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Current Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 6, Number 4, June 2006
Contents
Antiestrogenic Therapies in Solid Cancers and
Multiple Myeloma Pp. 359-368
Brigitte Sola and Jack-Michel Renoir
[Abstract]
Islet Cell Transplantation Pp. 369-374
Federico Bertuzzi, Simona Marzorati and Antonio Secchi
[Abstract]
Apoptosis in Physiological and Pathological Skin:
Implications for Therapy Pp. 375-394
Ingrid Boehm
[Abstract]
Bone Diseases Associated with Human Immunodeficiency
Virus Infection: Pathogenesis, Risk Factors and Clinical Management
Pp. 395-400
Marco Bongiovanni and Camilla Tincati
[Abstract]
CpG Island Methylation in Precursors of Gastrointestinal
Malignancies Pp. 401-408
Annie On On Chan and Asif Rashid
[Abstract]
EGF and PDGF Receptor Tyrosine Kinases as Therapeutic
Targets for Chronic Lung Diseases Pp. 409-421
Jennifer L. Ingram and James C. Bonner
[Abstract]
Acetylcholine Receptors and Tau Phosphorylation Pp.
423-428
A. Rubio, M. Pérez and Jesús Ávila
[Abstract]
Alterations of Biological Features of the Cerebellum in Sudden
Perinatal and Infant Death Pp. 429-435
Anna M. Lavezzi, Giulia Ottaviani, Maria Mauri and Luigi
Matturri
[Abstract]
Abstracts
[Back to top]
Antiestrogenic Therapies in Solid Cancers and Multiple
Myeloma
Brigitte Sola and Jack-Michel Renoir
Estrogens are essential for human health. Their physiological
effects are primarily mediated by two types of intracellular
estrogen receptors (ERα
and ERβ)
that function as DNA-binding transcription factors. However,
estrogens are also involved in the development and progression
of breast cancers. Endocrine therapy aims to reduce the availability
of the hormone or to counteract its action. This can be achieved
by preventing estrogen production or administrating antiestrogens
(AEs), synthetic drugs belonging to several distinct structural
categories. Selective estrogen receptor modulators (or SERMs)
bind ERs but have a mixed agonist/antagonist profile. Selective
estrogen receptor downregulators (or SERDs) are pure antiestrogens,
acting by decreasing the level of ERs through their ubiquitinylation
and subsequent targeting to the proteasome. We review most
of the usual antiestrogenic therapies for estrogen-dependent
and estrogen-independent solid cancers and present our recent
results on the use of AEs against multiple myeloma. In breast
cancer treatments, the most commonly used antiestrogen, tamoxifen,
has major limitations: side effects due to its partial agonist
activity and constitutive or acquired resistance. We propose
that novel AE drug delivery systems may enhance the overall
beneficial effects by targeting tumoral cells.
[Back to top]
Islet Cell Transplantation
Federico Bertuzzi, Simona Marzorati and Antonio Secchi
Islet cell transplantation is an attractive alternative therapy
to conventional insulin treatment or vascularized whole pancreas
transplantation for type 1 diabetic patients. It represents
a successful example of somatic cell therapy in humans based
on complex procedures for islet isolation from whole pancreas.
The islets, that are only 1% of the total pancreas tissue,
are isolated by two steps method starting with collagenase
digestion that operates a rapid dissociation of the stromal
component of the gland, while preserving islet anatomical
integrity. After digestion, islets are then separated from
exocrine tissue by centrifugation in density gradients.
Transplantation consists of a simple injection of few milliliter-purified
tissue in the portal vein through a percutaneous trans- hepatic
approach performed in local anesthesia.
Several studies have now demonstrated that islet transplant
can replace pancreatic endocrine function without major side
effects and with liver viability preservation in selected
patients affected by long-term type 1 diabetes. It can restore
endogenous insulin secretion, achieve insulin independence
in more than 80% of patients, and recover the metabolism of
glucose, protein and lipids. Improved control of glycated
HbA1c, reduced risk of recurrent hypoglycemia and of diabetic
complications are also seen as important benefits of islet
cell transplantation, irrespective of the status of insulin
independence.
Many protocols are now on going for reduction of immunosuppression
therapy in recipients, induction of tolerance, and prolongation
of graft function.
