Mini-Reviews in Medicinal Chemistry, Volume 3, No. 1, 2003
Contents
DNA-Telomerase-Targeted
Anti-Cancer Agents
Executive Editor: Manlio
Palumbo
Did Quadruplex DNA Play a Role in the
Evolution of the Eukaryotic Linear Chromosome? Pp.1-9
Haribabu
Arthanari and Philip H. Bolton
The Design of G-quadruplex Ligands as
Telomerase Inhibitors
Pp.11-21
Javier
Cuesta, Martin A. Read and Stephen Neidle
Nucleic Acids as Targets for Antitelomerase
Agents Pp.23-36
Patrizia
Alberti, Laurent Lacroix, Lionel Guittat, Claude Hélène and Jean-Louis Mergny
Alternative Approaches to the Discovery and
Development of Telomerase- Targeted Anticancer Drugs Pp.37-49
Sara
Richter and Manlio Palumbo
Approaches for the Inhibition of Human Telomerase
Based on the Use of Peptide Nucleic Acids and Hammerhead Ribozymes Pp.51-60
N.
Zaffaroni, R. Villa, M. Pennati and M. Folini
Abstracts
[Back to top] Did Quadruplex DNA Play a Role in the
Evolution of the Eukaryotic Linear Chromosome?
Haribabu
Arthanari and Philip H. Bolton
The current
evidence on prokaryotic linear chromosomes, the eukaryotes that do not use
telomerase and quadruplex DNA has been considered. This has lead to the
suggestion that quadruplex DNA may have played a role in the evolution of the
protection linear chromosomes rather than in overcoming the end replication
problem.
[Back to top] The Design of G-quadruplex Ligands as Telomerase
Inhibitors
Javier
Cuesta, Martin A. Read and Stephen Neidle
Guanine-rich
repetitive DNA sequences are of particular importance at the ends of
chromosomes, where they are associated with a number of proteins to form
telomeres. Their function is in large part to protect chromosomal ends from
unwanted degradation and chromosomal fusions, although in normal somatic cells
telomeres progressively shorten, eventually becoming non-proliferating and
consequently these cells have a finite lifetime. By contrast tumour cell
telomeres are maintained in length so that tumour cells are effectively
immortalised. The reverse transcriptase enzyme telomerase is activated in over
80% of tumour cells, and it undertakes the synthesis of further telomeric DNA
repeats, so directly maintaining telomeres. The inhibition of telomerase leads
to the senescence and eventual apoptosis of tumour cells, and thus telomerase
is an attractive target for selective chemotherapy. This review describes an
approach to the inhibition of telomerase that involves the folding of telomeric
DNA into a four-stranded quadruplex structure, held together by Hoogsteen
hydrogen-bonded arrays of guanine bases. The formation of a quadruplex
structure at the 3' end of telomeric DNA effectively hinders telomerase from
adding further repeats. A number of small-molecule ligands are described that
stabilise quadruplex formation, and which result in telomerase inhibition.
Implications for antitumour therapy with such molecules are discussed, and the
particular challenges and problems discussed.
[Back to top] Nucleic Acids as Targets for Antitelomerase
Agents
Patrizia
Alberti, Laurent Lacroix, Lionel Guittat, Claude Hélène and Jean-Louis Mergny
Telomeric DNA
progressively erodes with each round of cell division in cells that do not
express telomerase, a specialized reverse transcriptase necessary to fully
duplicate the chromosomal ends. Telomerase is expressed in tumor cells but not
in most somatic cells and thus telomeres and telomerase may be proposed as
attractive targets for the discovery of new anticancer agents. In this paper we
will present different strategies to inhibit telomerase activity via an
interaction with a telomere/telomerase nucleic acid component, with a special emphasis
on quadruplex ligands.
[Back to top] Alternative Approaches to the Discovery and
Development of Telomerase- Targeted Anticancer Drugs
Sara Richter and Manlio Palumbo
Four different
approaches have been reviewed herein: i) nucleoside analogs as mock agents of
the reverse transcriptase (hTERT) catalytic site; ii) miscellaneous molecules
with unknown mechanism(s) of action; iii) inhibitors of upstream processes of
regulation of the hTERT subunit; iiii) immunotherapy against immunogenic hTERT-
derived peptides.
[Back to top] Approaches for the Inhibition of Human
Telomerase Based on the Use of Peptide Nucleic Acids and Hammerhead Ribozymes
N.
Zaffaroni, R. Villa, M. Pennati and M. Folini
The ability of
peptide nucleic acids and hammerhead ribozymes, which target different subunits
of human telomerase, to efficiently inhibit the enzyme’s catalytic activity has
been clearly demonstrated in several in vitro studies carried out in human
immortalized and cancer cell lines. However, the actual efficacy of these
molecules still needs to be validated in in vivo human tumor models, and such
validation appears to be largely dependent on the development of reliable
systems for their intracellular delivery.