Current Medicinal Chemistry–Immunology, Endocrine & Metabolic Agents Volume 2, No. 4, 2002
Endostatin: Preclinical Development as an
Anticancer Agent Pp. 233-243
T.
Bachelot, R. Pawliuk, E. Jouanneau and P. Leboulch
[Abstract]
Genetic Lipodystrophies: Models for Insulin
Resistance Pp. 245-250
Robert
A. Hegele
[Abstract]
Recent Advances in the Diagnosis and Therapy
of Primary Adrenal Insufficiency Pp.251-272
Stefano
Laureti, Fausto Santeusanio and Alberto Falorni
[Abstract]
Cerebral Hemorrhage Produced by Thrombolytic
and Anti-Thrombotic Agents: A Review >Pp. 273-278
Y.
Suzuki, B.Q. Zhao and K. Umemura
[Abstract]
Inhibitor at the Gates, Inhibitor in the
Chamber:
Allosteric and
Competitive Inhibitors of the Proteasome as Prospective Drugs Pp. 279-301
M.
Gaczynska and P.A. Osmulski
[Abstract]
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Endostatin: Preclinical Development as an Anticancer Agent.
T.
Bachelot, R. Pawliuk, E. Jouanneau and P. Leboulch
Advances in
angiogenesis research have shed a new light on the growth and metastasic spread
of solid tumors, allowing to define new paradigms for cancer treatment. These
studies have highlighted the dramatic therapeutic potential of natural
inhibitors of angiogenesis, which were found capable of maintaining tumors in a
state of dormancy. One of the most promising of these recently described
natural inhibitors of angiogenesis is endostatin, a C-terminal fragment of collagen
XVIII. In-vitro, endostatin strongly inhibits endothelial cell proliferation
and migration. Initial in-vivo studies were impressive, recombinant endostatin
was shown to induce regression and prevent the growth of experimental tumors in
mice. Several studies by independent teams were published thereafter, they
either described different forms of the recombinant protein, or
developed gene therapy approaches. Most groups have shown perceptible activity
in mouse tumor models, albeit without evidence of tumor regression. More recent
studies have failed to show any significant antitumor activity. The resolution
of these paradoxes is fundamental for obtaining a better view of the
therapeutic potential of endostatin. This may require a better understanding of
the mechanism of action of endostatin at the molecular level, which remains
largely unknown.
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Genetic Lipodystrophies: Models for Insulin Resistance
Robert
A. Hegele
The common syndrome of
insulin resistance with hyperinsulinemia is frequently associated with a
collection of metabolic abnormalities, including dyslipidemia,
hypertension and diabetes. Lipodystrophy syndromes, which include both genetic
and acquired forms, resemble the insulin resistance syndrome, particularly with
respect to the presence of associated biochemical disturbances such as
hyperlipidemia and diabetes. Since the discovery in 1999 that mutant LMNA
causes Dunnigan-type partial lipodystrophy, human mutations in three other
genes have been implicated in inherited lipodystrophy syndromes, namely PPARG
in partial lipodystrophy, and AGPAT and BSCL2 in complete lipodystrophy. There
is evidence for additional genetic heterogeneity for lipodystrophy syndromes.
Delineation of the human molecular genetic basis of forms of inherited
lipodystrophy may help to identify pathways and molecular targets for the
common insulin resistance syndrome and for acquired drug-induced lipodystrophy
syndromes.
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Recent Advances in the Diagnosis and Therapy of Primary Adrenal Insufficiency
Stefano
Laureti, Fausto Santeusanio and Alberto Falorni
Primary adrenal
insufficiency (PAI) is the consequence of the bilateral destruction or impaired
function of the adrenal cortex. The reduction of adrenocortical cell mass is
responsible for a deficiency of glucocorticoids and, in some cases, of
mineralocorticoids and adrenal androgens. Over the past few decades, new data
on the prevalence of PAI, advances in the procedure for the clinical
testing of the adrenal function, and the development of novel genetic and molecular
biology techniques have improved our understanding of the physiopathological
mechanisms involved in the process of adrenal dysfunction and its genetic
background. The estimated prevalence of PAI is 110-120 subjects per million
individuals, being slightly higher among females than among males. The
diagnosis of PAI is made in the presence of the typical symptoms and signs
accompanied by reduced levels of serum cortisol and elevated levels of
plasmatic ACTH. The intravenous injection of synthetic ACTH (250 mg) (HDT) is helpful for testing cortisol response
in patients with suspected PAI. Recently, we have demonstrated that the intravenous
injection of very low doses of synthetic ACTH (1 mg)
(LDT) has a high diagnostic sensitivity and specificity for PAI, and this test
could be proposed as an accurate way to identify subjects with adrenal
dysfunction. The presence of a mineralocorticoid deficiency can be tested by
measuring plasmatic or urinary aldosterone levels, which can be low in PAI, and
plasma renin activity, which is elevated. Adrenal androgen deficiency (i.e.
