Current Drug Targets-Immune, Endocrine & Metabolic Disorders, Volume 2, No. 2, 2002
Recombinant Adenovirus-mediated Cytotoxic Gene
Therapy and Lymphoproliferative Disorders:Analysis Based on Pharmacodynamics Pp.109-118
Francesco Turturro
Targeting the AMP-Activated Protein Kinase
for the Treatment of Type 2 Diabetes Pp.119-127
Nicolas Musi and Laurie J. Goodyear
Inhibitors of Post-Translational
Modifications of G-Proteins as Probes to Study the Pancreatic b Cell Function: Potential Therapeutic
Implications Pp.129-139
A. Kowluru and R. Amin
Novel Targets for Therapy in Paediatric
Oncology Pp.141-150
E.J. Estlin
Therapeutic potential of the mammalian
pyruvate dehydrogenase kinases in the prevention of hyperglycaemia Pp.151-165
M.C. Sugden and M.J. Holness
Molecular Basis of Hyperparathyroidism and
Potential Targets for Drug Development Pp.167-179
L.J. Krebs and A. Arnold
Apoptotic Cell Death in Renal Injury: The
Rationale for Intervention
Pp.181-192
A. Ortiz, P. Justo, M.P. Catalán, A.B. Sanz, C. Lorz and J. Egido
[Back to top] Recombinant Adenovirus-mediated Cytotoxic
Gene Therapy and Lymphoproliferative Disorders:Analysis Based on
Pharmacodynamics
The literature has seen an incredible booming of publications related
to the use of adenovirus-mediated gene therapy in cancer over the past decade.
The use of recombinant adenoviruses as a therapeutic tool for
lymphoproliferative disorders has also been evaluated in this context. Several
approaches of adenovirusmediated gene expression have been used to transfect
cell lines that are derived from lymphoid tumors and would have otherwise been
refractory to other transfection methods. The identification of high affinity
receptor for human adenoviruses serotype 2 and 5, the coxsackie-adenovirus
receptor (CAR), has raised the question about its relevance for the efficacy of
recombinant adenovirus-mediated gene therapy.
We have reviewed the published studies that have examined the use of
recombinant adenovirus vectors expressing cytotoxic genes for gene therapy in
lymphomas, chronic lymphocytic leukemia and multiple myeloma. Based on the
concept that a recombinant adenovirus particle behaves like a drug, we address
the issue of adenovirus-mediated gene therapy in terms of classic
pharmacodynamics. We have analyzed the use of recombinant adenovirus-mediated
cytotoxicity by assessing the importance of the biochemical and physiological
signaling pathways interacting with these particular drugs and their mechanisms
of action. The case of anaplastic large cell lymphoma is discussed as an
example that better illustrates the concept of pharmacodynamics of recombinant
adenoviral-mediated expression of cytotoxic genes. Ultimately, the issues
derived from the use of such a modality of therapy that require further
evaluation, are discussed in this review.
[Back to top] Targeting the AMP-Activated Protein Kinase
for the Treatment of Type 2 Diabetes
Nicolas
Musi and Laurie J. Goodyear
The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme
that is activated in response to conditions of cellular stress such as muscle
contraction and hypoxia. In skeletal muscle, activation of AMPK leads to
increased glucose uptake, enhanced insulin sensitivity and oxidation of fatty
acids. In the liver, AMPK activation causes an increase in fatty acid oxidation
and inhibition of glucose production. These effects on glucose and fat
metabolism make AMPK an important pharmacological target for the treatment of
type 2 diabetes. Studies done in animal models of type 2 diabetes have shown
that pharmacological activation of AMPK
with the compound 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)
decreases blood glucose and insulin concentrations. While strong efforts are
underway in order to identify novel AMPKactivating compounds, the safety of chronic
pharmacological activation of AMPK remains to be determined.
