. 5).”
Quote in the paperSubstantial claim - Findingown data§ Results
Telomeres of DU145 cells treated with fully complementary oligomers remained near their initial lengths when measured a second time at 5 weeks after stopping inhibitor.
“Telomeres remained near their initial lengths when measured a second time at 5 weeks.”
Quote in the paperSubstantial claim - Findingreasoning§ Discussion
Proliferation of treated HME50-hTERT cells did not decrease.
“proliferation of treated HME50-hTERT cells did not decrease”
Quote in the paperSubstantial claim - Findingown data§ Results
Within 3 weeks of terminating inhibitor treatment, previously static HME50-5E cells treated with fully complementary 2′-O-MeRNA regained the ability to grow at the same rate as cells treated with mismatch-containing 2′-O-MeRNA.
“We observed that, within 3 weeks of terminating inhibitor treatment, previously static HME50-5E cells regained the ability to grow at the same rate as cells treated with mismatch-containing 2′-O-MeRNA.”
Quote in the paperSubstantial claim - Findingown data§ Results
A PNA directed to a nontemplate region of hTR did not cause telomeres to shorten.
“and did not cause telomeres to shorten (results not shown).”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Treatment with match 2′-O-MeRNA and PNA oligomers causes much greater decreases in telomere length and cell proliferation than does treatment with oligomers that contain mismatched bases or treatment with a less efficient PNA inhibitor directed to a nontemplate region of hTR.
“Treatment with match 2′-O-MeRNA and PNA oligomers cause much greater decreases in telomere length and cell proliferation than does treatment with oligomers that contain mismatched bases or treatment with a less efficient PNA inhibitor directed to a nontemplate region of hTR.”
Quote in the paperSubstantial claim - Findingreasoning§ Discussion
PNA and 2′-O-MeRNA oligomers cause similar reductions in telomere length.
“PNA and 2′-O-MeRNA oligomers cause similar reductions in telomere length”
Quote in the paperSubstantial claim - Findingreasoning§ Discussion
Inhibition of telomerase has a more rapid and pronounced effect on proliferation of HME50-5E cells, which have shorter telomeres than DU145 cells.
“The fact that inhibition of telomerase has a more rapid and pronounced effect on proliferation of HME50-5E cells, which have shorter telomeres than DU145 cells”
Quote in the paperSubstantial claim- Rests on an assumption: HME50-5E cells have shorter telomeres than DU145 cells.
- Findingown data§ Discussion
No evidence for adoption of an ALT pathway for telomere maintenance was observed.
“No evidence for adoption of an ALT (alternative lengthening of telomeres) pathway for telomere maintenance was observed”
Quote in the paperSubstantial claim - Interpretationreasoning§ Abstract
The long lag between loss of telomerase activity and a detrimental phenotype suggests that telomerase will be a difficult target for effective chemotherapy.
“The long lag between loss of telomerase activity and a detrimental phenotype suggests that telomerase will be a difficult target for effective chemotherapy”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
Mice lacking mTR survived for four to six generations with few detectable phenotypic changes, depending on their genetic backgrounds.
“Depending on their genetic backgrounds, these mice survived for four to six generations with few detectable phenotypic changes (13, 14);”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [13] Blasco M A, Lee H-W, Hande M P, Samper E, Lansdorp P M, DePinho R A, Greider C W. Cell. 1997;91:25–34. doi: 10.1016/s0092-8674(01)80006-4. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
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Not checked in the free run.
- Premisecitation§ Abstract
By the seventh generation, mTR-deficient mice were no longer able to reproduce.
“and the mice were no longer able to reproduce (15).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Lee H-W, Blasco M A, Gottlieb G J, Horner J W, Greider C W, DePinho R A. Nature (London) 1998;392:569–574. doi: 10.1038/33345. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Premisecitation§ Abstract
Evidence for the existence of the ALT pathway is found in yeast in which the gene for est1 has been deleted.
“Evidence for the existence of this pathway is found in yeast in which the gene for est1, a protein involved in telomere-length maintenance, has been deleted (31).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Lunblad V, Blackburn E H. Cell. 1993;73:347–360. doi: 10.1016/0092-8674(93)90234-h. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Results
The signal intensity of probe hybridization for DU145 cells was greatly reduced because of the reduction in telomeric repeats.
