Drug Design Reviews - Online, Volume 2, No. 5, 2005
Contents
Improving the Development on New Cancer
Treatments: Challenges and Opportunities Pp.341-348
Carolina Vicente Duenas, Felipe Voces, Maria Perez-Caro, Ines Gonzalez-Herrero and Isidro Sanchez-Garcia
Fucose Specific Lectins in Cancer Research
and Diagnosis Pp.349-359
Oksana
Yu. Praizel, Rima P. Evstigneeva, Igor A. Yamskov and Alexander A. Shtil
mRNA as a Therapeutic Target in Lung Disease Pp.361-372
B.
A. Jones and A. D. Schreiber
Current Prodrug Strategies for the Delivery
of Nucleotides into Cells
Pp.373-387
Maria
Eugenia Ariza
Stereoselective Interactions Between Local
Anesthetics and Cardiac K+ Channels Pp.389-396
M.
Guizy, C. Arias, M. David and C. Valenzuela
Therapeutic Relevance of Targeting Nuclear
Factor kappaB with Transcription Factor Decoy Molecules Pp.397-407
Roberto
Gambari
Modulating Agents in Resistant Malaria Pp.409-418
C.
M. S. Menezes and E. I. Ferreira
Abstracts
[Back to top] Improving the Development on New Cancer
Treatments: Challenges and Opportunities
Carolina
Vicente Duenas, Felipe Voces, Maria Perez-Caro, Ines Gonzalez-Herrero and
Isidro Sanchez-Garcia
At present, there are
ten times more anticancer drugs being tested in clinical trials than there were
15 years ago. However, many of the new anticancer agents target unconventional
aspects of cancer development, interact with other drugs in an unpredictable
manner and are predicted to show clinical benefit in only small subpopulations
of patients. How can clinical trials be re-designed to accommodate the new
features of targeted anticancer drugs and/or approaches? Herein we will review
these obstacles: i) limitations in our knowledge of molecular and systems
biology of cancer, ii) application of new agents in inappropriate clinical
settings, in unselected patients, and without a clear understanding of the role
of the putative target in mediating the antitumour effect. Collection of
tissues from models mimicking human cancer at time points that correspond with
maximal clinical effect will provide the best opportunity to gain insight into
the reasons why agents work or, more commonly, don’t work before going into a
clinical trial.
[Back to top] Fucose Specific Lectins in Cancer Research
and Diagnosis
Oksana
Yu. Praizel, Rima P. Evstigneeva, Igor A. Yamskov and Alexander A. Shtil
Lectins represent a
class of proteins that recognize and interact with the carbohydrate moieties on
biological polymers. Analyzed here are the lectins that interact with the
fucose, the terminal carbohydrate residue of secretory glycoconjugates and
plasma membrane glycopolymers of eukaryotic cells. The ability to selectively
bind the unique fucose containing determinants, referred to as fine
carbohydrate specificity, makes these proteins valuable in experimental and
clinical cancer research. This review analyzes the state-of-the-art and recent
advances in chemistry, isolation and biomedical applications of fucose specific
lectins, the proteins that bind the fucose residues of carbohydrate antigens.
Emphasizing the role of fucose containing determinants in cancer progression,
the authors focus on fucose specific lectins as the tools for laboratory
diagnosis of major human malignancies including leukemia and carcinomas of the
colon, stomach and breast. Studies of this class of proteins may be highly
productive for both understanding the mechanisms of the disease and for
rational design of lectin-based diagnostic and therapeutic reagents.
[Back to top] mRNA as a Therapeutic Target in Lung Disease
B.
A. Jones and A. D. Schreiber
Most current
therapeutic approaches focus on targeting a protein or its function after it
has been translated. A therapeutic approach that is gaining interest is
altering the mRNA that encodes for a disease associated protein and preventing
the protein from being produced. There are two major therapeutic methods to
alter mRNA levels, antisense and RNA interference (RNAi). Currently, antisense
is the more developed technology and has been extensively used in vivo.
As this review will mostly focus on in vivo studies, animal models or
humans, it will concentrate on antisense. The lung is an attractive target for
this technology as the drug can be introduced to the organ with limited
systemic involvement. Inflammatory diseases of the lung, such as allergy or
asthma, are potential areas in which antisense technology could be beneficial.
There are many mRNA targets being investigated for treatment in inflammatory
lung disease that include signaling molecules as well as receptors. Also,
antisense is being investigated for treatment of lung cancers. In lung cancer,
some oncogenic genes may be unique to the tumor and can be specifically
targeted without affecting other cellular processes. Thus, antisense and RNAi
potentially provide an alternative to current therapy for treatment of
pulmonary disorders.
[Back to top] Current Prodrug Strategies for the Delivery
of Nucleotides into Cells
Maria
Eugenia Ariza
Nucleosides are
currently used in the treatment of many infections caused by viruses and
against various cancers. The principal
historic limitations of the development of nucleoside drugs that either
directly inhibit DNA or RNA polymerases or that inhibit RNA and DNA replication
by virtue of their ability to act as alternative substrates for these
polymerases, have been the requirements for cellular penetration of the
uncharged nucleosides and their subsequent biological conversion to the pharmacologically active nucleoside
triphosphate (NTP) species.
