Recent
Patents on Anti-Cancer Drug Discovery
ISSN: 1574-8928
Recent Patents on Anti-Cancer
Drug Discovery
Volume 1, Number 1, January 2006
Contents
Platinum Complexes as Anticancer Agents Pp. 1-22
Irena Kostova
[Abstract] [Full
Text Article]
Older and New Formulations of Cladribine. Pharmacology and
Clinical Efficacy in Hematological Malignancies Pp. 23-38
Tadeusz Robak, Anna Korycka & Ewa Robak
[Abstract] [Full
Text Article]
Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors in Cancer
Chemotherapy Pp. 39-53
Victoria Cepeda, Miguel A. Fuertes, Josefina Castilla,
Carlos Alonso, Celia Quevedo, Manwel Soto & José
M. Pérez
[Abstract] [Full
Text Article]
Novel Checkpoint 1 Inhibitors Pp. 55-68
Michelle Prudhomme
[Abstract] [Full
Text Article]
Inhibitors for Metastasis Development Pp. 69-80
Kerstin Lang, Theodore L. Drell IV, Kurt S. Zaenker
& Frank Entschladen
[Abstract] [Full
Text Article]
Targeting Inhibitor of Apoptosis Proteins (IAPs) for Diagnosis
and Treatment of Human Diseases Pp. 81-89
Simone Fulda & Klaus-Michael Debatin
[Abstract] [Full
Text Article]
Natural Bio-Drugs as Matrix Metalloproteinase Inhibitors:
New Perspectives on the Horizon? Pp. 91-103
Ferdinando Mannello
[Abstract] [Full
Text Article]
Intracellular Calcium, Endothelial Cells and Angiogenesis
Pp. 105-119
Luca Munaron
[Abstract] [Full
Text Article]
Tumor Stem Cell Niches: A New Functional Framework for the
Action of Anticancer Drugs Pp. 121-127
Bruce C. Baguley
[Abstract] [Full
Text Article]
Potential and Cytotoxicity of cis-Platinum Complex
with Anti-tumor Activity in Combination Therapy Pp. 129-134
John W. Ho
[Abstract] [Full
Text Article]
Patent Annotations
Pp. 135-140
Patent Selections
Pp. 141-152
Abstracts
[Back to top]
Platinum Complexes as Anticancer Agents
Irena Kostova
[Full Text Article]
The application of inorganic chemistry to medicine is a rapidly
developing field, and novel therapeutic and diagnostic metal
complexes are now having an impact on medical practice. Advances
in biocoordination chemistry are crucial for improving the
design of compounds to reduce toxic side effects and understand
their mechanisms of action. Cisplatin, as one of the leading
metal-based drugs, is widely used in the treatment of cancer.
Significant side effects and drug resistance, however, have
limited its clinical applications. Biological carriers conjugated
to cisplatin analogs have improved specificity for tumor tissue,
thereby reducing side effects and drug resistance. Platinum
complexes with distinctively different DNA binding modes from
that of cisplatin also exhibit promising pharmacological properties.
This review focuses on recent advances in developing platinum
anticancer agents with an emphasis on platinum coordination
complexes.
[Back to top]
Older and New Formulations of Cladribine. Pharmacology
and Clinical Efficacy in Hematological Malignancies
Tadeusz Robak, Anna Korycka & Ewa Robak
[Full Text Article]
The purine nucleoside analog (PNA) - cladribine (2-CdA, 2-chlorodeoxyadenosine)
is a cytotoxic agent of high efficacy in lymphoid and myeloid
malignancies. This drug was approved by the FDA for treatment
of hairy cell leukemia and in some European countries for
treatment of refractory/relapsed chronic lymphocytic leukemia.
2-CdA is usually administered as continuous or intermittent
intravenous infusion. Recently however, new formulations of
this agent has been developed for subcutaneous and oral administration.
In contrast to other PNA, 2-CdA is equally cytotoxic to both
proliferating and quiescent cells and several pathways may
be responsible for the mechanism of its action. In addition,
recent data indicate that 2-CdA combined with other cytotoxic
agents and monoclonal antibodies show synergistic proapoptotic
and cytotoxic activity on lymphoid and myeloid neoplastic
cells. This review article summarizes recent achievements
in the understanding of 2-CdA mechanism of action, pharmacokinetics
of different pharmaceutical formulations and its approved
and possible future applications in the treatment of hematological
malignancies.
The most important recent patents concerning oral formulations
of 2-CdA have been presented.
[Back to top]
Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors in Cancer
Chemotherapy
Victoria Cepeda, Miguel A. Fuertes, Josefina Castilla,
Carlos Alonso, Celia Quevedo, Manwel Soto & José
M. Pérez
[Full Text Article]
Poly(ADP-ribose) polymerases (PARPs) are defined as a family
of cell signaling enzymes present in eukaryotes, which are
involved in poly(ADP-ribosylation) of DNA-binding proteins.