“the signal intensity of probe hybridization was greatly reduced because of the reduction in telomeric repeats.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Abstract
Inhibition of telomerase in human cancer would be expected to produce effects more rapidly than in mTR-deficient mice.
“inhibition of telomerase in human cancer would be expected to produce effects more rapidly.”
Quote in the paperSubstantial claim- Rests on an assumption: The mice used in these experiments possessed much longer telomeres than those found in cancerous human cells.
- Premisecitation§ Abstract
Transfection of cells with hTERT and subsequent expression of active telomerase extend the life spans of normal human fibroblasts and epithelial cells.
“transfection of cells with the gene encoding the human telomerase reverse transcriptase component (hTERT) and subsequent expression of active telomerase have been shown to extend the life spans of normal human fibroblasts and epithelial cells (25–27).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [25] Bodnar A G, Oullette M, Frolkis M, Holt S E, Chiu C P, Morin G B, Harley C B, Shay J W, Lichtsteiner S, Wright W E. Science. 1998;279:349–352. doi: 10.1126/science.279.5349.349. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
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Not checked in the free run.
- Premisecitation§ Abstract
mTR-deficient mice have a slight increase in spontaneous malignancies.
“and a slight increase in spontaneous malignancies (16).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Rudolph K L, Chang S, Lee H-W, Blasco M, Gottlieb G J, Greider C W, DePinho R A. Cell. 1999;96:701–712. doi: 10.1016/s0092-8674(00)80580-2. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Abstract
Inhibition of cell proliferation suggests that oligonucleotides are a viable approach to antitelomerase therapy.
“Inhibition of cell proliferation suggests that oligonucleotides are a viable approach to antitelomerase therapy”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
mTR-deficient mice have an increased incidence of chromosomal abnormalities.
“an increased incidence of chromosomal abnormalities”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Rudolph K L, Chang S, Lee H-W, Blasco M, Gottlieb G J, Greider C W, DePinho R A. Cell. 1999;96:701–712. doi: 10.1016/s0092-8674(00)80580-2. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Premisecitation§ Abstract
Expression of antisense RNA complementary to hTR caused decreased proliferation of HeLa cells after 23 to 26 doublings.
“expression of antisense RNA complementary to the human telomerase RNA component (hTR) caused decreased proliferation of HeLa cells after 23 to 26 doublings (24).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Feng J, Funk W D, Wang S-S, Weinrich S L, Avilion A A, Chiu C-P, Adams R R, Chang E, Allsopp R C, Yu J, et al. Science. 1995;269:1236–1241. doi: 10.1126/science.7544491. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Results
The finding that proliferation of treated HME50-5E cells decreases more dramatically than does cell proliferation of treated DU145 cells may be due to HME50-5E cells possessing shorter telomeres.
“the finding that proliferation of treated HME50-5E cells decreases more dramatically than does cell proliferation of treated DU145 cells may be due to HME50-5E cells possessing shorter telomeres.”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
By the seventh generation, highly proliferative organ systems like the testis, bone marrow, and spleen appeared abnormal in mTR-deficient mice.
“by the seventh generation, highly proliferative organ systems like the testis, bone marrow, and spleen appeared abnormal”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Lee H-W, Blasco M A, Gottlieb G J, Horner J W, Greider C W, DePinho R A. Nature (London) 1998;392:569–574. doi: 10.1038/33345. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Abstract
Our results validate telomerase as a target for the discovery of anticancer drugs.
“Our results validate telomerase as a target for the discovery of anticancer drugs”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
mTR-deficient mice have shortened life spans.
“Other studies of these mice revealed shortened life spans”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Rudolph K L, Chang S, Lee H-W, Blasco M, Gottlieb G J, Greider C W, DePinho R A. Cell. 1999;96:701–712. doi: 10.1016/s0092-8674(00)80580-2. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationreasoning§ Results
The reduced inhibition at 3 days is likely due to dilution of inhibitor as the cell population increases.