Unfortunately, intracellular phosphorylation of nucleosides frequently results in toxic by-products,
limiting the drug dose that can be administered. In the past few decades, intensive research has provided
insights into the nature of chemical and biological requirements associated
with the in vitro selective delivery of nucleotides into cells. As such,
cleavable protecting groups represent a very powerful tool to increase not only
drug delivery but also bioavailability.
This review presents an update of prodrug strategies in which the most
prominent masking groups currently in use for the treatment of cancer and viral
diseases, their stability, toxicities and biological activities are discussed.
In particular, the following prodrugs: S-acyl-2-thioethyl (SATE),
pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC), amino acid
esters, and polyethylene glycol drug conjugates will be addressed.
[Back to top] Stereoselective Interactions Between Local Anesthetics and Cardiac K+
Channels
M.
Guizy, C. Arias, M. David and C. Valenzuela
Ionic channels are
membrane proteins that can be blocked by many different types of drugs such as
local anesthetics, antiarrhythmics, etc. Therefore, they are considered drug
targets, whose topology, at the ion channel level, has been analyzed by
studying the interactions of specific ion channel blockers and site-directed
mutant ion channels. Stereoselective interactions are especially interesting
because they can reveal three-dimensional relationships between drugs and
channels with otherwise identical biophysical and physicochemical properties.
Furthermore, stereoselectivity suggests direct and specific receptor-mediated
action, and identification of such stereospecific interactions may have
important clinical consequences. However, =25% of drugs used in clinical
practice are racemic mixtures, the individual enantiomers of which frequently
differ in both their pharmacodynamic and pharmacokinetic profile. Furthermore,
these different effects induced by one of the enantiomers of a racemic drug may
contribute to the undesired effects that can be similar or different to the
pharmacological effect of the racemic drug. In other cases, the enantiomers on
the molecular target are opposite. In this review, we focus on the
stereoselective effects of bupivacaine on different Kv channels. Bupivacaine
stereoselectively blocks Kv1.5 and Kv11.1 channels, whereas
non-stereoselectively it blocks Kv2.1 and Kv4.3 channels.
[Back to top] Therapeutic Relevance of Targeting Nuclear
Factor kappaB with Transcription Factor Decoy Molecules
Roberto
Gambari
Transcription factors
belonging to the NF-kappaB superfamily are involved in several human
pathologies, as well as in biological processes facilitating the onset of
diseases. Among well established functions of NF-kappa B factors is the
promotion of osteoclast differentiation in osteopenic diseases, the enhancement
of inflammatory processes in cystic fibrosis, the involvement in asthma and
pulmonary diseases associated to dust or smoke. In consideration of these roles
of NF-kappaB, targeting of these transcription factors could be of great
interest. A very promising approach to alter NF-kappaB regulated gene
expression is the transcription factor decoy (TFD) strategy. The TFD approach
employs double stranded oligodeoxyribonucleic acids mimicking the NF-kappaB
binding sites or bioactive analogues; therefore, treatment of cells with these
decoy molecules causes a binding of NF-kappaB factors to them and not to the
target promoter sequences, leading to a strong inhibition of NF-kappaB
dependent biological functions. Decoy molecules targeting NF-kappaB factors
were found in vitro inducers of apoptosis, and strong inhibitors of cell
cycle progression, and TNF-alpha induced gene expression in several
experimental cell systems. In vivo, decoy molecules targeting NF-kappaB
factors were employed for prolonged survival of renal allografts, regression of
atopic dermatitis, and cardiac protective effects. Therefore, the design and
development of novel molecules able to target NF-kappaB, including modified
oligonucleotides, LNA (locked nucleic acids) and peptide nucleic acids (PNA)
based transcription factors decoys are of great interest. In this respect, TFD
activity of double stranded PNA-DNA-PNA chimeras has been demonstrated to be
useful to inhibit NF-kappaB dependent functions.
[Back to top] Modulating Agents in Resistant Malaria
C.
M. S. Menezes and E. I. Ferreira
Modulating agents in
combination with major chemotherapeutics have been proposed for restoring drug
effectiveness in cellular or parasite resistance. Verapamil was the first in
vitro modulating agent reported for resistant malaria followed by psychoactive
drugs, natural products and other diverse structural compounds. However,
conflicting results for in vitro and in vivo assays and in
clinical tests have been reported following the use of modulating agents in
combination with antimalarial drugs, mainly, chloroquine. We, herein,
demonstrated the failure of modulating agents to restore the in vitro
sensibility of Brazilian chloroquine-resistant P. falciparum isolates.
In contrast, a significant intrinsic antiplasmodial effect, which was not
dependent on the chloroquine combination, was observed. Nevertheless, it is
currently recognized that the effectiveness or failure of modulating agents
depends on genotypic characteristics, the observed intrinsic activity may be
hypothesized based on the common biological or antiplasmodial effect. This may
occur due to the structural similarities of chloroquine and the modulating
agents. Similar features have also been observed in the new lead modulating
agents. In this paper, an overview of the evaluation, use and perspectives of
modulating agents against drug and multidrug-resistant malaria is presented.