Current Drug Targets, Volume 4, No. 1, 2003
Contents
Molecular Aspects of Drug Recognition by
Specific T Cells Pp. 1-11
Markus
Britschgi, Salome von Greyerz, Christoph Burkhart and Werner J. Pichler
Emerging Drug Toxicities of Highly Active Antiretroviral Therapy for Human Immunodeficiency Virus (HIV) Infection Pp.13-22
K.V.
Heath, J.S.G. Montaner, G. Bondy, J. Singer, M.V. O'Shaughnessy and R.S. Hogg
Lipids as a Target for Drugs Modulating Multidrug Resistance of Cancer Cells Pp. 23-30
A.B.
Hendrich and K. Michalak
New Multidrug Resistance Reversal Agents Pp. 31-43
Masami
Kawase and Noboru Motohashi
Cancer Chemoprevention Drug Targets Pp. 45-54
K.
Krishnan, S. Campbell, F. Abdel-Rahman, S. Whaley and W.L. Stone
Central Oxytocinergic Neurotransmission: A Drug Target for the Therapy of Psychogenic Erectile Dysfunction Pp. 55-66
M.R.
Melis and A. Argiolas
Membrane Receptors for Vitamin D Steroid
Hormones: Potential New Drug Targets Pp. 67-76
M.C. Farach-Carson and I. Nemere
Phytoestrogens: Pharmacological and Therapeutic Perspectives Pp. 77-87
C. Bolego, A. Poli, A. Cignarella and R. Paoletti
Abstracts
[Back to top] Molecular Aspects of Drug Recognition by
Specific T Cells
Markus
Britschgi, Salome von Greyerz, Christoph Burkhart and Werner J. Pichler
Adverse reactions
to drugs are a major problem in pharmacotherapy. About 1/6 of all side-effects
are thought to be drug-induced immune-mediated reactions. It is well established
that T and B cells recognize a drug if it is bound as hapten to carrier
molecules. However, the model does not explain many T cell-mediated reactions
with chemically inert compounds. This review will first discuss the
hapten-carrier concept of drug-presentation to T cells and the currently used
methods to predict an allergenic potential of a drug. It then introduces our
new model of drug-uptake- and processing-free HLA class II-restricted T-cell
response termed “direct metabolism-independent T-cell stimulation”. This led us
to an other new concept: the pharmacological interaction of drugs with
immunological receptors, namely the MHC and T-cell receptors. Additionally, we
focus on certain conditions of non-covalent drug presentation by antigen presenting
cells and on the molecular recognition of MHC/peptide/drug complexes by
specific T-cell receptors. Finally, we discuss the clinical relevance of
drug-specific T cells, namely that T cells seem to exert a certain pathology
(e.g. drug-induced exanthema or pustular eruptions) depending on their
function. These findings, which are based on the analysis of clinical drug
allergy, have major implications for our understanding of T-cell biology and on
the concept how to test and predict the allergenic potential of a drug.
[Back to top] Emerging Drug Toxicities of Highly Active Antiretroviral Therapy for Human Immunodeficiency Virus (HIV) Infection
K.V.
Heath, J.S.G. Montaner, G. Bondy, J. Singer, M.V. O'Shaughnessy and R.S. Hogg
To provide an
overview of the epidemiologic parameters of emerging adverse effects associated
with antiretroviral therapy for human immunodeficiency virus (HIV) disease.
All available
antiretroviral agents are associated with significant adverse drug effects. Of
particular interest are newly emerging suspected adverse drug effects which
were not generally noted in pre-marketing trials nor captured under current
standard clinical care practices. Suspected antiretroviral toxicities meeting
these criteria include: HIV-associated lipodystrophy which can include
peripheral lipoatrophy, lipohypertrophy and metabolic abnormalities;
hyperlactatemia and lactic acidosis; and metabolic bone abnormalities such as
decreased bone mineral density, osteoporosis and osteonecrosis. Results of
prospective and observational studies reported to date suggest that these
abnormalities, while aetiologically complex, are likely attributable to
treatment factors and may be intricately interrelated. The medical management
of these symptoms remains unsatisfactory given the unexplored efficacy of
traditional approaches in the HIV positive population. While the pathogenic
mechanism of these disorders remains obscure, a theory of tissue-specific
mitochondrial toxicity has been proposed.