The best studied of these enzymes (PARP-1) is involved in
the cellular response to DNA damage so that in the event of
irreparable DNA damage overactivation of PARP-1 leads to necrotic
cell death. Inhibitors of PARP-1 activity in combination with
DNA-binding antitumor drugs may constitute a suitable strategy
in cancer chemotherapy. When DNA is moderately damaged, PARP-1
participates in the DNA repair process and the cell survives.
However, in the case of extensive DNA damage PARP-1 overactivation
induces a decrease of NAD+ and ATP levels leading to cell
dysfunction or even to necrotic cell death. So, due to PARP-1
involvement in cell death, pharmacological inhibition of PARP-1
activity by PARP-1 inhibitors may constitute a suitable target
to enhance the activity of antitumor drugs through inhibition
of necrosis and activation of apoptosis. PARP-1 inhibitors
such as 3-aminobenzamide, 1,5-dihydroxyisoquinolinone and
the recently patented tryciclic benzimidazoles have shown
potent inhibitory effects of PARP-1 activity in tumor cells.
The present review gives an update of the state-of-the-art
of inhibition of PARP-1 activity as adjuvant therapy in cancer
treatment.
[Back to top]
Novel Checkpoint 1 Inhibitors
Michelle Prudhomme
[Full Text Article]
Cell cycle ckeckpoints are activated in response to DNA damage.
Their role consists in blocking the cell cycle to allow time
for DNA repair. The activity of the G1 checkpoint is dependent
on the p53 protein. In more than 50% of human tumor cells,
the p53 gene is mutated. In the p53
mutated cells, the G1 checkpoint is lacking. In these cells,
only the G2 checkpoint, although weaker than in healthy cells,
provides cancer cells with the opportunity to repair the DNA
after damage. Therefore, combining a G2 checkpoint inhibitor
with a DNA damaging agent should force, selectively cancer
cells, into a premature and lethal mitosis, due to an accumulation
of DNA lesions. Among the regulators of the G2 checkpoint,
Checkpoint 1 kinase (Chk1) plays a major role. A widespread
interest has been recently devoted to the discovery of Chk1
inhibitors, as potential useful compounds to enhance the antitumor
efficiency of DNA damaging agents. This review article will
summarize: (i) the chemical structures of the novel Chk1 inhibitors
reported in the recent patents; (ii) their inhibitory activity
towards Chk1; (iii) their effects on tumor cells in combination
with DNA damaging agents; and (iv) the in vivo results
on animal models.
[Back to top]
Inhibitors for Metastasis Development
Kerstin Lang, Theodore L. Drell IV, Kurt S. Zaenker
& Frank Entschladen
[Full Text Article]
A leading cause of death, cancer remains the bane of modern
society and one of the most challenging research fields. Cancer
is initially a localized disease that can be often treated
well at a very early stage. However the vast majority of cancer
deaths result from a pernicious progression of the disease,
the development of distant metastases. It must therefore be
a pressing research goal to focus on the pharmacological prevention
of metastasis development. This review summarizes the current
understanding of the cellular and molecular mechanisms of
metastasis development, and suggests possible approaches for
its inhibition.
[Back to top]
Targeting Inhibitor of Apoptosis Proteins (IAPs) for Diagnosis
and Treatment of Human Diseases
Simone Fulda & Klaus-Michael Debatin
[Full Text Article]
Since cell death by apoptosis plays a key role in the regulation
of tissue homeostasis, any defect in this intrinsic death
program may result in tumor formation. “Inhibitor of
apoptosis proteins” (IAPs) block apoptosis at the core
of the apoptotic machinery by inhibiting effector caspases.
Aberrant expression and/or function of IAPs have been implied
to be involved in the pathogenesis and progression of various
human diseases including cancer, autoimmune disorders or neurodegeneration.
Recent insights into the regulation of IAPs have provided
the basis for various exciting discoveries aimed at modulating
expression or dysfunction of IAPs. Thus, targeting IAPs, e.g.
by antisense approaches, RNA interference or small molecules,
may proof to be a novel strategy for the diagnosis and treatment
of human diseases.
[Back to top]
Natural Bio-Drugs as Matrix Metalloproteinase Inhibitors:
New Perspectives on the Horizon?
Ferdinando Mannello
[Full Text Article]
The matrix metalloproteinases (MMPs), belonging to the family
of proteolytic enzymes, are well-known for their ability to
degrade the extracellular matrix, and are involved in many
aspects of both physiologic cellular processes and pathologic
situations, such as tumour growth, invasion and metastasis.
