CURRENT MEDICAL RESEARCH AND OPINION 0300-7995

VOL. 19, NO. 6, 2003, 470472 doi:10.1185/030079903125002081

2003 LIBRAPHARM LIMITED

BRIEF REVIEW

The evolving role of telomerase

inhibitors in the treatment of
cancer
Kefah Mokbel
Institute of Cancer Genetics and Pharmacogenomics, Brunel University,
and St Georges and the Princess Grace Hospitals, London, UK
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Address for correspondence: Professor Kefah Mokbel, Consultant Breast and Endocrine Surgeon,
The Princess Grace Hospital, Nottingham Place, London W1M 3FD, UK. Tel. +44 (0)207 908 2040;
Fax +44 (0)207 908 2275; email kefahmokbel@hotmail.com
Key words: Cancer Inhibitors Telomerase Therapy

SUMMARY

Telomerase is a ribonucleoprotein that maintains G-quadruplex represent promising therapeutic

telomeres and is essential for cellular immortality strategies. Human trials investigating the potential
For personal use only.

and tumour growth. The differential expression of
telomerase in cancer cells makes it an attractive
therapeutic target. Anti-sense oligonucleotides
directed against the RNA template of hTR and
small molecules that can interact and stabilise the
role of the catalytic subunit hTERT as a universal
cancer vaccine have already commenced.
Alternative lengthening of telomeres (ALT) and
efficacy delay remain important limitations to anti-
telomerase therapy.

Introduction
Telomerase is a multi-component ribonucleoprotein
located within the nucleus. It is an RNA-dependant
DNA polymerase, the function of which is to synthesise
the repetitive nucleotide sequence (TTAGGG in
humans) forming the telomeres at the end of
chromosomes1. Without telomerase activity, each round
of cellular division results in the shortening of telomeres
and reaching a critical length seems to trigger off cellular
apoptosis. Telomerase appears to stabilise telomeres,
thus leading to cellular immortality2. The enzyme is
active in most human cancers and immortal cell lines2,3.
Most normal somatic cells have no detectable
telomerase activity, with the exception of certain stem
cells, lymphocytes and germline cells4. The activation of
telomerase does not cause carcinogenesis but it does
allow a cell to continue division and attain immortality,
a necessary achievement for a cancerous cell to be
successful. Although alternative methods of maintaining
telomere stability have been identified5,6, the majority of
tumours in all types investigated appear to employ
telomerase activation as a means of maintaining
proliferation at a high rate without becoming senescent.
Human telomerase consists of an RNA subunit
human telomerase RNA (hTR), a protein component
(human telomerase associated protein 1 (hTEP1),
chaperones such as hsp90, and the catalytic subunit,
human telomerase reverse transcriptase known as
hTERT5,7,8. The differential expression of telomerase in
most malignant cells makes it an attractive target for
cancer therapy. All telomerase components represent
potential therapeutic targets.
Targeting hTERT
hTERT can be targeted by nucleoside analogues,
antisense oligonucleotides, hammerhead ribozymes and
phosphorylation inhibitors915. The nucleoside
azidothymidine (AZT) has been shown to inhibit