With the continued introduction of novel therapies and standard treatment with combination therapy, new adverse events will continue to emerge among persons being treated for HIV disease. Beyond their immediate clinical implications, these events may contribute to changing patterns of antiretroviral utilisation including therapy initiation, adherence and cessation.
[Back to top] Lipids as a Target for Drugs Modulating Multidrug Resistance of Cancer Cells
A.B.
Hendrich and K. Michalak
In this review we
focus on the role of the membrane lipids in multidrug resistance and its
modulation. Results of the research performed in recent years indicate the
importance of lipid phase playing active role in many membrane processes. Along
with the alterations of lipid membrane composition of cancer cells (with
respect to the normal ones) the resulting changes of the biophysical membrane
properties are discussed. Next we describe the general features of multidrug
resistance phenomenon paying a special attention to the role of lipids and
alterations of lipid membrane composition in MDR cells. Taking into account the
phase separation properties of sphingolipids the importance of membrane
heterogeneity (presence of caveole and lipid rafts) is emphasised. On the basis
of vacuum cleaner hypothesis of drug transport proteins action we discuss the
importance of lipid bilayer as medium in which diffusion of drugs takes place.
Considering the membrane fluidity and its influence on the integral proteins
activity, we underline the role of balance between the passive cellular influx
and active efflux of the drug molecules. Finally the effects exerted on
membranes by different kinds of multidrug resistance modulators
(chemosensitizers) are described. In this part we discuss the influence of
verapamil, phenothiazine derivatives, tamoxifen and chosen flavonoids on the
biophysical properties of membrane lipids. Some further consequences of the
alteration of membrane state are also considered.
[Back to top] New Multidrug Resistance Reversal Agents
Masami
Kawase and Noboru Motohashi
Multidrug resistance (MDR) to antitumor agents represents a significant challenge to effective chemotherapy. The use of MDR modulators is a promising approach to overcome the undesired MDR phenotype. The more effective MDR modulators are urgently needed for clinical use. This review focuses on literatures published in 1998-2001.
[Back to top] Cancer Chemoprevention Drug Targets
K. Krishnan, S. Campbell, F. Abdel-Rahman, S. Whaley and
W.L. Stone
Cancer chemoprevention is a new approach in the management of cancer. Traditional cytotoxic chemotherapeutic approaches cannot cure most advanced solid malignancies. Chemoprevention can be defined as the use of non-cytotoxic drugs and natural agents to block the progression to invasive cancer. Chemoprevention can either prevent DNA damage that initiates the neoplastic transformation process or reverses the progression of pre-invasive lesions. Epidemiological observations, experimental evidence from animal carcinogenesis models, knock-out models, cancer cell lines and clinical trials have shown the efficacy of this approach. Recent advances in our understanding of carcinogenesis have led to the synthesis of new drugs that target specific receptors. Non-steroidal anti-inflammatory drugs target the prostaglandin pathway. The identification of the role of cyclooxygenase-2 in epithelial carcinogenesis led to the synthesis of selective cyclooxygenase-2 inhibitors (Celecoxib). Celecoxib was subsequently approved for the prevention of colon polyps in familial adenomatous polyposis after the completion of a randomized clinical trial. The large chemoprevention clinical trial with the selective estrogen receptor modulator, tamoxifen, showed the benefit of tamoxifen in the prevention of breast cancer in high-risk women. Retinoids and rexinoids target the retinoid receptors and have a role in chemoprevention of aerodigestive, hepatic and cervical neoplasia. Selenium, an inhibitor of the glutathione peroxidase system, is being tested in the chemoprevention of prostate cancer and lung cancer. The different isoforms of vitamin E (tocopherols) may be chemopreventive. Recent evidence indicates that g-tocopherol may be a more powerful chemopreventive than the a-tocopherol. The review details the rationale, experimental and clinical evidence and the drug targets of the chemopreventive agents that are currently in various phases of clinical development.
[Back to top] Central Oxytocinergic Neurotransmission: A Drug Target for the Therapy of Psychogenic Erectile Dysfunction
M.R.