MMPs have been considered prognostic factors in various types
of cancer as well as promising targets for cancer therapy.
Although preclinical studies of a number of different synthetic
MMP inhibitors have been identified as cytostatic and anti-angiogenic
agents and have begun clinical testing, the past years have
produced a consistent number of disappointments and limited
successes. In view of their specific implication in malignant
tissues, several natural compounds were utilized, and the
results were so satisfactory as to encourage several clinical
trials in order to improve efficacy and to reduce the side
effect profile. The natural protection against cancer has
been receiving a great deal of attention, and the critical
examination of previous studies shed light on new information
about the source and function of MMPs, focusing the attention
on the identification of MMP targets in tumours. In this review
we discuss the current knowledge and research in the field
of natural MMP inhibitor as innovative therapeutic intervention
in cancer.
[Back to top]
Intracellular Calcium, Endothelial Cells and Angiogenesis
Luca Munaron
[Full Text Article]
The proliferation and motility of vascular endothelial cells
(ECs) are critical steps in angiogenesis and are strictly
controlled by different extracellular signals. Among mitogens,
peptides binding to tyrosine kinase receptors (i.e. VEGFs
and FGFs) are well known and are released by several cell
types, including ECs and tumor cells. The binding of mitogens
to their specific receptors triggers intracellular signalling
cascades, involving a number of messengers working in a sort
of network. In particular, in this review we describe the
increases of calcium levels in the cytosol, a universal, evolutionary
conserved and highly versatile signal involved in the regulation
of EC’s proliferation and motility.
Most mitogens, including angiogenic factors, generate cytosolic
calcium rises through two mechanisms: entry from extracellular
medium, through the opening of calcium permeable channels
in the plasmamembrane, or release from intracellular organelles
(mainly endoplasmic reticulum, ER).
Calcium entry, the main topic of this review, can be dependent
on previously IP3-activated emptying of calcium stores (store-dependent
or capacitative calcium entry - CCE), or independent on it
(non capacitative calcium entry, NCCE). The intracellular
pathways underlying calcium entry are under investigation
and recently arachidonic acid (AA) and nitric oxide (NO) metabolism
have been suggested to play a key role, at least in some cell
types. Even if some calcium entry blockers are under clinical
trial with encouraging results, a better knowledge about the
molecular nature of calcium channels and their intracellular
regulation, together with a more detailed description of spatiotemporal
dynamics of intracellular calcium events, could lead to new
and more specific strategies in therapeutical approach to
cancer progression and angiogenesis.
[Back to top]
Tumor Stem Cell Niches: A New Functional Framework for
the Action of Anticancer Drugs
Bruce C. Baguley
[Full Text Article]
Newer treatments of advanced human cancer increasingly rely
on combinations of drugs that have quite different actions
yet unexpectedly potentiate each other’s effects. Recent
research in stem cell biology suggests a model for tumors
in which tumor growth is governed by the generation of cells
from tumor cell niches rather than from the population as
a whole. Each niche contains a population of tumor stem cells
supported by a closely associated vascular bed comprising
mesenchyme-derived cells and an extracellular matrix. Division
of tumor stem cells is asymmetric in the sense that some daughter
cells are always retained within the niche while others leave
the niche to proliferate further and eventually die. One important
potential difference between normal and tumor stem cell niches
is that while most normal stem cells are in a non-proliferating
or G0-state, tumor stem cells are continuously in cycle. Combinations
of cytotoxic drugs and antagonists of survival factors to
reduce the stem cell population may require the addition of
vascular disrupting agents to compromise the function of the
tumor cell niche. As well as providing opportunities for new
drug discovery, this model of tumor growth also presents challenges
as to how the contributions of individual drugs in a combination
might be assessed in individual patients.
[Back to top]
Potential and Cytotoxicity of cis-Platinum Complex
with Anti-tumor Activity in Combination Therapy
John W. Ho
[Full Text Article]
The use of anticancer agents forms an important part for
treatment of cancer of various types. Complexes with cis-platinum
compounds have been used for the prevention and treatment
of cancers. Quite a number of these metal-containing complexes
have been isolated, chemically prepared and characterized
for the treatment of cancer. Many of these compounds display
potent cytotoxic effects, although there is a considerable
progress made in the design of novel anticancer agents. Some
of these compounds showed strong inhibitory effects on cancer
growth with a potential to become anti-cancer drugs. However,
the unwanted deleterious effects hamper the common use of
these agents as anticancer drugs. Nevertheless, the use of
protective agents during, before or after treatment with anti-cancer
agents in combination therapy has proven effective in the
treatment. The results prompt the study of the biologic activities
and the design of better modality for treatment and prevention
of cancer. Here, we review the potential and reduction of
cytotoxic properties of the prominent member of this class
of metal compounds for the treatment of cancer.
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