[Back to top] Inhibitors of Post-Translational
Modifications of G-Proteins as Probes to Study the Pancreatic b Cell Function: Potential Therapeutic Implications
A.
Kowluru and R. Amin
It is well established that glucose-induced insulin secretion involves
generation of intracellular second messengers. Using specific inhibitors of
guanosine triphosphate [GTP] biosynthesis [e.g., mycophenolic acid; MPA], we
have identified a permissive role for GTP in glucose-stimulated insulin
secretion. While the exact site of action for GTP within the islet b cell remains to be identified and defined,
recent evidence from several laboratories, including our own, indicate that it
could involve activation of GTPbinding proteins [G-proteins]. These studies
have identified both trimeric and monomeric forms of G-proteins within the
pancreatic b cell. Recent data also indicate that these
G-proteins, specifically the monomeric Gproteins and the g subunits of trimeric G-proteins undergo a
series of posttranslational modifications at their C-terminal cysteine. Such
modifications include, isoprenylation, carboxyl methylation and palmitoylation.
These modification steps appear to be essential for translocation of these
proteins to the membrane sites for interaction with their respective effector
proteins. This review primarily focuses on recent findings that clearly support
the viewpoint that these posttranslational modification steps not only play
obligatory roles in fuel-induced insulin secretion, but also in
cytokine-mediated apoptotic demise of the b
cell. In this review, we also attempted to describe those findings involving
the use of specific inhibitors for each of these pathways, and it is our hope
that these aspects of b cell metabolism and
function generate interest in development of therapeutic intervention
modalities to states of perturbed insulin release.
[Back to top] Novel Targets for Therapy in Paediatric
Oncology
E.J.
Estlin
Although the majority of children with cancer are now cured of their
disease, a significant number either have disease resistant to current therapy,
or are unable to tolerate the short and long term complications of their
treatment. Therefore new therapeutic strategies which optimise existing agents
by use of their clinical and molecular
pharmacology are needed, along with the development of new agents.
Accordingly, the agents chosen for the study need to be prioritised,
and are thus selected on the basis of categories such as encouraging
pre-clinical data from xenografts of paediatric tumours, novel mechanisms of
action, drugs that modify or overcome cellular resistance and drugs that are
active in adult studies. In this review, novel targets for chemotherapy such as
topoisomerase I, angiogenesis and signal transduction will be discussed. In
addition, the circumvention of methotrexate resistance by novel antifolate
thymidylate synthase inhibition, and the modulation of alkylating agents by
inhibition of 06-alkylDNA-alkyltransferase will be discussed
as strategies to overcome potentially important resistance mechanisms in
paediatric oncology. Finally, recent advances in biological therapies, tumour
vaccination and gene therapy will be highlighted. In the future, investigation
of cancer biology, selection of new drugs, and securing of funds to support the
conduct of integrated early clinical studies that maximise the pharmacological,
cellular biological and molecular pathological information gained, will be the
major challenges to be faced by paediatric oncologists.
[Back to top]Therapeutic potential of the mammalian pyruvate dehydrogenase kinases
in the prevention of hyperglycaemia
M.C.
Sugden and M.J. Holness
The mitochondrial pyruvate dehydrogenase complex (PDC) catalyses the
oxidative decarboxylation of pyruvate, and links glycolysis to the
tricarboxylic acid cycle and ATP production. Adequate flux through PDC is
important in tissues with a high ATP requirement, in lipogenic tissues (since
it provides cytosolic acetyl-CoA for fatty acid (FA) synthesis), and in
generating cytosolic malonyl-CoA, a potent inhibitor of carnitine
palmitoyltransferase (CPT I). Conversely, suppression of PDC activity is
crucial for glucose conservation when glucose is scarce. This review describes
recent advances relating to the control of mammalian PDC activity by
phosphorylation (inactivation) and dephosphorylation (activation,
reactivation), in particular regulation of PDC by pyruvate dehydrogenase kinase
(PDK) which phosphorylates and inactivates PDC. PDK activity is that of a
family of four proteins (PDK1-4). PDK2 and PDK4 appear to be expressed in most
major tissues and organs of the body, PDK1 appears to be limited to the heart
and pancreatic islets, and PDK3 is limited to the kidney, brain and testis.