470 Paper 2342

 telomerase activity and reduce telomeric length in
malignant cells, but this effect seems to be
cell-type specific9. A potent nucleoside analogue
inhibitor of hTERT, 6-thio-7-deaza-2-deoxyguanosine
5-triphosphate has been recently described10. The role
of antisense nucleotides directed against hTERT mRNA
has not been adequately investigated. Yokoyama et al.
have demonstrated that a hammerhead ribozyme
targeting the 5-terminal of hTERT mRNA can suppress
telomerase activity11. Inhibition of hTERT
phosphorylation by phosphokinase C (PKC) inhibitors
such as bis-indolylmaleimide I and H-7 is unlikely to be
an effective therapeutic strategy due to potential
interference with physiologically active PKCs12. hTERT
can also be inhibited by drugs capable of down-
regulating the upstream regulators of c-Myc13.
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Targeting hTR
The RNA template of hTR is easily accessible to
hybridisation with complementary oligonucleotides and
serves a critical function. Inhibition of hTR RNA
template does not seem to affect the function of hTR
positive cells, but does affect telomerase negative cells.
Herbert et al. have recently observed that a
For personal use only.
phosphoramidate oligonucleotide directed against the
RNA template can inhibit telomerase in cell culture14.
More recently, Chen et al. have demonstrated that a
2-methoxy-ethyl RNA oligonucleotide (ISIS 24691) is a
potent growth inhibitor of cancer cell lines without the
need for a lipid carrier. ISIS 24691 also reduced telomeric
length and cellular proliferation with IC50 values ranging
from 0.3 to 1 micro-molar15. This agent is currently being
investigated using xenograft animal models. Other
phosphoramidate derivatives have been shown to inhibit
telomerase activity in a sequence-specific and dose-
dependent fashion with nano-molar IC50 values16. Unlike
ISIS 24691, these compounds require a lipid vector.
Other antisense oligomers targeting hTR include 2,5-
oligoadenylate which has been found to exhibit anti-
tumour activity in both in vitro and in vivo experimental
models17. The hTR sub-unit can be also targeted by
hammerhead ribozymes18, compounds that bind to the
RNA/DNA heteroduplex19 and mutant RNA templates
that can exert a dominant negative effect20.
Miscellaneous targets
TEP1 is not essential for telomerase activity and it has
not therefore been investigated for anti-cancer
therapeutic targets. Inhibition of the chaperone protein
2003 LIBRAPHARM LTD Curr Med Res Opin 2003; 19(6)
hsp90 is unlikely to be a successful therapeutic strategy
due to interference with normal physiological processes.
There are also indirect therapeutic approaches against
telomerase. These include suicide gene therapy21 and
immunotherapy22.
Koga et al. demonstrated that hTERT/caspase 8
constructs exhibited anti-tumour activity in vivo in
animal studies21. hTERT is a widely expressed tumour
associated antigen that can be recognised by cytotoxic
T-lymphocytes. Cytotoxic T-cells induced by hTERT
have been reported to lyse melanoma cells and exhibit
anti-tumour activity in animal studies22. Ayyoub et al.
have recently reported lack of tumour recognition by
hTERT peptides 540548-specific CD8 +ve T cells
from melanoma patients, thus raising the possibility of
inadequate antigen processing by the proteosome23.
Small molecules interacting and stabilising the four-
stranded telomeric G-quadruplex have been shown to
be potent inhibitors of telomerase and human cancer
cell line growth24. Such compounds (e.g. cationic
porphyrins, pentacyclic acridines) may also interact with
telomere-like DNA regions, guanine rich RNA or DNA
enzymes, thus interfering with normal cellular function.
Future prospects
Although inhibition of telomerase and telomeres offers
exciting therapeutic possibilities in the fight against
human cancer, further basic scientific research is
required in order to overcome two important limitations
to this approach. Firstly, alternative lengthening of
telomeres (ALT) by copy switching and homologous
recombination occurs in up to 10% of human cancers.
The process is suppressed in telomerase-positive
tumours and is reactivated in telomerase-negative
cancer.
Theoretically ALT can lead to anti-telomerase
resistance. Such resistance is least likely with anti-G-
quadruplex small molecules. Secondly, anti-telomerase
therapy is associated with efficacy delay which seems to
be dependant on the tumour doubling time and the size
distribution of telomeres25. This observation suggests
that cancer cells will be affected before telomerase
positive normal cells (long telomeres, long doubling
time) by anti-telomerase therapy.
Furthermore normal cells are likely to recover rapidly
after the completion of treatment.
Phase I and II clinical trials evaluating indirect
inhibitors of telomerase such as hTERT immunotherapy
have already commenced. However, careful animal
studies are required to evaluate anti-sense
oligonucleotides and anti-G-quadruplex small molecules
before planning clinical trials in humans.
Telomerase Inhibitors in the Treatment of Cancer Mokbel 471
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CrossRef links are available in the online published version of this paper:
http://www.cmrojournal.com
Paper CMRO-2342, Accepted for publication: 30 March 2003
Published Online: 11 July 2003
doi:10.1185/030079903125002081
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2003 LIBRAPHARM LTD Curr Med Res Opin 2003; 19(6)