DHEA) can be assessed by specific radioimmunoassays, but they are not usually performed
in routine clinical practice. The clinical spectrum of Addison’s disease has
expanded dramatically, and a long series of additional causative mechanisms has
been identified. In Western countries, up to 70% of cases of PAI is the
consequence of the autoimmune destruction of adrenocortical cells. The enzyme
steroid 21-hydroxylase (21OH) is the major adrenal autoantigen in autoimmune
PAI and the appearance of adrenal cell autoantibodies (ACA) and 21OH antibodies
(21OHAb) is considered a sensitive and specific immune marker of this
condition. The genetic risk for autoimmune PAI is associated with HLA-DR3-DQ2
and with allele 5.1 of the MHC class I chain-related A (MICA) gene. Chronic PAI
may also result from targeting of the adrenal gland by Mycobacterium
tuberculosis, fungal agents, Cytomegalovirus infection during AIDS or
coagulative diseases and bilateral metastasis. Many genetic disorders, such as
X-linked adrenoleukodystrophy (ALD), adrenal hypoplasia congenita (AHC) and ACTH
resistance syndrome, can cause PAI in children, and sometimes also in adult
subjects. ALD is a hereditary peroxisomal disorder characterized by
demyelination of the nervous system and PAI, the detection of increased
plasmatic levels of VLCFA is the biochemical marker of this disease. AHC is another
X-linked disorder, in which affected males present with hypogonadotropic
hypogonadism and PAI, the gene involved is known as DAX-1 and is located in the
long arm of chromosome X. Familial ACTH resistance syndrome is characterized by
high levels of ACTH and adrenal insufficiency due to mutations of the ACTH
receptor gene, located on chromosome 18p11. This clinical form should be
differentiated from triple A syndrome (achalasia, alacrimia, adrenal insufficiency),
which is caused by a recently identified gene located on chromosome 12q13. This
wide range of forms of PAI suggests that identification of the etiologic cause
of PAI in the individual patient is an important diagnostic step, due to the
different clinical management. The treatment of PAI is based on
hormone-replacement therapy. Cortisol deficiency can be compensated by oral
administration of hydrocortisone or cortisone acetate twice or three times a
day. The mineralocorticoid drug used for aldosterone replacement is
9-alpha-fluoro-cortisol, administered orally every day or on alternate days.
Recent clinical studies have shown that the administration of DHEA is beneficial
in PAI patients, and for this reason it has been proposed that treatment with
DHEA could be a useful supplement to the replacement therapy for PAI.
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Cerebral Hemorrhage Produced by Thrombolytic and Anti-Thrombotic Agents: A
Review.
Y.
Suzuki, B.Q. Zhao and K. Umemura
Although tissue-type
plasminogen activator (t-PA) is believed to be beneficial in the treatment of
acute strokes, t-PA treatment increases the risk of symptomatic cerebral
hemorrhage. Therefore, the possibility of a fatal complication of cerebral
hemorrhage may limit the potential benefits of anti-thrombotic and thrombolytic
agents. The potential mechanisms of hemorrhage may be activated by an increase
of plasmin activity that produces systemic hemostatic defects. Furthermore,
plasmin activates matrix metalloproteinases (MMPs), which degrade extracellular
matrix components including laminin and fibronectin. The impairment of vascular
integrity and the production of hemorrhage then follow. It has been reported
that MMP activity increased in hemorrhagic transformation after cerebral ischemia
/ reperfusion injury in primates, and that the activated forms of MMPs may play
an essential role in opening theblood-brain barrier and in
cerebral hemorrhage. Recently, two spin trap agents and a metalloproteinase
inhibitor have been reported to reduce cerebral hemorrhage following thrombotic
stroke. Although it is unclear by what mechanism(s) free radicals may increase
MMP expression, these findings suggest that free radicals and MMPs may play
essential roles in cerebral hemorrhage from the treatments with thrombolytic
and anti-thrombotic agents in acute strokes. We demonstrated that a free
radical scavenger inhibited cerebral hemorrhage produced by heparin, and that
the combination of heparin and such a free radical scavenger reduced infarct
size and improved neurological symptoms. Our observations point to combination
therapy with thrombolytic or anti-thrombotic agents and a free radical scavenger
having implications for treatment of acute stroke in human.
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Inhibitor at the Gates, Inhibitor in the Chamber:
Allosteric and Competitive
Inhibitors of the Proteasome as Prospective Drugs
M.
Gaczynska and P.A. Osmulski
In the pursuit of new
drug targets and novel drugs, finding a promising remedy for an incurable
disease is an unusual feat. This exactly happened recently with the proteasome
and its inhibitor, PS-341, which emerged in initial clinical trials as a
prospective drug against multiple myeloma. The proteasome is the major executor
of a tightly regulated nonlysosomal proteolysis in human cells and constitutes
an attractive target for the development of drugs against cancer, autoimmune
diseases, muscle wasting, inflammation and stroke. Synthetic peptide derivatives:
boronates, epoxides, aldehydes, vinyl sulfones, cyclic peptides and lactones
are tested for their in vivo and in vitro performance. These compounds block
the N-terminal threonine-type active centers of the enzyme, halting cleavage of
all proteasomal substrates in the cell and triggering apoptosis. Apparently,
cancer cells are more susceptible than normal cells to such drastic treatment.
The great advantage of competitive proteasome inhibitors as drugs derives from
the apparent lack of drug-induced resistance. On the other hand, there is an
emerging field of noncompetitive inhibitors targeting allosteric interactions
between proteasomal subunits and offering a great potential of precise interventions
into the cellular physiology. One of such inhibitors, a natural antibacterial
peptide PR-39, has been shown recently to specifically block activation of a
major transcription factor, NFkB, by the
proteasome, and degradation of a regulator of oxygen distribution, HIF-1a, without affecting a gross intracellular protein
catabolism. PR-39 and its derivatives are promising antiinflammatory agents and
regulators of angiogenesis. Rational design of competitive and allosteric
effectors of the proteasome is the challenge pursued by combined efforts of
chemists and biologists.