“thus, it is likely that the reduced inhibition is due to dilution of inhibitor as the cell population increases.”
Quote in the paperNot a substantial claim - Premisecitation§ Abstract
In some genetic backgrounds, an increased incidence of neural tube defects limited viability of mTR-deficient mice after only four generations.
“In some genetic backgrounds, an increased incidence of neural tube defects limited viability after only four generations (14).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Herrera E, Samper E, Martin-Caballero J, Flores J M, Lee H W, Blasco M A. EMBO J. 1999;18:1172–1181. doi: 10.1093/emboj/18.5.1172. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Premisecitation§ Abstract
Mutation of the RNA component of telomerase of human cells leads to decreased cell proliferation.
“and human cells (23) also leads to decreased cell proliferation”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Marusic L, Anton M, Tidy A, Wang P, Villeponteau B, Bacchetti S. Mol Cell Biol. 1997;17:6394–6401. doi: 10.1128/mcb.17.11.6394. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationreasoning§ Abstract
The inhibitors described are practical lead compounds for testing for an antitelomerase chemotherapeutic strategy.
“making the inhibitors we describe practical lead compounds for testing for an antitelomerase chemotherapeutic strategy.”
Quote in the paperNot a substantial claim- Rests on an assumption: Chemically similar oligonucleotides are in clinical trials and have well characterized pharmacokinetics.
- Premisecitation§ Results
The 2'-O-MeRNA oligomers used in these studies are stable to degradation inside cells.
“The 2′-O-MeRNA oligomers used in these studies are stable to degradation inside cells (38)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] Pitts A E, Corey D R. Proc Natl Acad Sci USA. 1998;95:11549–11554. doi: 10.1073/pnas.95.20.11549. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Discussion
The decreased proliferation caused by telomerase inhibition involves telomere shortening rather than nonselective toxicity.
“supports a mechanism of decreased proliferation involving telomere shortening rather than nonselective toxicity.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Inhibition of telomerase must be maintained at a sustained high level over time to prevent the rapid regrowth of telomeres.
“inhibition of telomerase must be maintained at a sustained high level over time to prevent the rapid regrowth of telomeres.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Inhibitors will be most effective against tumor cells with short telomeres.
“Inhibitors will be most effective against tumor cells with short telomeres”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
The effects of PNA and 2′-O-MeRNA oligomers are caused by Watson-Crick recognition rather than by non-base-pair-mediated contacts with backbone phosphodiester or phosphorothioate linkages.
“suggesting that the effects are caused by Watson–Crick recognition rather than by non-base-pair-mediated contacts with backbone phosphodiester or phosphorothioate linkages.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion
If neutral and anionic oligomers produce the same effects, they likely derive from specific Watson-Crick base pairing rather than misleading non-sequence-specific interactions.
“If neutral and anionic oligomers produce the same effects, they likely derive from specific Watson–Crick base pairing rather than misleading non-sequence-specific interactions.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Obtaining a striking phenotypic effect does not require full inhibition of telomerase.
“although obtaining a striking phenotypic effect does not require full inhibition of telomerase”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion
Telomerase is an unusually challenging target for drug discovery because a cellular response that depends on telomere shortening will require weeks to become apparent.
“Telomerase is an unusually challenging target for drug discovery, because a cellular response that depends on telomere shortening will require weeks to become apparent.”
Quote in the paperNot a substantial claim - Interpretationown data§ Discussion
There is a "set point" for telomere length in human cells.
“Regrowth to initial telomere length on cessation of inhibitor addition suggests that there is a “set point” for telomere length in human cells”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
The ALT pathway may not be readily adopted by some immortal cell types.
“suggesting that this pathway may not be readily adopted by some immortal cell types.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Discussion
The lack of decreased proliferation in treated HME50-hTERT cells is presumably because their initial telomere length is approximately 4,000 bp longer than that of HME50-5E cells.
“presumably because their initial telomere length of HME50-hTERT cells is approximately 4,000 bp longer.”
Quote in the paperSubstantial claim- Rests on an assumption: HME50-hTERT cells have an initial telomere length approximately 4,000 bp longer than that of HME50-5E cells.
