|
Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 15, Number 16, 2009
Contents
Inflammation as Target for Pharmaceutical
Intervention in Cancer
Executive Editors: R.M. Schiffelers and
K.E. de Visser
Editorial: Pp.
1822-1824
Targeted Delivery of Anti-Inflammatory Agents to Tumors Pp.
1825-1843
M. Coimbra, S.A. Kuijpers, S.P. van Seters, G.
Storm and R.M. Schiffelers
[Abstract] [Purchase
Article] [PMID:
19519426 PubMed - indexed for MEDLINE]
Towards Understanding the Role of Cancer-Associated
Inflammation in Chemoresistance Pp. 1844-1853
K.E. de Visser and J. Jonkers
[Abstract] [Purchase
Article] [PMID:
19519427 PubMed - indexed for MEDLINE]
III. Angiogenesis: Complexity of Tumor Vasculature and Microenvironment
Pp. 1854-1867
M. Furuya, Y. Yonemitsu and I.
Aoki
[Abstract] [Full
Text Article] [PMID:
19519428 PubMed - indexed for MEDLINE]
Mast Cells as Target in Cancer Therapy
Pp. 1868-1878
T.G. Kormelink, A. Abudukelimu and
F.A. Redegeld
[Abstract] [Purchase
Article] [PMID:
19519429 PubMed - indexed for MEDLINE]
Regulatory T Cells: Major Players in
the Tumor Microenvironment Pp. 1879-1892
M. Beyer and J.L. Schultze
[Abstract] [Purchase
Article] [PMID:
19519430 PubMed - indexed for MEDLINE]
General Articles
Designed Multiple Ligands: An Emerging Anti-HIV Drug Discovery
Paradigm Pp. 1893-1917
P. Zhan and X. Liu
[Abstract] [Purchase
Article] [PMID:
19519431 PubMed - indexed for MEDLINE]
Scientific and Clinical Challenges in
Sepsis Pp. 1918-1935
L. Ulloa, M. Brunner, L. Ramos and
E.A. Deitch
[Abstract] [Purchase
Article] [PMID:
19519432 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
Editorial: Inflammation as Target for Pharmaceutical
Intervention in Cancer
Inflammation and cancer are closely associated. Crosstalk
between both disease processes starts at the level of carcinogenesis
but is also implicated in tumor growth, progression and metastasis
[1-4]. Although the inflammatory response can play a role
in tumor suppression by stimulating an antitumor immune response,
support of tumor development is more dominant. This makes
a variety of anti-inflammatory pharmaceuticals interesting
candidates for therapeutic intervention in cancer [5-8]. At
the same time, it is not completely understood how cancer-associated
inflammation is regulated and how pro- and anti inflammatory
pathways can optimally be manipulated to maximize anticancer
effects. Improving insight into the cells and mediators that
play a role in the crosstalk between inflammation and cancer
is the aim of this issue.
In some cancer types, inflammation is present before a malignant
change occurs. This so-called tumor-initiating inflammatory
response can be caused by infectious agents, chronic irritation
or chemical damage [9-11]. For example persistent bacterial
infections, like Helicobacter pylori, predispose
for gastric cancer, and Crohn’s disease is associated
with colon cancer. In addition, chronic inflammation caused
by reflux esophagitis or asbestosis is clearly linked with
esophageal adenocarcinoma and mesothelioma respectively. In
many other types of cancer, however, inflammation is not the
initiating trigger. Instead, oncogenic changes in these cancers
frequently elicit an inflammatory tumor microenvironment that
facilitates further tumor development and progression, i.e.
cancer-associated inflammation [12]. For example, human breast
cancer is frequently characterized by abundant presence of
infiltrating immune cells, whereas breast cancer has not been
directly linked with infectious conditions. Thus, also malignancies
not directly linked to bacterial or viral infections are often
associated with inflammation.