Melis and A. Argiolas
A group of
oxytocinergic neurons originating in the paraventricular nucleus of the
hypothalamus and projecting to extrahypothalamic brain areas (e.g. hippocampus,
medulla oblongata and spinal cord) control penile erection. Activation of these
neurons by dopamine and dopamine agonists, excitatory amino acids
(N-methyl-D-aspartic acid) or oxytocin itself, or by electrical stimulation
leads to penile erection, while their inhibition by GABA and GABA agonists or
by opioid peptides and opiate-like drugs inhibits this sexual response. The
activation of oxytocinergic neurons in the paraventricular nucleus by dopamine,
oxytocin and excitatory amino acids is apparently secondary to the activation
of nitric oxide (NO) synthase. NO in turn activates, by a mechanism that is as
yet unidentified, the release of oxytocin from oxytocinergic neurons in
extrahypothalamic brain areas. Several peptide analogues of hexarelin, a growth
hormone releasing peptide, also induce penile erection when injected into the
paraventricular nucleus and, to a lesser extent, systemically, apparently by
acting on a specific receptor to activate oxytocinergic neurons as shown for
the above drugs and oxytocin. Paraventricular oxytocinergic neurons and
mechanisms similar to those reported above are also involved in the expression
of penile erection in physiological contexts, namely when penile erection is
induced in the male by the presence of an inaccessible receptive female, which
is considered a model for psychogenic impotence in man, as well as during
copulation. These findings show that paraventricular oxytocinergic neurons
projecting to extra-hypothalamic brain areas and to the spinal cord are a
likely target for the treatment of erectile dysfunction of central origin.
[Back to top]
Membrane Receptors for Vitamin D
Steroid Hormones: Potential New Drug Targets
M.C. Farach-Carson and I. Nemere
There is
increasing evidence that steroid hormones derived from vitamin D act through
classical nuclear receptors (nVDR), as well as specific binding sites on the
plasma membrane of target cells that are coupled to signal transduction
systems. These sites are referred to as Membrane Associated, Rapid
Response Steroid (MARRS) binding proteins or complexes. In the case of the seco-steroid
1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the two ‘receptors’ appear to be
different proteins with distinct affinities for vitamin D analogs. These
differences may be useful in a number of clinical situations. In treating
leukemias, it would be useful to promote the actions of the nVDR for
differentiation to macrophages while blocking the 1,25D3-MARRS in intestine,
which might contribute to the undesirable side effect of hypercalcemia. In
contrast, stimulation of the intestinal 1,25D3-MARRS would be desirable in the
elderly, since this signalling system appears to decline with age in model
systems, potentially contributing to diminished intestinal absorption of
calcium and associated bone loss. Bone itself is known to have osteoblasts that
respond to 1,25(OH)2D3 through both nVDR and 1,25D3-MARRS mechanisms. Both
systems are required for bone-building activities. Osteoclasts lack the nVDR,
but may become activated through the 1,25D3-MARRS, offering another site of
drug intervention in the treatment of osteoporosis. Finally, during tooth
mineralization, immunohistochemical studies reveal an absence of the nVDR and a
marked appearance of the 1,25D3-MARRS. In addition to our growing knowledge of
1,25(OH)2D3, the physiological actions of a lesser studied metabolite of
vitamin D, 24,25(OH)2D3, are coming to light and may offer additional targets
for pharmaceutical modulation.
[Back to top] Phytoestrogens: Pharmacological and Therapeutic Perspectives
C. Bolego, A. Poli, A. Cignarella and R. Paoletti
Phytoestrogens
exert different estrogen receptor-dependent and -independent pharmacological
actions. They share with estrogens several structural features and show greater
affinity for the newly described estrogen receptor-beta. Many hope that
phytoestrogens can exert the cardioprotective, anti-osteoporotic and other
beneficial effects of the estrogens used in hormone replacement therapy in
postmenopausal women without adversely affecting the risk of thrombosis and the
incidence of breast and uterine cancers.
Although there are many positive indications that phytoestrogens can fulfil this role, it remains to be proven: controlled interventional studies are lacking, and many questions remain unanswered. This review analyzes, on the basis of available experimental and epidemiological studies, the pros and cons of phytoestrogen use and describes the potential tissue targets and mechanisms of action of phytoestrogens.