Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 27, 2007
Contents
Target Specificity of Effective Anticancer Therapeutics
Executive Editor: G. Capranico
Editorial Pp. 2742-2743
Modulation of Gene Transcription by Natural Products
– A Viable Anticancer Strategy Pp. 2744-2750
M. D’Incalci, D. Brunelli, E. Marangon, M. Simone,
M. Tavecchio, A. Gescher and R. Mantovani
[Abstract]
Protein Kinase Inhibitors: Structural Insights Into
Selectivity Pp. 2751-2765
R. Thaimattam, R. Banerjee, R. Miglani and J. Iqbal
[Abstract]
DNA Topoisomerase II Structures and Anthracycline
Activity: Insights into Ternary Complex Formation
Pp. 2766-2780
D. Dal Ben, M. Palumbo, G. Zagotto, G. Capranico and S.
Moro
[Abstract]
The Relation Between Stereochemistry and Biological
Activity of Platinum(II) Complexes Chelated with Chiral Diamine
Ligands: An Intricate Problem Pp. 2781-2794
F. Dufrasne and M. Galanski
[Abstract]
Angiogenesis Inhibitors. Drug Selectivity and Target
Specificity Pp. 2795-2809
G. Kesisis, H. Broxterman and G. Giaccone
[Abstract]
Targeted Therapies for Non-Small Cell Lung Cancer
Pp. 2810-2831
G.S. Papaetis, C.Roussos and K.N. Syrigos
[Abstract]
General Articles
Food-Derived Advanced Glycation end Products (AGEs): A Novel
Therapeutic Target for Various Disorders Pp. 2832-2830
S.-i. Yamagishi, S. Ueda and S. Okuda
[Abstract]
The Advance of Dendrimers - A Versatile Targeting
Platform for Gene/Drug Delivery Pp. 2837-2850
H.S. Parekh
[Abstract]
Abstracts
[Back to top]
Editorial: Target Specificity of
Effective Anticancer Therapeutics
The great progress in genomic research of past decades has
fueled the expectation that compounds specifically targeting
single disease-causing protein or gene could cure human cancers.
The list of proposed targets, from those directed against
DNA replication processes and mitosis, or against hormonal
regulation of cell growth, has been markedly extended to many
cellular processes. Newer targets have been proposed among
proteins in aberrant signaling pathways, present as second
messengers, on the cell surface (receptors) or externally
(ligands). Others encompass cancer cell interactions with
the environment involving blood supply (angiogenesis), immune
function (evasion), or matrix (invasion and metastasis). Even
though some progress has been attained, many agents directed
against new targets have been found to be ineffective or to
cause significant side effects, and indeed cancer mortality
remains high. This disappointing outcome likely highlights
the limited value of the single-target paradigm. Thus, much
interest has increased towards multiple-targeted drugs or
combinatorial drugs as well as novel rationals for drug development
that take into account the complexity of mammalian cells and
organisms.
Our understanding of the mechanisms of action of current clinically-useful
antitumor drugs is rather limited as we miss a full understanding
of the behavior of highly-complex regulatory networks of organisms
and how they respond to effective agents. Moreover, this limited
knowledge prevents a truly rational approach to drug discovery
and identification of new effective targets. In the present
issue of Current Pharmaceutical Design we have attempted
to review and discuss the concept of single-target specificity
of new and classical antitumor drugs with proven clinical
efficacy.
D’Incalci et al. [1] have discussed the attempts,
mostly unsuccessful, of drug design in the case of transcription
factors involved in the pathogenesis of human neoplasms. The
failure is likely due to the high complexity of transcription
regulation networks, still too inadequately understood to
be a suitable target for drug design. It seems plausible that
the high selectivity of some human tumors to some DNA-interactive
drugs is related to an effect on the transcription of genes
that are crucial for the tumors. Taking the marine natural
product Yondelis (Trabectedin, ET-743) as an example, the
authors suggest that natural products have been selected during
evolution to possess highly specialized functions, including
modulation of the expression of specific genes. Moreover,
they indicate that exploitation of natural products as modulators
of gene expression is a promising approach to discover new
effective anti-neoplastic drugs.
Protein kinases are highly involved in cancer development
and have constituted attractive targets for drug discovery
in the past. By revising the large structural information
on protein kinases, Thaimattam et al. [2] discuss
recent insights into selectivity and mechanisms of inhibition.
They pointed out that prediction of binding specificity of
kinase inhibitors, based on structural information alone,
appears to be poor or unsatisfactory. Thus, the authors have
attempted to gain insights into the rules that govern protein
kinase inhibitor selectivity by revising the published information.