Inflammation may develop into a chronic process when the cause
for the inflammatory response is not eliminated or when the
normal mechanisms that terminate the process fail. As a result,
the balance between pro-and anti-inflammatory mediators is
not restored and inflammation continues. It is believed that
carcinogenesis is promoted by chronic inflammation as a result
of local activation of stromal cells that release a variety
of pro-inflammatory molecules that activate endothelium and
attract circulatory inflammatory cells [13, 14]. The ensuing
inflammatory reaction can promote tumor progression via direct
and indirect mechanisms. For example, macrophages may be a
source of reactive oxygen and nitrogen species which can cause
direct damage to DNA by forming single or double-stranded
breaks and stimulate recombination [15, 16]. Central enzyme
in the damage by free radicals is cyclooxygenase 2 (COX-2)
[17]. Consequently, drugs that inhibit this enzyme have been
under investigation for their prophylactic activity. Apart
from damage by reactive molecules, inflammatory cells also
release cytokines that favor cell proliferation and survival,
thereby increasing the number of cells that are at risk for
mutations [18]. At the same time, angiogenic factors are released
that stimulate new blood vessel growth [19, 20]. All in all,
these pathways create a microenvironment that is susceptible
to cancer development. It is important to recognize that the
relation between pro-inflammatory stimuli and cancer is more
subtle than suggested by the previous examples. There are
also cases where infiltration of immune cells protects against
cancer and examples of anti-inflammatory therapies that promote
tumorigenesis [21, 22]. It is particularly the balance between
anti and pro–inflammatory stimuli which needs to be
repaired, requiring a pharmaceutical strategy that reflects
this dual approach.
Also after formation of a cancer in situ, the infiltration
of inflammatory cells, stimulation of angiogenesis and increased
capillary permeability contributes to cancer proliferation
and colonization of distant sites rather than raising an effective
anti-tumor response. This makes anti-inflammatory treatments
not only interesting in a prophylactic but also in a therapeutic
setting. In this stage, it is believed that tumor cells contribute
to chronic inflammation by further stimulation of the infiltration
of inflammatory cells, which in turn are capable of activating
a multitude of inflammatory cascades [1, 4]. Interestingly,
both mediators that promote and suppress tumor cell proliferation
are produced. Again, the imbalance between the effects of
these two classes of activity ultimately results in tumor
progression. Tumor-associated macrophages are a cell type
that embodies this dual role as they are both capable of tumor
cell killing and secretion of factors that promote tumor cell
growth [23, 24]. These factors include angiogenic factors,
growth factors, proteases and cytokines that directly favor
tumor progression or inhibit anti-tumor activities. Macrophages
also secrete proteases that degrade the matrix, which is a
source of growth factors. The difficulty in identifying suitable
drugs for treatment of cancer lies in the multitude of pro-
and anti-inflammatory cascades that are activated at a given
time-point in the tumor, of which the critical pathways should
be controlled to affect disease outcome. These critical pathways
may very well differ depending on tumor stage and origin possibly
requiring individualized pharmaceutical treatments.
Inflammation is also suggested to play a role in metastasis
formation, although the exact underlying mechanisms are less
well understood [25, 26]. The same mediators that are important
in primary tumor proliferation can also play a role in tumor
metastasis as they also enhance tumor cell motility and tumor
vascularization, thus increasing chances of tumor cells entering
and leaving the blood stream. At the site of colonization
it appears again that establishment and growth of a metastasis
depends on stimulating the correct pro-inflammatory molecular
triggers that create a supporting tumor microenvironment.
This issue of Current Pharmaceutical Design is an example
of the interdisciplinary research approach that is needed
to chart cancer inflammation and to evaluate its therapeutic
potential. It approaches the difficulties and opportunities
from different angles and offers insights into the current
status of this rapidly progressing field. The key challenges
in this area are:
• how to model the complex interactions between tumor,
inflammatory, endothelial and stromal cells in vitro
and in vivo with clinical relevance and predictive
therapeutic value
• to understand which pathways are active at specific
stages of cancer growth in specific tissues and how to optimally
modulate them
• to dissect how interactions between the inflammatory
tumor microenvironment and cancer cells influence current
anti-cancer strategies, and how to use this knowledge to improve
anti-cancer therapy
With the current level of interest in this topic in cancer
research we believe that in the coming years rationally designed
anti-inflammatory strategies for cancer will become an integral
part of cancer treatment.