- Interpretationreasoning§ Discussion
The telomeres of stem cells that erode during therapy may recover once treatment is terminated.
“and that the telomeres of stem cells that erode during therapy may recover once treatment is terminated.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Telomerase is a viable target for chemotherapeutic drugs or synthetic agents aimed at controlling proliferation of immortal human cells.
“Our primary finding is that telomerase is a viable target for synthetic agents aimed at controlling proliferation of immortal human cells.”
- Also stated in: § Discussion · hedged
“Our findings indicate that telomerase is a viable target for chemotherapeutic drugs”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Interpretationreasoning§ Discussion
Functional p53 is not necessary for the reduced proliferation of HME50-5E and DU145 cell lines on treatment with telomerase inhibitors.
“indicating that functional p53 is not necessary for the reduced proliferation of these cell lines on treatment with telomerase inhibitors.”
Quote in the paperSubstantial claim- Rests on an assumption: HME50-5E cells were derived from HME50 preimmortal cells that had one mutant p53 allele and lost the second allele during spontaneous immortalization.
- Rests on an assumption: DU145 cells have two mutant p53 alleles.
- Interpretationown data§ Discussion
The effects observed in the present study are due to Watson-Crick recognition of telomerase.
“We offer multiple independent lines of evidence in the present study that the effects we observe are due to Watson–Crick recognition of telomerase.”
Quote in the paperSubstantial claim
- May combine two claims. 14
- Classified as probably not a substantial claim. 23
May combine two claims.
Findingown data§ ResultsThe TRF length of HME50-5E cells treated with mismatch 2'-O-MeRNA remained at 2,000 bp, and the signal intensity of probe hybridization was undiminished.
“The TRF length of cells treated with 2-O-MeRNA containing mismatches relative to hTR remained at 2,000 bp, and the signal intensity of probe hybridization was undiminished.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ DiscussionTelomere shortening and decreased cell proliferation were observed even though between 5% and 30% of telomerase activity remained after treatment with inhibitor.
“We observe telomere shortening and decreased cell proliferation, even though between 5% and 30% of telomerase activity remained after treatment with inhibitor.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ AbstractTelomerase activity has been found in almost all human tumors but not in adjacent normal cells.
“Telomerase activity has been found in almost all human tumors but not in adjacent normal cells (3, 4).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3] Kim N W, Piatyszek M A, Prowse K R, Harley C B, West M D, Ho P L C, Coviello G M, Wright W E, Weinrich S L, Shay J W. Science. 1994;266:2011–2015. doi: 10.1126/science.7605428. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [4] Counter C M, Hirte H W, Bachetti S, Harley C B. Proc Natl Acad Sci USA. 1994;91:2900–2904. doi: 10.1073/pnas.91.8.2900. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ AbstractHuman telomerase is a ribonucleoprotein that adds repeated units of TTAGGG to the ends of telomeres.
“Human telomerase is a ribonucleoprotein that adds repeated units of TTAGGG to the ends of telomeres (1, 2).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [1] Morin G B. Cell. 1989;59:521–529. doi: 10.1016/0092-8674(89)90035-4. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [2] Bryan T M, Cech T R. Curr OpIN Cell Biol. 1999;11:318–324. doi: 10.1016/S0955-0674(99)80043-X. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductcitation§ Materials and MethodsThe levels of telomerase activity were within the linear range of the TRAP assay.
“The levels of telomerase activity were within the linear range of the TRAP assay (40).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Holt S E, Norton J C, Wright W E, Shay J W. Methods Cell Sci. 1996;18:237–248. [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ AbstractTelomerase activity is correlated with tumor aggressiveness.
“or tumor aggressiveness (11, 12).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [11] Ohyashiki J H, Ohyashiki K, Iwama I, Hayashi S, Toyama K, Shay J W. Clin Cancer Res. 1997;3:619–625. [PubMed] [Google Scholar]
Not checked in the free run.
