The
Genome as a Drug Target: Sequence Specific Minor Groove Binding Ligands Pp. 1-14
[Abstract] [Full text article]
Oligonucleotides-based
Gene Therapy for Cardiovascular Disease: Are Oligonucleotides Therapeutics Novel
Cardiovascular Drugs ? Pp.
15-23
[Abstract] [Full text article]
Ginkgo Biloba Extract (EGb 761) and CNS Functions: Basic Studies and Clinical Applications Pp. 25-58
F. V. DeFeudis and K. Drieu
[Abstract] [Full text article]
Proteases Involved in Erythrocyte Invasion by
the Malaria Parasite: Function and Potential as Chemotherapeutic Target Pp. 59-83
Michael J. Blackman
[Abstract] [Full text article]
P-glycoprotein as a Drug Target in the Treatment of Multidrug Resistant Cancer Pp. 85-99
Gustav Lehne
[Abstract] [Full text article]
The
DNA Methylation Machinery as a Therapeutic Target Pp. 101-118
Moshe Szyf
[Abstract] [Full text article]
Abstracts
Back to top] The
Genome as a Drug Target: Sequence Specific Minor Groove Binding Ligands
P. R. Turner and
W. A. Denny
The ability to target defined sequences on the DNA molecule would be of
enormous benefit to the treatment of human disease. Towards this goal much
research has been invested in examining the DNA binding and biological
mechanisms of action of sequence selective minor groove binding
ligands. These compounds act in a variety of ways to inhibit gene expression
and DNA replication and also alter nuclear architecture. Concomitant with
this, minor groove adducts formed by certain compounds are inefficiently removed
by cellular DNA repair systems and are extremely cytotoxic. Additionally compounds
targeting A.T rich DNA sequences have found clinical use in the treatment
of particular parasitic infections.
[Back to top] Oligonucleotides-based Gene Therapy for Cardiovascular
Disease: Are Oligonucleotides Therapeutics Novel Cardiovascular Drugs ?
Ryuichi Morishita, Motokuni Aoki and Yasufumi Kaneda
[Full text article]
Gene therapy is emerging as a potential strategy
for the treatment of cardiovascular disease such as restenosis after angioplasty,
vascular bypass graft occlusion, transplant coronary vasculopathy, for which
no known effective therapy exists. One strategy for combating disease processes
has been to target to the transcriptional process. Two approaches have been
used to accomplish this. One is the use
of antisense that is complimentary to the mRNA of interest.
The second approach is the use of ribozymes, a unique class of RNA
molecules that not only store information but also process catalytic activity.
Ribozymes are known to catalytically cleave specific target RNA leading to
degradation, whereas antisense inhibit translation by binding to mRNA sequences
on a stoicheometric basis. Theoretically, ribozymes are more effective to
inhibit target gene expression. Especially, the application of DNA technology
such as antisense strategy to regulate the transcription of disease-related
genes in vivo has important therapeutic potential.
More recently, transfection of cis-element double stranded (ds) oligodeoxynucleotides
(ODN) (= decoy) as a powerful tool in a new class of anti-gene strategies
for gene therapy has been reported. Transfection of ds ODN corresponding to
cis sequence will result in the attenuation of authentic cis-trans interaction,
leading to the removal of trans-factors from the endogenous cis-elements with
subsequent modulation of gene expression. This ôdecoyö strategy is not only
a novel strategy for gene therapy as an anti-gene strategy, but also a powerful
tool for the study of endogenous gene regulation in vivo as well as in vitro. In this review, we have focused on the future potential
of oligonucleotide (antisense, decoy & ribozyme)-based gene therapy for
the treatment of cardiovascular disease.
.
[Back to top] Ginkgo Biloba Extract (EGb 761) and CNS Functions: Basic Studies and Clinical Applications
The effects
of EGb 761 on the CNS underlie one of its major therapeutic indications; i.e.,
individuals suffering from deteriorating cerebral mechanisms related to age-associated
impairments of memory, attention and other cognitive functions. EGb 761 is
currently used as symptomatic treatment for cerebral insufficiency that occurs
during normal ageing or which may be due to degenerative dementia,
vascular dementia or mixed forms of both, and for neurosensory disturbances.
Depressive symptoms of patients with Alzheimer's disease (AD) and aged non-Alzheimer
patients may also respond to treatment with EGb 761 since this extract has
an "anti-stress" effect. Basic and clinical studies, conducted both
in vitro and in vivo, support these beneficial
neuroprotective effects of EGb 761. EGb 761 has several major actions; it
enhances cognition, improves blood rheology and tissue metabolism, and opposes
the detrimental effects of ischaemia. Several mechanisms of action are useful
in explaining how EGb 761 benefits patients with AD and other age-related,
neurodegenerative disorders. In animals, EGb 761 possesses antioxidant and
free radical-scavenging activities, it reverses age-related losses in brain
a1-adrenergic, 5-HT1A
and muscarinic receptors, protects against ischaemic neuronal death, preserves
the function of the hippocampal mossy fiber system, increases hippocampal
high-affinity choline uptake, inhibits the down-regulation of hippocampal
glucocorticoid receptors, enhances neuronal plasticity, and counteracts the
cognitive deficits that follow stress or traumatic brain injury. Identified
chemical constituents of EGb 761 have been associated with certain actions.