REFERENCES
[1] Allavena P, Garlanda C, Borrello MG, Sica A,
Mantovani A. Pathways connecting inflammation and cancer.
Curr Opin Genet Dev 2008; 18: 3-10.
[2] Hussain SP, Harris CC. Inflammation and cancer: An ancient
link with novel potentials. Int J Cancer 2007; 121: 2373-80.
[3] Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related
inflammation. Nature 2008; 454: 436-44.
[4] Stix G. A malignant flame. Understanding chronic inflammation,
which contributes to heart disease, alzheimer's and a variety
of other ailments, may be a key to unlocking the mysteries
of cancer. Sci Am 2007; 297: 60-7.
[5] Cha YI, DuBois RN. Nsaids and cancer prevention: Targets
downstream of cox-2. Annu Rev Med 2007; 58: 239-52.
[6] Harris RE, Beebe-Donk J, Doss H, Burr Doss D. Aspirin,
ibuprofen, and other non-steroidal anti-inflammatory drugs
in cancer prevention: A critical review of non-selective cox-2
blockade (review). Oncol Rep 2005; 13: 559-83.
[7] Rostom A, Dube C, Lewin G, Tsertsvadze A, Barrowman N,
Code C, et al. Nonsteroidal anti-inflammatory drugs
and cyclooxygenase-2 inhibitors for primary prevention of
colorectal cancer: A systematic review prepared for the u.S.
Preventive services task force. Ann Intern Med 2007; 146:
376-89.
[8] Schonthal AH, Chen TC, Hofman FM, Louie SG, Petasis NA.
Celecoxib analogs that lack cox-2 inhibitory function: Preclinical
development of novel anticancer drugs. Expert Opin Investig
Drugs 2008; 17: 197-208.
[9] Algul H, Treiber M, Lesina M, Schmid RM. Mechanisms of
disease: Chronic inflammation and cancer in the pancreas--a
potential role for pancreatic stellate cells? Nat Clin Pract
Gastroenterol Hepatol 2007; 4: 454-62.
[10] Baniyash M. Chronic inflammation, immunosuppression and
cancer: New insights and outlook. Semin Cancer Biol 2006;
16: 80-8.
[11] Karin M, Lawrence T, Nizet V. Innate immunity gone awry:
Linking microbial infections to chronic inflammation and cancer.
Cell 2006; 124: 823-35.
[12] de Visser KE. Spontaneous immune responses to sporadic
tumors: Tumor-promoting, tumor-protective or both? Cancer
Immunol Immunother 2008; 57: 1531-9.
[13] Ganss R. Tumor stroma fosters neovascularization by recruitment
of progenitor cells into the tumor bed. J Cell Mol Med 2006;
10: 857-65.
[14] Pourgholami MH, Morris DL. Inhibitors of vascular endothelial
growth factor in cancer. Cardiovasc Hematol Agents Med Chem
2008; 6: 343-7.
[15] Bartsch H, Nair J. Chronic inflammation and oxidative
stress in the genesis and perpetuation of cancer: Role of
lipid peroxidation, DNA damage, and repair. Langenbecks Arch
Surg 2006; 391: 499-510.
[16] Okada F. Beyond foreign-body-induced carcinogenesis:
Impact of reactive oxygen species derived from inflammatory
cells in tumorigenic conversion and tumor progression. Int
J Cancer 2007; 121: 2364-72.
[17] Evans JF, Kargman SL. Cancer and cyclooxygenase-2 (cox-2)
inhibition. Curr Pharm Des 2004; 10: 627-34.
[18] Mumm JB, Oft M. Cytokine-based transformation of immune
surveillance into tumor-promoting inflammation. Oncogene 2008;
27: 5913-9.