- cites [12] Hoos A, Hepp H H, Kaul S, Ahlert T, Bastert G, Wallwiener D. Int J Cancer. 1998;79:8–12. doi: 10.1002/(sici)1097-0215(19980220)79:1<8::aid-ijc2>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation§ AbstractRecent reports of the effect of the mTR deletion in different genetic backgrounds suggest that the role of telomerase in cancer development could be highly context dependent.
“recent reports of the effect of the mTR deletion in different genetic backgrounds (17, 18) suggest that the role of telomerase in cancer development could be highly context dependent (19).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [17] Greenberg R, Chin L, Femino A, Lee K, Gottlieb G J, Greider C W, DePinho R A. Cell. 1999;97:515–525. doi: 10.1016/s0092-8674(00)80761-8. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [18] Chin L, Artandi S E, Shen Q, Tam A, Lee S L, Gottlieb G J, Greider C W, DePinho R A. Cell. 1999;97:527–538. doi: 10.1016/s0092-8674(00)80762-x. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [19] de Lange T, Jacks T. Cell. 1999;98:273–275. doi: 10.1016/s0092-8674(00)81955-8. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ AbstractIn est1-deleted yeast, cells divide normally until telomeres shorten sufficiently to affect proliferation, at which stage most cells die.
“The cells divide normally until telomeres shorten sufficiently to affect proliferation. At this stage, most cells die”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Lunblad V, Blackburn E H. Cell. 1993;73:347–360. doi: 10.1016/0092-8674(93)90234-h. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ AbstractExpression of telomerase in conjunction with SV40 large T oncoprotein and an oncogenic allele of H-ras promotes tumorigenic conversion of normal human cells.
“expression of telomerase in conjunction with expression of simian virus 40 large T oncoprotein and an oncogenic allele of H-ras has been shown to promote tumorigenic conversion of normal human cells (28).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Hahn W C, Counter C M, Lundberg A S, Beijersbergen R L, Brooks M W, Weinberg R A. Nature (London) 1999;400:464–468. doi: 10.1038/22780. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ AbstractLate-stage neuroblastoma has high telomerase activity and correlates with a poor outcome.
“whereas the late-stage disease has high telomerase activity and correlates with a poor outcome (6).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Hiyama E, Hiyama K, Yokoyama T, Matsuura Y, Piatyszek M A, Shay J W. Nat Med. 1995;1:249–255. doi: 10.1038/nm0395-249. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Interpretationreasoning§ ResultsThe decrease in measured TRF length may be an underestimate of the total loss of chromosomal DNA because the TRF assay does not monitor erosion of subtelomeric regions and because relatively little telomeric DNA remained to hybridize with radiolabeled probe.
“This decrease in measured TRF length may be an underestimate of the total loss of chromosomal DNA, because the TRF assay does not monitor erosion of subtelomeric regions and because relatively little telomeric DNA remained to hybridize with radiolabeled probe.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ ResultsThe 2'-O-MeRNA inhibitor contained four phosphorothioate linkages, a chemical moiety noted for its propensity to produce misleading cellular effects that seem sequence-specific but are actually unrelated to binding to the intended target.
“The 2′-O-MeRNA inhibitor contained four phosphorothioate linkages, a chemical moiety noted for its propensity to produce misleading cellular effects that seem sequence-specific but are actually unrelated to binding to the intended target (42).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Stein C A. Antisense Res Dev. 1997;7:207–209. [Google Scholar]
Not checked in the free run.
May combine two claims.
Interpretationcitation§ AbstractThe lack of telomerase expression seems to curb growth of rapidly proliferating cells eventually, whereas an increase in telomerase permits indefinite proliferation.
“Thus, the lack of telomerase expression seems to curb growth of rapidly proliferating cells eventually, whereas an increase in telomerase permits indefinite proliferation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ AbstractMutation of the RNA component of telomerase of Tetrahymena, Kluyveromyces lactis, and Saccharomyces cerevisiae leads to decreased cell proliferation.