PDK4 is selectively upregulated in the longer term in most tissues and organs
in response to starvation and hormonal imbalances such as insulin resistance,
diabetes mellitus and hyperthyroidism. Parallel increases in PDK2 and PDK4
expression appear to be restricted to gluconeogenesic tissues, liver and
kidney, which take up as well as generate pyruvate. Factors that regulate PDK4
expression include FA oxidation and adequate insulin action. PDK4 is also
either a direct or indirect target of peroxisome proliferator-activated receptor
(PPAR) a. PPARa
deficiency in liver and kidney restricts starvation-induced upregulation of
PDK4; however, the role of PPARa in heart
and skeletal muscle appears to be more complex. These observations may have
important implications for the pharmacological modulation of PDK activity (e.g.
use of PPARa activators) for the control of whole-body
glucose, lipid and lactate homeostasis in disease states and suggest that
therapeutic interventions must be tissue targeted so that whole-body fuel
homeostasis is not adversely perturbed.
[Back to top] Molecular Basis of Hyperparathyroidism and
Potential Targets for Drug Development
L.J.
Krebs and A. Arnold
Our appreciation of the molecular pathogenesis of primary
hyperparathyroidism (HPT) has seen great advances over the past decade. This
improved understanding may well lead to the development of new treatment
options that are specifically targeted to defective pathways. This review
summarizes recent advances in the molecular basis of HPT and associated
endocrinopathies, and discusses the potential for these and future findings to
provide targets for alternative approaches to therapy. The only proven
contributors to common sporadic HPT, by virtue of clonal genetic abnormalities,
are the cyclin D1 and MEN1 genes. Cyclin D1 is an oncogene that encodes a key
regulator of the cell cycle, while MEN1 is a tumor suppressor gene that has
also been implicated in familial multiple endocrine neoplasia type 1 (MEN1), in
which primary HPT is common. In addition, other key parathyroid regulatory
pathways may play a role in HPT pathogenesis. 1,25 (OH)2-vitamin
D, Ca2+ and phosphate are regarded as principal
regulators of parathyroid cell proliferation and PTH secretion. Therefore,
prime candidate targets include the Ca2+ sensing receptor (CASR) gene, the vitamin D
receptor (VDR) gene, a putative phosphate receptor gene, their cognate gene
products, and other genes or proteins involved in their respective biochemical
pathways. Attempts to identify new therapies based specifically on the
defective pathways in HPT could complement or eventually supplant traditional
approaches.
[Back to top] Apoptotic Cell Death in Renal Injury: The
Rationale for Intervention
A. Ortiz, P. Justo, M.P. Catalán, A.B. Sanz, C. Lorz and J. Egido
Cell number abnormalities are frequent in renal diseases, and range
from the hypercellularity of postinfectious glomerulonephritis to the cell
depletion of chronic renal atrophy. Recent research has shown that apoptosis
and its regulatory mechanisms contribute to cell number regulation in the
kidney. The potential role of apoptosis ranges from induction and progression
to repair of renal injury. Death ligands and receptors, such as tumor necrosis
factor and Fas ligand, proapoptotic and antiapoptotic Bcl2 family members and
caspases have all been shown to participate in apoptosis regulation in the
course of renal cell injury. However, the precise role of these proteins is
unclear, and the participation of most known apoptosis regulatory proteins has
not been studied. We now review the role of apoptosis in renal injury, the
potential molecular targets of therapeutic intervention, the therapeutic
weapons to modulate the activity of these targets and the few examples of
therapeutic intervention on apoptosis, with emphasis on the acute tubular
necrosis.