[19] Favaro E, Amadori A, Indraccolo S. Cellular interactions
in the vascular niche: Implications in the regulation of tumor
dormancy. APMIS 2008; 116: 648-59.
[20] Lee DF, Hung MC. All roads lead to mtor: Integrating
inflammation and tumor angiogenesis. Cell Cycle 2007; 6: 3011-4.
[21] Ren JL, Pan JS, Lu YP, Sun P, Han J. Inflammatory signaling
and cellular senescence. Cell Signal 2009; 21: 378-83.
[22] Conroy H, Marshall NA, Mills KH. Tlr ligand suppression
or enhancement of treg cells? A double-edged sword in immunity
to tumours. Oncogene 2008; 27: 168-80.
[23] Nardin A, Abastado JP. Macrophages and cancer. Front
Biosci 2008; 13: 3494-505.
[24] Sica A, Allavena P, Mantovani A. Cancer related inflammation:
The macrophage connection. Cancer Lett 2008; 267: 204-15.
[25] Lu H, Ouyang W, Huang C. Inflammation, a key event in
cancer development. Mol Cancer Res 2006; 4: 221-33.
[26] Radisky ES, Radisky DC. Stromal induction of breast cancer:
Inflammation and invasion. Rev Endocr Metab Disord 2007; 8:
279-87.
Raymond M. Schiffelers
Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences,
Faculty of Science, Utrecht University,
Utrecht, Room Z735a, FAFC Went Building,
PO Box 80.0082, 3508 TB,
The Netherlands
Tel: +31 30 2539392,
Fax: +31 30 2517839,
E-mail: R.M.Schiffelers@uu.nl
Karin E. de Visser
Molecular Biology
Netherlands Cancer Institute
Plesmanlaan 121
1066 CX Amsterdam
The Netherlands
[Back to top]
[Purchase
Article] [PMID:
19519426 PubMed - indexed for MEDLINE]
Targeted Delivery of Anti-Inflammatory Agents to Tumors
M. Coimbra, S.A. Kuijpers, S.P. van Seters, G.
Storm and R.M. Schiffelers
Inflammation is considered a hallmark of cancer. The chronic
inflammatory process is driven by the interaction of cells,
proteins, cytokines, transcription factors, and lipid mediators
within the tumor microenvironment giving rise to complex pro-inflammatory
cascades. These can be inhibited by a variety of different
anti-inflammatory compounds, like non-steroidal anti-inflammatory
drugs, glucocorticoids, anti-inflammatory biologicals, phytotherapeutics
(mainly polyphenols), and drugs with pleiotropic anti-inflammatory
effects. In general, it appears that the anti-tumor activity
of these compounds occurs at higher doses than the doses used
in conventional anti-inflammatory therapy. To optimally take
advantage of the anti-tumor activity and at the same time
limit side effects, targeted delivery of anti-inflammatory
drugs appears an attractive approach.
[Back to top]
[Purchase
Article] [PMID:
19519427 PubMed - indexed for MEDLINE]
Towards Understanding the Role of Cancer-Associated Inflammation
in Chemoresistance
K.E. de Visser and J. Jonkers
Acquisition of resistance to the cytotoxic effects of
anticancer agents is one of the most significant impediments
to effective cancer therapy. Although various cancer-cell
intrinsic mechanisms of drug resistance have been identified,
chemotherapy resistance remains one of the major causes of
cancer patient death. Emerging evidence suggests that the
inflammatory tumor-microenvironment plays an important additional
role in modulating drug responsiveness and drug resistance;
however, underlying mechanisms are still largely unknown.
In this review, we discuss data supporting the idea that crosstalk
between components of the immune system and cancer cells can
influence chemoresistance, and we will speculate on possible
underlying pathways and clinical implications. A deeper understanding
of the cancer cell-intrinsic and –extrinsic mechanisms
of drug resistance will accelerate the development of novel
combinatorial anticancer therapies in which drug resistance
is prevented or reversed.