Dal Ben et al. [3] have built a computer model of
the human DNA Topoisomerase II structure to investigate the
receptor site of antitumor inhibitors. The reported analyses
suggest a model wherein the drug specifically contacts the
cleaved DNA as well as amino acid residues of the enzyme CAP-like
domain. The findings can explain several established structure-activity
relationships of antitumour anthracyclines, and provide a
framework for further developments of effective Top2 poison.
Dufrasne and Galanski [4] present the case of platinum complexes.
The authors discuss the mode of interaction with DNA of anticancer
platinum(II) complexes and their relevant pharmacological
effects. The platinum-DNA interaction model has been widely
accepted, nevertheless, as other chiral bio-molecules are
very reactive towards the platinum complexes, they may contribute
to stereoselectivity, and to resistance and toxicity. The
authors provide an insightful discussion of bionucleophiles
that have been identified to react with platinum(II) complexes
and of analytical methods to investigate these interactions.
The importance of angiogenesis for tumor progression has long
been appreciated, and consequently, the emergence of anticancer
drugs targeting the tumor vasculature has been a breakthrough
for the treatment of several tumors in the recent past. Kesisis
et al [5] have reviewed the principle of anti-angiogenic
therapies, illustrating the complexity of growth signal networks
involved in tumor angiogenesis and interactions with microenvironment
factors. The authors also provide a discussion of relevant
clinical findings and of the limitations due to the emergence
of resistance.
Papaetis et al. [6] have addressed the therapeutic
developments for human non-small cell lung cancer (NSCLC).
The authors have reviewed novel agents in current clinical
trials, and suggest that there is still much to be learned
about the proper design of clinical trials and the selection
of patient population enrolled in them. Multi-targeted therapy
still remains the most attractive avenue for future treatment
strategies.
Finally, I wish to thank all the authors for the excellent
contributions, and Mr. Kazim Ali Baig for constant support
and help in preparing the issue.
References
[1] D’Incalci M, Brunelli D, Marangon E, Simone M, Tavecchio
M, Gescher A, Mantovani R. Modulation of gene transcription
by natural products – a viable anticancer strategy?
Curr Pharm Des 2007; 13(27): 2744-2750.
[2] Thaimattam R, Banerjee R, Miglani R, Iqbal J. Protein
kinase inhibitors: structural insights into selectivity. Curr
Pharm Des 2007; 13(27): 2751-2765.
[3] Dal Ben D, Palumbo M, Zagotto G, Capranico G, Moro S.
DNA topoisomerase II structures and anthracycline activity:
insights into ternary complex formation. Curr Pharm Des 2007;
13(27): 2766-2780.
[4] Dufrasne F, Galanski M. The relation between stereochemistry
and biological activity of platinum(II) complexes chelated
with chiral diamine ligands: an intricate problem. Curr Pharm
Des 2007; 13(27): 2781-2794.
[5] Kesisis G, Broxterman H, Giaccone G. Angiogenesis inhibitors.
Drug selectivity and target specificity. Curr Pharm Des 2007;
13(27): 2795-2809.
[6] Papaetis GJ, Roussos C, Syrigos KN. Targeted therapies
for non-small cell lung cancer. Curr Pharm Des 2007; 13(27):
2810-2831.
Giovanni Capranico
“G. Moruzzi”
Department of Biochemistry
University of Bologna
via Irnerio 48, 40126 Bologna
Italy
Tel: +39 051 2094282
Fax: +39 051 2094283
E-mail: giovanni.capranico@unibo.it
[Back to top]
Modulation of Gene Transcription by Natural Products
– A Viable Anticancer Strategy
M. D’Incalci, D. Brunelli, E. Marangon, M. Simone,
M. Tavecchio, A. Gescher and R. Mantovani
Drug design based on the structure of specific enzymes playing
a role in carcinogenesis, e.g. tyrosine kinases, has been
successful at identifying novel effective anticancer drugs.
In contrast, no success has been achieved in drug design attempts,
in which transcription factors or DNA-transcription factor
complexes involved in the pathogenesis of human neoplasms
were targeted. This failure is likely to be due to the fact
that the mechanism of transcription regulation is probably
too complex and still too inadequately understood to be a
suitable target for drug design. It seems plausible that the
high selectivity of some human tumors to some DNA-interactive
anticancer drugs, e.g. cisplatin, is related to an effect
on the transcription of genes that are crucial for those tumors.