“Mutation of the RNA component of telomerase of Tetrahymena (20), Kluyveromyces lactis (21), Saccharomyces cerevisiae (22)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [20] Yu G-L, Bradley J D, Attardi L D, Blackburn E H. Nature (London) 1990;344:126–132. doi: 10.1038/344126a0. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [21] McEachern M J, Blackburn E H. Nature (London) 1995;376:403–409. doi: 10.1038/376403a0. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [22] Singer M S, Gottschling D E. Science. 1994;266:404–409. doi: 10.1126/science.7545955. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Interpretationreasoning§ AbstractAlthough telomerase activity can confer extended life span to cells, other mechanisms may also exist.
“Thus, although telomerase activity can confer extended life span to cells, other mechanisms may also exist.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationreasoning§ AbstractTelomerase will be an unusually challenging target for drug development because of the long lag period expected before telomeres shorten sufficiently to produce detrimental effects on cell growth and because of the possibility of alternate mechanisms for maintenance of telomeres.
“Telomerase will be an unusually challenging target for drug development because of the long lag period expected before telomeres would shorten sufficiently to produce detrimental effects on cell growth and because of the possibility of alternate mechanisms for maintenance of telomeres.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ AbstractTelomerase activity is correlated with pathologic stage.
“other studies have suggested that telomerase activity is correlated with the pathologic stage (8–11)”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [8] Albanell J, Lonardo F, Rusch V, Engelhardt M, Langenfeld J, Han W, Klimstra D, Venkatraman E, Moore M A S, Dmitrovsky E. J Natl Cancer Inst. 1997;89:1609–1615. doi: 10.1093/jnci/89.21.1609. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [9] Tahara H, Kuniyasu H, Yokozaki H, Yasui W, Shay J W, Ide T, Tahara E. Clin Cancer Res. 1995;1:1245–1251. [PubMed] [Google Scholar]
Not checked in the free run.
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Not checked in the free run.
- cites [11] Ohyashiki J H, Ohyashiki K, Iwama I, Hayashi S, Toyama K, Shay J W. Clin Cancer Res. 1997;3:619–625. [PubMed] [Google Scholar]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ AbstractIn est1-deleted yeast, some rare survivors continue to proliferate through a recombination mechanism to maintain telomere length.
“but some rare survivors continue to proliferate through a recombination mechanism to maintain telomere length.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Lunblad V, Blackburn E H. Cell. 1993;73:347–360. doi: 10.1016/0092-8674(93)90234-h. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ AbstractA few rare tumors and some experimentally immortalized cell lines lack detectable telomerase activity.
“a few rare tumors (29) and some experimentally immortalized cell lines (30) lack detectable telomerase activity.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [29] Gupta J, Han L P, Wang P, Bacchetti S. J Natl Cancer Inst. 1996;88:1152–1157. doi: 10.1093/jnci/88.16.1152. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
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Not checked in the free run.
May combine two claims.
Study design and conductown data§ ResultsTreatment of HME50-5E cells with 2'-O-MeRNA was repeated, and a similar decrease in proliferation was observed.
“To confirm that the effects of inhibitor addition were reproducible, treatment of HME50-5E cells with 2′-O-MeRNA was repeated, and a similar decrease in proliferation was observed.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone given§ ResultsStringent precautions were taken to avoid contamination of cultured cells, and all experiments were completed successfully without interruption.
“Because of the extreme length of these experiments, stringent precautions were taken to avoid contamination of cultured cells, and all experiments were completed successfully without interruption.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionRecent work with PNAs introduced into cells by electroporation has shown decreased cell viability.
“Recent work with PNAs introduced into cells by electroporation has shown decreased cell viability, supporting our findings (49).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Shammas M A, Simmons C S, Corey D R, Shmookler-Reis R J. Oncogene. 1999;18:6191–6200. doi: 10.1038/sj.onc.1203069. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Interpretationreasoning§ DiscussionInhibition of telomerase in normal stem cells may result in few side effects because the relatively short telomeres of tumors may erode to a critical length before irreversible harm is done to other cells.
“This inhibition may result in few side effects, because the relatively short telomeres of tumors may erode to a critical length before irreversible harm is done to other cells.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Premisereasoning§ DiscussionTelomerase is an ideal target for oligonucleotides because its RNA template is essential for activity and is intrinsically accessible to binding by nucleic acids.