[Back to top]
[Full
Text Article] [PMID:
19519428 PubMed - indexed for MEDLINE]
III. Angiogenesis: Complexity of Tumor Vasculature and Microenvironment
M. Furuya, Y. Yonemitsu and I.
Aoki
Vascular system plays critical roles in tumor progression
and metastasis. Tumor vessels generally sprout from preexisting
vascular cells. In addition, pluripotent progenitor cells
also participate in tumor neovascularization. The latter populations
include endothelial progenitor cells, hematopoietic stem cells
and mesenchymal stem cells that are stimulated and attracted
into the lesion. Recent studies on tumor microenvironment
have disclosed that BM (bone marrow)-derived progenitor cells
contain unique subpopulations that do not become fully-differentiated
vascular constituents; instead, they show the nature of immature
myeloid or mesenchymal lineage, and they enhance tumor angiogenic
milieu in close contact with tumor vessels. BM-derived cells
also migrate into pre-metastatic niche and stimulate vascular
beds of distant organ for attracting circulating tumor cells.
Currently, several antiangiogenic molecules are under clinical
trials and they are expected to improve overall prognosis.
Humanized monoclonal antibody bevacizumab specifically targeting
VEGF (vascular endothelial growth factor), and several tyrosine
kinase inhibitors targeting VEGF receptors-mediated pathways
are the most widely studied agents in several types of advanced
cancers. It is obvious that VEGF contributes to tumor neovascularization
as a mastermind molecule. On the other hand, the mechanism
has also been elucidated how tumors evade VEGF targeting therapies.
To establish safer and more effective antiangiogenic therapies,
it is important to understand the cross-communication between
tumors and hosts in proinflammatory milieu. In this review,
we discuss features of tumor angiogenic vessels and their
microenvironment. Recent topics on the contribution of BM-derived
cells, complexities of VEGF-targeting approaches, and chemoattractants
that activate tumor vascular beds are summarized.
[Back to top]
[Purchase
Article] [PMID:
19519429 PubMed - indexed for MEDLINE]
Mast Cells as Target in Cancer Therapy
T.G. Kormelink, A. Abudukelimu and
F.A. Redegeld
A close interaction of cancer cells with their microenvironment
is important for their growth and survival. In this respect,
the involvement of inflammatory cells in the initiation, promotion
and progression of cancer has pointed to new therapeutic opportunities
in the treatment of cancer. The main immune cell types implicated
in tumor-associated inflammation are macrophages, dendritic
cells, lymphocytes, neutrophils, eosinophils and mast cells.
Their precise role in intercellular communication, regulation
of tumor inflammation, and to what respect this inflammation
contributes to tumor development, are not completely understood.
Mast cells are key effector cells in allergic diseases, but
it has become apparent that they also contribute to other
pathologies, including autoimmune diseases and cancer. Activated
mast cells can release many pro-angiogenic and tumor growth
stimulatory mediators. Increased numbers of mast cells are
found in many tumors and it has been shown that the number
of tumor infiltrating mast cells correlate with increased
intratumoral microvessel density, enhanced tumor growth and
tumor invasion, and poor clinical outcome. Therefore, modulating
mast cell recruitment, viability, activity, or mediator release
patterns at malignant sites can be of importance to control
tumor growth. In this review, we will focus on the contribution
of mast cells to tumor development and growth and the possibilities
to interfere in mast cell activation and proliferation in
the therapy of cancer.