[Back to top]
Apoptosis in Physiological and Pathological Skin:
Implications for Therapy
Ingrid Boehm
Apoptosis is an inducible suicide program that occurs in
all phases of multicellular as well as in protozoa life and
gains more and more importance in all medical disciplines.
It is required for normal ontogenesis, organ and tissue remodeling,
function of the immune system, prevention of inappropriate
cellular proliferation and of survival of inappropriate mutations.
Thereby apoptosis represents the key event which guarantees
differentiation and maintenance of homeostasis. Terminal differentiation
seems to be a special form of apoptosis. Dysregulated apoptosis
is associated with various pathological conditions, including
inflammation, and cancer. Acanthosis, the hallmark of psoriatic
skin, is an example for diminished epidermal apoptosis. Defects
in termination of inflammatory reactions occur in atopic dermatitis.
Lupus erythematosus may arise due to disturbed apoptosis on
several check points of the apoptosis cascade. Experimental
evidence suggests a role for Bcl-2 and CD95L in the inhibition
of programmed cell death in UV-induced skin cancer or malignant
melanoma cells. Thus, it leads to survival of malignant cell
clones. The slow growth of basal cell carcinomas is due to
an increased apoptosis to mitosis ratio. Spontaneous regression
of tumors is associated with increased apoptotic rates. Malignant
melanoma cells characteristically show different anti-apoptotic
strategies which underscore its aggressive behavior and its
refractory towards classic therapeutic regimens. Additionally,
induction of apoptosis in tumor infiltrating immune cells
seems to be a strategy by which the tumor escapes from an
immunological attack (tumor counter-attack). Since apoptosis
is either absent or altered under pathological conditions
therapeutic procedures should correct this. Established therapies
like dithranol, vitanin-D3 analogs, low-dose methotrexate,
induce apoptosis. Future treatment regimens like vaccine and
gene therapy are designed to selectively induce apoptosis.
Therefore, pharmacological agents and therapeutic strategies
interfering with disrupted apoptosis regulation could improve
the therapeutic arsenal in the future.
[Back to top]
Bone Diseases Associated with Human Immunodeficiency
Virus Infection: Pathogenesis, Risk Factors and Clinical Management
Marco Bongiovanni and Camilla Tincati
Bone disorders such as osteopenia and osteoporosis have been
recently reported in patients infected with the human immunodeficiency
virus (HIV), but their etiology remains still unknown. The
prevalence estimates vary widely among the different studies
and can be affected by concomitant factors such as the overlapping
of other possible conditions inducing bone loss as lypodystrophy,
advanced HIV-disease, advanced age, low body weight or concomitant
use of other drugs. All the reports at the moment available
in the literature showed a higher than expected prevalence
of reduced bone mineral density (BMD) in HIV-infected subjects
both naïve and receiving potent antiretroviral therapy
compared to healthy controls. This controversial can suggest
a double role played by both antiretroviral drugs and HIV
itself due to immune activation and/or cytokines disregulation.
An improved understanding of the pathogenesis of bone disorders
can result in better preventative and therapeutic measures.
However, the clinical relevance and the risk of fractures
remains undefined in HIV-population.
The clinical management of osteopenia and osteoporosis in
HIV-infected subjects is still being evaluated. Addressing
potential underlying bone disease risk factors (e.g., smoking
and alcohol intake, use of corticosteroids, advanced age,
low body weight), evaluating calcium and vitamin D intake,
and performing dual x-ray absorptiometry in HIV-infected individuals
who have risk factors for bone disease can be important strategies
to prevent osteopenia and osteoporosis in this population.
The administration of bisphosphonates (e.g., alendronate),
with calcium and vitamin D supplementation, may be a reasonable
and effective option to treat osteoporosis in these subjects.
[Back to top]
CpG Island Methylation in Precursors of Gastrointestinal
Malignancies
Annie On On Chan and Asif Rashid
Gastrointestinal malignancies account for about 20% of all
cancers worldwide. It is widely accepted that cancer evolves
through several stepwise morphological stages such as the
adenoma-carcinoma and hyperplastic polyp-serrated adenoma-carcinoma
sequences in colorectal cancers, and the metaplasia-dysplasia-carcinoma
sequences in esophageal and gastric cancers. The morphological
progression is associated with the accumulation of multiple
genetic and epigenetic events. It is now recognized that epigenetic
silencing of gene expression by CpG island methylation is
an important alternative mechanism of inactivating tumor suppressor
genes. Inflammatory conditions of the gastrointestinal and
pancreaticobiliary tracts and liver such as Barrett esophagus,
Helicobacter pylori gastritis, inflammatory bowel
disease and viral hepatitis, are associated with increased
frequency of malignancies and CpG methylation. In addition,
CpG methylation is present in aberrant crypt foci and pancreatic
intraepithelial neoplasia that are considered putative precursors
of colon and pancreatic carcinomas, respectively. Understanding
of these early genetic and epigenetic changes allows for the
discoveries of potential screening, monitoring and therapeutic
strategies. Targeting of the epigenetic changes that occur
before the development of frank malignancy offers a potential
chemopreventive strategy.