“Telomerase is an ideal target for oligonucleotides, because its RNA template is essential for activity and is intrinsically accessible to binding by nucleic acids.”
- Also stated in: § Discussion · plain
“The exposed RNA template of hTR makes telomerase an ideal target for oligonucleotides”
Quote in the paperSubstantial claim- Also stated in: § Discussion · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion2′-O-MeRNA and other 2′-O-alkyl-derivatized oligomers bind more tightly to complementary RNA sequences than do analogous DNA oligomers.
“In addition, 2′-O-MeRNA and other 2′-O-alkyl-derivatized oligomers bind more tightly to complementary RNA sequences than do analogous DNA oligomers”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [45] Agrawal S, Jiang Z, Zhao Q, Shaw D, Cai Q, Roskey A, Channavajjala L, Saxinger C, Zhang R. Proc Natl Acad Sci USA. 1997;94:2620–2625. doi: 10.1073/pnas.94.6.2620. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [46] Zhou W, Agrawal S. Bioorg Med Chem Lett. 1998;8:3269–3274. doi: 10.1016/s0960-894x(98)00591-5. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone given§ DiscussionSystemic administration of telomerase inhibitors will also inhibit telomerase in normal stem cells.
“Systemic administration of telomerase inhibitors will also inhibit telomerase in normal stem cells.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionOligonucleotides are being tested in 13 ongoing clinical trials.
“Oligonucleotides are being tested in 13 ongoing clinical trials (43)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Hogrefe R I. Antisense Nucleic Acid Drug Dev. 1999;9:351–357. doi: 10.1089/oli.1.1999.9.351. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionNon-sequence-selective effects may be at least partially implicated in results reported in 94% of the 2,026 studies published through 1997.
“Tu et al. (47) have performed a comprehensive survey of the literature, leading Stein (48) to estimate that non-sequence-selective effects may be at least partially implicated in results reported in 94% of the 2,026 studies published through 1997.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [47] Tu G C, Cao Q, Zhou F, Israel Y. J Biol Chem. 1998;273:25125–25131. doi: 10.1074/jbc.273.39.25125. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [48] Stein C A. Nat Biotechnol. 1999;17:209. doi: 10.1038/6909. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion2′-O-MeRNA and other 2′-O-alkyl-derivatized oligomers have improved resistance to degradation by nucleases.
“and have improved resistance to degradation by nucleases, reducing the need for phosphorothioate linkages and improving the selectivity of antisense effects (45, 46)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [45] Agrawal S, Jiang Z, Zhao Q, Shaw D, Cai Q, Roskey A, Channavajjala L, Saxinger C, Zhang R. Proc Natl Acad Sci USA. 1997;94:2620–2625. doi: 10.1073/pnas.94.6.2620. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [46] Zhou W, Agrawal S. Bioorg Med Chem Lett. 1998;8:3269–3274. doi: 10.1016/s0960-894x(98)00591-5. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DiscussionOligonucleotides that contain uniform phosphorothioate oligonucleotides inhibit telomerase in a non-sequence-specific fashion, presumably through binding to hTERT.
“Indeed, we have previously observed that oligonucleotides that contain uniform phosphorothioate oligonucleotides inhibit telomerase in a non-sequence-specific fashion, presumably through binding to hTERT (38).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Pitts A E, Corey D R. Proc Natl Acad Sci USA. 1998;95:11549–11554. doi: 10.1073/pnas.95.20.11549. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionFomivirsen has been approved for the treatment of cytomegalovirus retinitis.
“one oligonucleotide, Fomivirsen, has been approved for the treatment of cytomegalovirus retinitis (44).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [44] Marwick C. J Am Med Assoc. 1998;280:871. [Google Scholar] source
Not checked in the free run.
The paper relies on this without support.
The mice used in these experiments possessed much longer telomeres than those found in cancerous human cells.
“the mice used in these experiments possessed much longer telomeres than those found in cancerous human cells”
The paper relies on this without support.
Chemically similar oligonucleotides are in clinical trials and have well characterized pharmacokinetics.