[Back to top]
[Purchase
Article] [PMID:
19519430 PubMed - indexed for MEDLINE]
Regulatory T Cells: Major Players in the Tumor Microenvironment
M. Beyer and J.L. Schultze
Over the last years a number of reports have described
elevated numbers of regulatory T (Treg)
cells inside of tumors, in close proximity of the tumor, draining
lymph nodes and also in peripheral blood of patients with
solid tumors and hematologic malignancies. There is increasing
evidence that Treg cells
can migrate into tumors and suppress effective anti-tumor
responses in the tumor microenvironment, thus contributing
to the prosperity and growth of human tumors. In addition,
several mechanisms have been described how conversion of conventional
CD4+ T cells into Treg
cells can occur in the context of human tumors, yet little
is known about the molecular and cellular features responsible
for the increase and maintenance of elevated levels of Treg
cells in cancer. Recent studies now have elucidated how Treg
cells mediate regulatory activity in the tumor microenvironment
and enhanced our understanding of the underlying molecular
mechanisms. Targeting Treg
cells therefore provides an attractive therapeutic strategy
to potentially influence the suppressed immune response in
tumor patients thereby altering and supporting anti-tumor
therapy.
[Back to top]
[Purchase
Article] [PMID:
19519431 PubMed - indexed for MEDLINE]
Designed Multiple Ligands: An Emerging Anti-HIV Drug Discovery
Paradigm
P. Zhan and X. Liu
Currently, the effect of AIDS single-target chemotherapy is
severely compromised by the quick emergence of resistant HIV
strains. Highly active antiretroviral therapy (HAART) combines
HIV reverse transcriptase inhibitors with protease inhibitors
or integrase inhibitors, and successfully suppresses HIV viral
load to an undetectable level, dramatically improving the
life quality of AIDS patients. However, the benefits of this
approach are often compromised by poor patient compliance.
Recently, there has been a move toward multicomponent drugs
whereby two or more agents are coformulated in a single tablet
to make dosing regimes simpler and thereby to improve patient
compliance, but there are significant risks involved in the
development of multicomponent drugs. Designed multiple ligands
(DMLs) therapy as an emerging anti-HIV drug discovery paradigm,
using a single entity to inhibit multitargets could yield
improved patient compliance, thus reducing the likelihood
of drug resistance. The exploration of such multifunctional
ligands has proven valuable for anti-HIV leads discovery.
However, presently many multifunctional scaffolds were first
discovered by serendipity or screening; rational design by
combining existing monofunctional scaffolds remains an enormous
challenge. A key issue in the design of multiple ligands is
attaining a balanced activity at each target of interest while
simultaneously achieving a wider selectivity and a suitable
pharmacokinetic profile. This review of literature examples
introduce numerous attractive lead compounds, capable of interfering
with different stages of HIV infection and AIDS pathogenesis,
which reveals trends and insights that might provide valuable
clues for novel anti-HIV drug design and help medicinal chemists
discover the next generation of multiple ligands.
[Back to top]
[Purchase
Article] [PMID:
19519432
PubMed - indexed for MEDLINE]
Scientific and Clinical Challenges in Sepsis
L. Ulloa, M. Brunner, L. Ramos and
E.A. Deitch
Advances in intensive care and antibiotics have prevented
the spread of some infections, though sepsis mortality rates
remain high. With failure of over thirty clinical trials,
sepsis remains a scientific and clinical challenge in modern
medicine. Sepsis is defined by the clinical signs of a systemic
inflammatory response to infection. “Severe sepsis”
is when these symptoms are associated with multiple organ
dysfunction. These definitions of sepsis may be too broad
and common to heterogeneous groups of patients who do not
necessarily have the same disorder. This consideration has
become especially evident in the clinical trials that have
failed to obtain consistent results in similar studies of
patients diagnosed with severe sepsis. In these trials, patients
with infections caused by different microorganisms, and affecting
different organs, have been combined under the general diagnosis
of severe sepsis. The situation is analogous to attempting
a clinical trial based on the general definition of cancer,
combining all patients with tumor independent of the type
of malignancy. In this consideration, it would not be very
surprising that activated protein C, the only treatment in
sepsis approved by the Food and Drug Administration, is projected
for use in only a small subset of patients with severe sepsis.
This article reviews novel inflammatory molecular aspects
and the experimental anti-inflammatory strategies for sepsis,
as they may represent particular pathological processes in
specific subsets of patients.
|