In this article we propose that some natural products have
evolutionarily evolved to exert highly specialized functions,
including modulation of the transcriptional regu-lation of
specific genes. We discuss in detail the marine natural product
Yondelis (Trabectedin, ET-743) that is effective against some
soft tissue sarcoma, possibly because it interferes with the
aberrant transcription mechanism in these tumors. In addition
we highlight the existing evidence that many different natural
products are effective inhibitors of NF-κB,
a transcription factor that plays a crucial role in inflammation
and cancer, indicating that some of these compounds might
possess antitumor properties. We propose that large-scale
characterization of natural products acting as potential modulators
of gene transcription is a realistic and attractive approach
to discover compounds therapeutically effective against neoplastic
diseases characterized by specific aberrations of transcriptional
regulation.
[Back to top]
Protein Kinase Inhibitors: Structural Insights Into
Selectivity
R. Thaimattam, R. Banerjee, R. Miglani and J. Iqbal
Protein kinases are involved in many diseases like cancer,
inflammation, cardiovascular disease, and diabetes. They have
become attractive target classes for drug development, making
kinase inhibitors as important class of therapeutics. The
success of small-molecule ATP-competitive kinase inhibitors
such as Gleevec, Iressa, and Tarceva has attracted much attention
in the recent past. Kinases make use of ATP for phosphorylation
of a specific residue(s) on their protein substrates. More
than 400 X-ray structures of about 70 different kinases are
publicly available. These structures provide insights into
selectivity and mechanisms of inhibition. However, prediction
of binding specificity of kinase inhibitors based on structural
information alone appears to be insufficient. Here, we will
review these observations to gain insights into the rules
that govern protein kinase inhibitor selectivity.
http://www.bentham.org/cpd/contabs/thaimattam/images
[Back to top]
DNA Topoisomerase II Structures and Anthracycline
Activity: Insights into Ternary Complex Formation
D. Dal Ben, M. Palumbo, G. Zagotto, G. Capranico and S.
Moro
DNA Topoisomerase II (Top2) is an essential nuclear enzyme
that regulates the topological state of the DNA, and a target
of very effective anticancer drugs including anthracycline
antibiotics. Even though several aspects of drug activity
against Top2 are understood, the drug receptor site is not
yet known. Several Top2 mutants have altered drug sensitivity
and have provided information of structural features determining
drug action. Here, we have revised the published crystal structures
of eukaryotic and prokaryotic Top2s and relevant biochemical
investigations of enzyme activity and anthracycline action.
In particular, we have considered Top2 mutations conferring
resistance to anthracyclines and related agents. Following
a previous study (Moro et al, Biochemistry, 2004;
43: 7503-13), we have then re-built a molecular model of the
entire enzyme in complex with DNA after the cleavage reaction,
and used it to define the receptor site of anthracyclines.
The results suggest a model wherein the drug specifically
contacts the cleaved DNA as well as amino acid residues of
the enzyme CAP-like domain. The findings can explain several
established structure-activity relationships of antitumour
anthracyclines, and provide a framework for further developments
of effective Top2 poison.
[Back to top]
The Relation Between Stereochemistry and Biological
Activity of Platinum(II) Complexes Chelated with Chiral Diamine
Ligands: An Intricate Problem
F. Dufrasne and M. Galanski
The origin of activity differences between stereoisomers of
anticancer platinum(II) complexes chelated with chiral diamine
ligands has been almost exclusively explained by diastereoselective
interactions with DNA. Although this model has been widely
accepted in vitro and in vivo experiments
showed some conflicting results, leading to the conclusion
that other biomolecules might be responsible for this stereoselectivity
as well. These compounds, called bionucleophiles, are in most
instances amino acids or proteins present in biological fluids.
As these chiral molecules are very reactive towards the platinum
complexes, they may contribute to stereoselectivity, but also
to resistance and toxicity. This review gives a general survey
of chiral platinum(II) complexes and their interactions with
DNA. The bionucleophiles which have been identified and the
consequences of their reaction with platinum(II) complexes
are discussed. Analytical techniques used to investigate interactions
between established and potential chiral platinum drugs and
bionucleophiles are presented.
