Current Drug Targets - Immune, Endocrine & Metabolic Disorders - Volume 1, Issue 2, 2001

In this contribution, we review the limitations of the currently applied standard treatments for well-differentiated, non-medullary thyroid cancer (ThyrCa), and describe the molecular and cellular biologic basis of potential novel therapeutic modalities currently under study and / or development. Conventional therapy for ThyrCa consists of total / near-total thyroidectomy, radioiodine (RAI or 131I), and long-term thyroid hormone suppressive therapy (THST). RAI therapy remains the cornerstone of the standard management strategies for metastatic ThyrCa, and when administered under optimal conditions can achieve either eradication or long-term clinical control of the disease. Despite increasing sophistication in the protocols using 131I over the last 30 years, no significant down-trend has been observed in the annual mortality rate for this disease, a fact reflecting the existence of a core population of patients with RAI-resistant disease. The molecular basis for this phenomenon is believed to be the progressive tumoral de-differentiation over time, with loss of (or marked decrease in) the expression of cellular components responsible for iodine uptake, organification and retention. Adjuvant methods to RAI, such as radiosensitizers and lithium carbonate, provide only marginal additional therapeutic effect. Further, the role of non-RAI-based modalities, such as secondary extensive metastatectomies with curative intent, external beam radiotherapy, and cytotoxic chemotherapy (mainly with doxorubicin-based regimens) has been unfortunately limited to highly selected cases. Palliative methods for acute clinical management of widely metastatic ThyrCa are also presented, along with anecdotal evidence for the potential therapeutic role for octreotide and its radiolabeled therapeutic peptide analogs, selective estrogen receptor modulators (SERMs), as well as bisphosphonates. Translational bench-to-bedside research has recently led to the identification of the transcriptional machinery as a valid target for future therapeutic efforts in ThyrCa. Indeed, pre-clinical studies with a variety or agents that affect the rate of thyroid-specific gene transcription, i.e. retinoids, DNA methyltransferase inhibitors, and histone deacetylase inhibitors, have shown their potential for induction of re-differentiation, growth inhibition, promotion of apoptosis and cell cycle regulation. These concerted genomic effects of the above compounds will probably yield novel types of therapies in the clinical arena, especially for RAI-non-avid tumors. Retinoid analogs have already been used in pilot studies in ThyrCa patients with limited success. These re-differentiating agents have raised our expectations for a type of therapy for this malignancy based on a solid molecular rationale, while future progress in the domains of tissue-targeted gene therapy and anti-angiogenesis is eagerly awaited.

Interferons (IFNs) are an important part of immune responses and are believed to protect the host from viral and bacterial pathogens as well as having a role in rejection of malignancies. The well-known anti-viral and cytostatic properties of IFNs have led to the clinical use of these proteins to treat some cancers and viral infections. Extensive research has begun to unravel much of the molecular basis for the biological effects of IFNs, and this information could now be used as a foundation for the development of novel therapeutic strategies that avoid some of the acknowledged shortcomings of cytokine therapies. This review explains the current model of IFN action, during viral infections and the potential for well-established and emerging groups of IFN inducible genes as therapeutic targets is highlighted.

beta-endorphins (beta-ends) are released from the anterior pituitary and from lymphocytes directly into inflammed tissue in response to stress and pain. At the site of inflammation and trauma, the link of beta- ends to opioid receptors hyperpolarizes nerve terminal, by blocking L-calcium gated channels, induces modifications of receptor stereoisomerism and alters the bond-energy. Opioids increase potassium and decrease calcium and sodium currents through interactions with G-protein.In some pathologies, it has been found a loss of desensitization and down regulation of opioid receptors by means of Ca++ blocking that, in turn, inhibits PKC-activation. The physiopathological mechanism dependent on the high concentration of linked opioids affects cellular level of Ca++, ATP and NADH. This biochemical reaction exerts deep influence on energetic cell status and metabolism. In gram negative bacteria, expression of m-receptors on cell surface has been observed, with a possibility to interfere with host cell metabolism. There are many human and veterinary pathologies in which the reported mechanisms are well known: polycystic ovary syndrome, gross cystic breast disease, milk fever, ruminal tympanites, pyometra, equine colic syndrome, ovarian follicular cyst in dairy cows, calcium deficit in post-partum cows, uterine involution in cows. Also incoming pathologies such as Electro-Magnetic-Field exposure may induce alteration of calcium channel activity through the same mechanism. On clinical bases, it has been pointed out that the therapeutic administration of an association of calcium salts and naloxone controls calcium turnover, pain and functional activity of endocrine glands, via down regulation / desensitization of opioid receptors, PKC stimulation and energy restoration.