“Chemically similar oligonucleotides are in clinical trials and have well characterized pharmacokinetics”
The paper relies on this without support.
HME50-5E cells were derived from HME50 preimmortal cells that had one mutant p53 allele and lost the second allele during spontaneous immortalization.
“HME50-5E cells were derived from HME50 preimmortal cells that had one mutant p53 allele and lost the second allele during spontaneous immortalization”
The paper relies on this without support.
DU145 cells have two mutant p53 alleles.
“whereas DU145 cells have two mutant alleles”
The paper relies on this without support.
The genetic background of HME50-hTERT cells is similar to that of HME50-5E cells.
“even though the genetic background of HME50-hTERT cells is similar to that of HME50-5E cells”
The paper relies on this without support.
HME50-5E cells have shorter telomeres than DU145 cells.
“which have shorter telomeres than DU145 cells”
The paper relies on this without support.
HME50-hTERT cells have an initial telomere length approximately 4,000 bp longer than that of HME50-5E cells.
“their initial telomere length of HME50-hTERT cells is approximately 4,000 bp longer.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Induction of ALT has never been reported in previous publications using other means of telomerase inhibition.
“Induction of ALT has also never been reported in previous publications using other means of telomerase inhibition (Hahn et al., 1999b;Herbert et al., 1999;Zhang et al., 1999).”
From A highly selective telomerase inhibitor limiting human cancer cell proliferation (2001) · cites this paper as Herbert et al., 1999
Reported telomerase inhibition strategies include peptide nucleic acids and 2'-O-MeRNA oligonucleotides against the telomerase RNA template, telomeric DNA binders such as cationic porphyrins or anthraquinones, and nucleosidic reverse transcriptase inhibitors.
“Several strategies to inhibit telomerase activity have been reported.These include peptide nucleic acids and 2¢-O-MeRNA oligonucleotides directed towards the telomerase RNA template (Herbert et al., 1999), compounds that target telomeric DNA such as cationic porphyrins or anthraquinones (Sun et al., 1997) and nucleosidic reverse transcriptase inhibitors (Strahl and Blackburn, 1996).”
From A highly selective telomerase inhibitor limiting human cancer cell proliferation (2001) · cites this paper as Herbert et al., 1999
Unlike earlier anti-sense oligonucleotide or dominant-negative hTERT studies, inhibitor-treated cells showed no evidence of increased apoptosis.
“In contrast to previous results employing anti-sense oligonucleotides or the expression of dominant-negative hTERT alleles (Hahn et al., 1999b;Herbert et al., 1999;Zhang et al., 1999) we saw no evidence for an increased rate of apoptosis in the inhibitor-treated cells.”
From A highly selective telomerase inhibitor limiting human cancer cell proliferation (2001) · cites this paper as Herbert et al., 1999
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Analysis of Telomerase Processivity
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10 Topics in Heterocyclic Chemistry
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Oligonucleotide N3′→P5′ phosphoramidates as efficient telomerase inhibitors
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- Authors
- Herbert, B.-S., Pitts, A. E., Baker, S. I., Hamilton, S. E., Wright, W. E., Shay, J. W., & Corey, D. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-12-07
- Volume
- 96
- Issue
- 25
- Pages
- 14276-14281
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC24427
- OpenAlex
- W2118228848
- Cited by
- 539
- References
- 48
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 11 · 2018: 9 · 2017: 9 · 2016: 5 · 2015: 18 · 2014: 7 · 2013: 12 · 2012: 13
- FWCI
- 27.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Ellison Medical Foundation
- National Institutes of Health
- National Cancer Institute (CA 74908, R01CA074908, CA-85143)
- National Institute of General Medical Sciences (T32GM007062, T32GM07062-23)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- telomerase inhibition, telomere shortening, apoptosis, peptide nucleic acid, 2'-O-methyl RNA, breast epithelial cells, cell immortalization, anticancer drug targets
- MeSH terms
- Antineoplastic Agents, Cell Division, Enzyme Inhibitors, Humans, Oligonucleotides, Telomere, Cell Death, Telomerase, Peptide Nucleic Acids
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
Statistics and arithmetic are recomputed, not judged.
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