[Back to top]
EGF and PDGF Receptor Tyrosine Kinases as Therapeutic
Targets for Chronic Lung Diseases
Jennifer L. Ingram and James C. Bonner
Cell-surface receptor tyrosine kinases play pivotal roles
in development, tissue repair, and normal cellular homeostasis.
Aberrant expression or signaling patterns of these kinases
has also been linked to the progression of a diversity of
diseases, including cancer, atherosclerosis, asthma, and fibrosis.
Two major families of receptor tyrosine kinases, the epidermal
growth factor receptor (EGFR) and platelet-derived growth
factor receptor (PDGFR) families, have received a great deal
of attention as potential therapeutic targets for pulmonary
diseases, as these receptors have been shown to play key roles
in chronic tissue remodeling in asthma, bronchitis, and pulmonary
fibrosis. The EGFR system on epithelial cells and underlying
mesenchymal cells (fibroblasts, myofibroblasts, and smooth
muscle cells) drives numerous phenotypic changes during the
progression of these pulmonary diseases, including epithelial
cell mucous cell metaplasia and mesenchymal cell hyperplasia,
differentiation, and extracellular matrix production. The
PDGFR system, located primarily on mesenchymal cells, transduces
signals for cell survival, growth and chemotaxis. The variety
of EGFR and PDGFR ligands produced by the airway epithelium
or adjacent mesenchymal cells allows for intimate epithelial-mesenchymal
cell communication. A full understanding of the complex mechanisms
involving these receptors and ligands should lead to therapeutic
strategies for the treatment of a wide range of fibroproliferative
lung diseases.
[Back to top]
Acetylcholine Receptors and Tau Phosphorylation
A. Rubio, M. Pérez and Jesús Ávila
Alzheimer's disease (AD) is characterized by the presence,
in the brain of the patients, of two aberrant structures:
intracellular neurofibrillary tangles (NFTs), containing an
abnormal hyperphosphorylated form of tau protein, and extracellular
senile plaques (SPs), mainly composed by fibrillar amyloid
β peptide.
Another feature of AD is the neurodegeneration and dysfunction
of basal forebrain cholinergic system. A possible connection
among those AD characteristics could occur. Thus, the purpose
of this short review is to summarize the involvement of nicotinic
(nAChR) and muscarinic (mAChR) receptors on tau phosphorylation,
in a direct way, or through the previous interaction of some
of these receptors with amyloid β.
Several studies have demonstrated that nAChR activation results
in a significantly increase of tau phosphorylation, whereas
mAChR activation, may prevent tau phosphorylation.
[Back to top]
Alterations of Biological Features of the
Cerebellum in Sudden Perinatal and Infant Death
Anna M. Lavezzi, Giulia Ottaviani, Maria Mauri and Luigi
Matturri
This article intends to show how the cerebellum, a structure
ordinarily not considered in mediating breathing or cardiovascular
control, may play a critical role in compensatory responses
particularly to hypoxic insults occurring pre and/or postnatally
and thus may be involved in the sudden unexplained perinatal
and infant death. Besides the ontogenesis of the cerebellar
cortex in man, we reported alterations of biopathological
features (neuronal immaturity, altered apoptotic programs,
negative expression of somatostatin and EN2 gene, intense
c-fos expression positivity, astrogliosis) in the cortex and
in the dentate nucleus of the 63% of sudden deaths, and only
in 10% of the controls. The correlation of these results with
the mother’s smoking habit was highly significant. Therefore,
we support the hypothesis, already expressed in previous studies
on brainstem, of a close relation between maternal cigarette
smoking and a wide range of morpho-physiological defects of
the brain, leading to unexplained sudden death in stillbirths,
newborns, and Sudden Infant Death Syndrome (SIDS) victims.
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