G protein coupled receptors or serpentine receptors work as signalling switches that turn extracellular signals into activation of multiple molecules at the intracellular face of the plasma membrane. Serpentine receptors are the targets of around 70 percent of all current drugs in clinical medicine. We suggest that these receptors can be pharmacologically targeted by modification of their unique internal inhibitors the G protein coupled receptor kinases (GRKs). The GRKs constitute a family of serine / threonine kinases that specifically bind to and phosphorylate agonist-activated serpentine receptors. The phosphorylated receptors are recognized by arrestins that bind to the receptor and uncouple them from attached G proteins thereby terminating G protein signalling. This review focuses on a ubiquitously expressed GRK family member dubbed GRK2 (previously called beta-adrenergic receptor kinase 1) that regulates cellular signalling at multiple levels. In Gq-coupled signalling modules GRK2 may function as a feedback inhibitor molecule that monitors, inhibits and re-directs the information flow. GRK2 acts as a negative feedback protein by interacting with at least six key signalling molecules in the Gq pathway including receptors, free G beta gama subunits, activated G alpha q subunits, phosphatidylinositol-4, 5-bisphosphate (PIP2), protein kinase C (PKC) and calmodulin (CaM). GRK signalling is important for immune, endocrine and cardiovascular function manifesting itself in disorders such as heart failure and lymphocyte activation especially in chronic inflammation. This review summarizes the advances made in understanding the many actions of GRKs and addresses their potential as novel therapeutic targets.

Retinoic acid receptors are ligand-regulated transcription factors belonging to the nuclear receptor superfamily, which comprises 49 members in the human genome. all-trans retinoic acid and 9-cis retinoic acid receptors (RARs and RXRs) are each encoded by three distinct genes and several isoforms arise from alternative splicing and the use of different promoters. While RXRs are promiscuous dimerization partners of several other nuclear receptors, RARs are active, in-vivo, when associated to RXRs. Retinoids are therefore regulators of multiple physiological processes, from embryogenesis to metabolism. Different combinations of RXR:RAR heterodimers occur as a function of their tissue-specific expression and their activity is mostly conditionned by the activation status of RAR. These heterodimers are defined as non permissive heterodimers, in opposition to permissive dimers whose transcriptional activity may be modulated through RXR and its dimerization partner. The transcriptional activity of these dimers also relies on their ability to recruit nuclear coactivators and corepressors, which function as multi proteic complexes harboring several enzymatic activities (acetylases, kinases). The structure of the ligand bound to the RAR moiety of the dimer, as well as the nature of the DNA sequence to which dimers are bound, dictate the relative affinity of dimers for coactivators and thus its overall transcriptional activity. RARs are also able to repress the activity of unrelated transcription factors such as AP1 and NF-k-B, and therefore have potent anti proliferative and anti inflammatory properties. This review summarizes our current view of molecular mechanisms governing these various activities and emphasizes the need for a detailled understanding of how retinoids may dictate transactivating and transrepressive properties of RARs and RXRs, which may be considered as highly valuable therapeutic targets in many diseases such as cancer, skin hyperproliferation and metabolical disorders (diabetes, atherosclerosis etc).

Malignant tumors of the female reproductive organs have a high incidence and mortality. Despite modern technology, diagnostics and therapeutics have substantial limitations. Detection of autofluorescence, photosensitizer mediated fluorescence, and near-infrared-spectra are new approaches to diagnose gynecologic malignancies and premalignant lesions. Photodynamic therapy (PDT) is currently being evaluated for the treatment of gynecologic cancers and precancers. New porphyrin based photosensitizers promise a selective tumor targeting and consequently a selective treatment of surgically not removable cancers. The present article summarizes the role of photomedicine in diagnostics and treatments of malignant disease of the female genital tract. Interactions between PDT and the immune system are discussed.

This review summarizes the state-of-the-art knowledge on diagnosis, pathogenesis, immune response to, clinical picture, treatment and prevention of cytomegalovirus (CMV) infection in humans. CMVs are ubiquitous betaherpesviruses that infect animals as well as humans.Primary infection with human cytomegalovirus (HCMV) is followed by persistence of the virus in a latent form. During life, the virus can reactivate, resulting in renewed shedding of the virus or development of disease. Redundant molecular mechanisms have been identified by which CMVs interfere with the host immune control, but finally, the infection is held in check by the hosts immune response. As a consequence, CMV disease is restricted to the immunocompromised or immunologically immature host. HCMV is the leading cause of congenital infections, with an incidence of 1- 2,4 percent of live births, with possible severe classic cytomegalovirus inclusion disease in 10 percent of them. Congenital CMV infection is the leading infectious cause of brain damage and hearing loss in children and also a relevant health issue to transplant recipients and human immunodeficiency virus (HIV) -infected patients.Significant progress has been made in the last few years in detecting CMV, but in the immunocompromised patients, establishing the diagnosis of CMV infection can still be problematic. The most sensitive molecular amplification methods such as polymerase chain reaction (PCR) should be used.The decision how to treat the infection depends mainly on the immune status of the host. In immunocompetent patients only symptomatic treatment is recommended, while in immunocompromised patients antiviral therapy and immunotherapy should be used. The most commonly used antivirotics are: ganciclovir, foscarnet, cidofovir, valganciclovir, valaciclovir.