Both flavonoid and ginkgolide constituents are involved in the
free radical-scavenging and antioxidant effects of EGb 761 which decrease
tissue levels of reactive oxygen species (ROS) and inhibit membrane lipid
peroxidation. Regarding EGb 761-induced regulation of cerebral glucose utilization,
bilobalide increases the respiratory control ratio of mitochondria
by protecting against uncoupling of oxidative phosphorylation, thereby increasing
ATP levels, a result that is supported by the finding that bilobalide increases
the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome
oxidase. With regard to its "anti-stress" effect, EGb 761 acts via
its ginkgolide constituents to decrease the expression of the peripheral
benzodiazepine receptor (PBR) of the adrenal cortex.
[Back to
top] Proteases Involved in Erythrocyte Invasion by
the Malaria Parasite: Function and Potential as Chemotherapeutic Target
Malaria places an increasing burden on global
public health resources. In the face of growing resistance of the malaria
parasite to available antimalarial drugs, there is a need for new drugs and
the identification of new chemotherapeutic targets. The malaria parasite has a complex
life cycle which includes a number of obligate intracellular stages. Clinical
malaria results from cyclic asexual replication of the blood-stage parasite
in circulating erythrocytes of the human host. Erythrocyte
entry and host cell rupture require the activity of parasite proteases, and
these enzymes are therefore attractive targets for rational approaches to
new drug development. Malarial proteases play a role in at least two distinct
aspects of host cell invasion; modification of parasite proteins involved
in host cell recognition and entry; and restructuring of the host cell itself
during and following invasion, and in order to allow parasite release from
the host cell. This review details recent advances in the identification of
these proteases, describes current understanding of their activation and functional
role, and discusses their potential as targets for protease inhibitor-based
drugs.
.[Back to top] P-glycoprotein as a Drug Target in the Treatment of Multidrug Resistant Cancer
Gustav Lehne
Multidrug resistance (MDR) is a major obstacle to successful
cancer chemotherapy. One important mechanism of MDR involves the multidrug
transporter, P-glycoprotein (Pgp), which confers upon cancer cells the ability
to resist lethal doses of certain cytotoxic drugs by pumping the drugs out
of the cells and thus reducing their cytotoxicity. Pgp belongs to the ATP-binding
cassette (ABC) family of transporter molecules which require hydrolysis of
ATP to run the transport mechanism. The substrates of Pgp may be endogenous
(steroid hormones, cytokines) or exogenous (cytostatic drugs). A number of studies have
demonstrated a negative correlation
between Pgp expression levels and chemosensitivity
or survival in a range of human malignancies. In principle, Pgp mediated drug
resistance can be circumvented by treatment regimens that either exclude Pgp substrate drugs or include Pgp inhibitory agents. Experimental studies
have demonstrated that certain structural modifications of anthracyclines
confer the ability to escape Pgp transport. The therapeutic benefit of Pgp
inhibitors as chemosensitizers is currently being explored in phase III clinical
trials, and the first promising results have already been reported. Another
therapeutic option for Pgp inhibitors has recently evolved as several Pgp
inhibitors, many of which are generally low-toxic substances, by themselves constrain proliferation and cause
cell death by apoptosis in certain MDR cancer cell lines. The dual effect
of Pgp inhibitors, targeting MDR cancer cells selectively, may translate into
improved efficacy of cancer chemotherapy and perhaps new and less toxic drug
treatment strategies in human MDR cancer.
[Back
to top] The
DNA Methylation Machinery as a Therapeutic Target
Moshe Szyf
Pharmacology and therapeutics have traditionally focused on altering the
activity of specific proteins that play an important physiological role either
to counteract disease processes or to achieve changes in physiology that are
of benefit to the patient. The explossion in our understanding of gene expression
programs opens up new horizons for pharmacological intervention. Key processes
reversibly controlling genetic programs are attractive drug targets. DNA methylation
is a fundamental feature of genomes and the control of their function and
is therefore a candidate for pharmacological manipulation that might have
important therapeutic advantage. This
review argues that DNA methylation plays an important role in the control
of genomic processes, suggests how the DNA methylation machinery is involved
in cancer, identifies the enzymatic processes that are a target for drug intervention,
proposes potential therapeutic utilities for agents that manipulate the DNA
methylation machinery and discusses novel drugs that target the DNA methylation
machinery.