[Back to top]
Angiogenesis Inhibitors. Drug Selectivity and Target
Specificity
G. Kesisis, H. Broxterman and G. Giaccone
The critical role of angiogenesis in tumor development and
progression has long been appreciated. The elucidation of
the mechanisms of tumor angiogenesis and the emergence of
anticancer drugs targeting the tumor vasculature has been
a breakthrough in the treatment of several tumors in the last
few years. Several novel molecules are being developed that
target different aspects of angiogenesis. This review outlines
the principle of anti-angiogenic therapies, illustrates the
main mechanisms and complexity of growth signals involved
in tumor angiogenesis, its interactions with hypoxia, stroma
and tumor microenvironment. It provides a comprehensive review
of clinical results obtained with anti-angiogenic agents (VEGF/VEGFR
signaling inhibitors, direct angiogenesis inhibitors, vascular
disrupting agents) and finally discusses the differences of
the several approaches and their limitations due to the emergence
of resistance.
[Back to top]
Targeted Therapies for Non-Small Cell Lung Cancer
G.S. Papaetis, C.Roussos and K.N. Syrigos
Conventional therapy for non-small cell lung cancer (NSCLC)
has reached a plateau in increasing patient survival and overall
prognosis still remains dismal. Advances in the knowledge
of molecular events governing oncogenesis has led to a number
of novel agents targeting specific pathways critical for tumour
growth and survival. In the present paper we have thoroughly
reviewed the existing evidence of novel agents currently studied
in clinical trials, focusing on epidermal growth factor receptor
family inhibitors, angiogenesis inhibitors, cyclooxygenase-2
inhibitors, Bcl-2 targeted agents, protein kinase C inhibitors,
proteasome inhibitors, farnesyl transferase inhibitors and
retinoids. Although erlotinib monotherapy in the second or
third line setting and bevacizumab combined with conventional
chemotherapy as a frontline therapy manage to prolong the
life of patients with NSCLC, there is still much to be learned
about the proper design of clinical trials and the selection
of patient population enrolled in them. Multi-targeted therapy
still remains the most attractive avenue for future treatment
strategies.
[Back to top]
Food-Derived Advanced Glycation end Products (AGEs): A Novel
Therapeutic Target for Various Disorders
S.-i. Yamagishi, S. Ueda and S. Okuda
Non-enzymatic modification of proteins by reducing sugars,
a process that is also known as Maillard reaction, leads to
the formation of advanced glycation end products (AGEs) in
vivo. It is now well established that formation and accumulation
of AGEs progress during normal aging, and at an extremely
accelerated rate under diabetes, thus being implicated in
various types of AGE-related disorders such as diabetic vascular
complications, neurodegenerative diseases and cancers. Further,
there is accumulating evidence that AGEs and their receptor
RAGE interaction elicits oxidative stress generation and subsequently
alters gene expression in various types of cells. In addition,
digested food-derived AGEs are found to play an important
role in the pathogenesis of the AGE-related disorders as well.
Indeed, restriction of diet-derived AGEs not only blocks the
progression of atherosclerosis and renal injury, but also
improves insulin resistance in animal models. AGE-poor diets
reduce serum levels of inflammatory biomarkers in patients
with diabetes or chronic renal failure. These observations
suggest that the restriction of food-derived AGEs or the inhibition
of absorption of dietary AGEs may be a novel target for therapeutic
intervention in the AGE-related disorders. In this paper,
we review the pathological role of food-derived AGEs in various
types of disorders and discuss the potential utility of oral
adsorbent that inhibits the absorption of AGEs in these devastating
diseases.
[Back to top]
The Advance of Dendrimers - A Versatile Targeting
Platform for Gene/Drug Delivery
H.S. Parekh
The quest towards achieving a better understanding of underlying
mechanisms by which genetic factors contribute to human disease
has gathered considerable momentum, most notably due to the
drafting of the complete human genome sequence. This has in
turn accelerated research into identifying genes responsible
for a plethora of genetic, infectious and metabolic diseases
with the vision that therapies can then be developed. Although
achieving a therapeutic intervention by gene delivery is perfectly
feasible, the practical approach to achieving such a goal,
at least in vivo, has proved far more challenging.
Employing viruses as gene vectors has to-date proven to be
the most effective method of delivery however concerns have
emerged about both the short and long-term risks they pose.
These fears being confirmed by incidents which led to the
tragic deaths of subjects believed to have been triggered
by adeno- & retroviral vectors used in clinical trials.
This prompted many in the field to turn their research focus
towards developing non-viral vectors deemed not only to be
safer (non-immunogenic) than their viral counterparts but
with a greater gene loading capacity. Polycationic dendrimers
(PCDs) as vectors for this purpose have attracted significant
interest due to their ease of synthesis, versatility and tolerability.
This review will explore the physicochemical parameters crucial
to PCD-mediated gene delivery and highlight some innovative
strategies designed to maximise transfection efficacy and
facilitate tissue-targeting of these elaborate macromolecules.
|
