Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 13, Number 29, 2006

Contents


Targeting the EGFR Pathway for Cancer Therapy Pp. 3483-3492
James B. Johnston, Sri Navaratnam, Marshall W. Pitz, Jerry M. Maniate, Emilia Wiechec, Heinrich Baust, Joel Gingerich, Georgios P. Skliris, Leigh C. Murphy and Marek Los
[Abstract]


Development of Novel Therapeutic Strategies for Lung Cancer:Targeting the Cholinergic System Pp. 3493-3512
P. Russo, A. Catassi, A. Cesario and D. Servent
[Abstract]


Anti-Galectin Compounds as Potential Anti-Cancer Drugs Pp. 3513-3527
Laurent Ingrassia, Isabelle Camby, Florence Lefranc, Véronique Mathieu, Prosper Nshimyumukiza, Francis Darro and Robert Kiss
[Abstract]


Antiviral Properties of Deazaadenine Nucleoside Derivatives Pp. 3529-3552
S. Vittori, D. Dal Ben, C. Lambertucci, G. Marucci, R. Volpini and G. Cristalli
[Abstract]


Nuclear Retinoic Acid Receptor Beta as a Tool in Chemoprevention Trials Pp. 3553-3563
B. Pavan, C. Biondi and A. Dalpiaz
[Abstract]


Current Concepts in Adult Stem Cell Therapy for Stroke Pp. 3565-3574
Dah-Ching Ding, Woei-Cherng Shyu, Shinn-Zong Lin and Hung Li
[Abstract]


Effects of Progesterone on Sleep: A Possible Pharmacological Treatment for Sleep-Breathing Disorders? Pp. 3575-3584
M.L. Andersen, L.R.A. Bittencourt, I.B. Antunes and S. Tufik
[Abstract]


Towards Predictive Ligand Design With Free-Energy Based Computational Methods? Pp. 3583-3608
N. Foloppe and R. Hubbard
[Abstract]




Abstracts


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Targeting the EGFR Pathway for Cancer Therapy
James B. Johnston, Sri Navaratnam, Marshall W. Pitz, Jerry M. Maniate, Emilia Wiechec, Heinrich Baust, Joel Gingerich, Georgios P. Skliris, Leigh C. Murphy and Marek Los

Clinical studies have shown that HER-2/Neu is over-expressed in up to one-third of patients with a variety of cancers, including B-cell acute lymphoblastic leukemia (B-ALL), breast cancer and lung cancer, and that these patients are frequently resistant to conventional chemo-therapies. Additionally, in most patients with multiple myeloma, the malignant cells over-express a number of epidermal growth factor receptors (EGFR)s and their ligands, HB-EGF and amphiregulin, thus this growth-factor family may be an important aspect in the patho-biology of this disease. These and other, related findings have provided the rationale for the targeting of the components of the EGFR signaling pathways for cancer therapy. Below we discuss various aspects of EGFR-targeted therapies mainly in hematologic malignancies, lung cancer and breast cancer. Beside novel therapeutic approaches, we also discuss specific side effects associated with the therapeutic inhibition of components of the EGFR-pathways. Alongside small inhibitors, such as Lapatinib (Tykerb, GW572016), Gefitinib (Iressa, ZD1839), and Erlotinib (Tarceva, OSI-774), a significant part of the review is also dedicated to therapeutic antibodies (e.g.: Trastuzumab / Herceptin, Pertuzumab / Omnitarg / rhuMab-2C4, Cetuximab / Erbitux / IMC-C225, Panitumumab / Abenix / ABX-EGF, and also ZD6474). In addition, we summarize, both current therapy development driven by antibody-based targeting of the EGFR-dependent signaling pathways, and furthermore, we provide a background on the history and the development of therapeutic antibodies.


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Development of Novel Therapeutic Strategies for Lung Cancer:Targeting the Cholinergic System
P. Russo, A. Catassi, A. Cesario and D. Servent

One of the earliest descriptions of non-neuronal ACh synthesis was by Morris who reported that ACh was synthesized in the placenta [1]; furthermore, Falugi et al. showed the presence of AChE in human fibrosarcoma cells [2]. Afterward, the expression of ACh, AChE, and cholinergic receptors in non-neuronal cells was reported in several studies [3-16]. Indeed, recent data reported that SCLC expresses a cholinergic autocrine loop that can regulate cell growth. Such work demonstrates that SCLC cells have a cholinergic phenotype and that ACh exerts as an autocrine growth factor in human lung tumours [16]. Moreover, it has been recently reported that nicotine in lung adenocarcinoma A549 cells, potently induces Bad phosphorylation at serine (S)¹¹², S¹³⁶ and S¹⁵⁵ in a mechanism involving activation of MAPKs, ERK1/2, PI3K/AKT and PKA through the linking to α7-receptors [9]. Bad phosphorylation results in sequestering Bad from mitochondria and subsequently interacting with 14-3-3 in the cytosol [9]. We have recently reported that human malignant pleural mesothelioma expresses a cholinergic system, involved in cell growth regulation. Hence, mesothelioma cells growth is modulated by the cholinergic system in which agonists (i.e. nicotine) have a proliferative effect and antagonists (i.e. curare or α-cobratoxin) have an inhibitory effect. Furthermore apoptosis mechanisms are under the control of the cholinergic system (nicotine antiapoptotic via induction of NF-κB complexes and phosphorylation of Bad at S¹¹², curare proapoptotic via G₀-G₁ arrest p21^waf-1-dependent, but p53-independent) [16].

The involvement of the non-neuronal cholinergic system in lung cancer and mesothelioma appears reasonable and opens up new translational research strategies.


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Anti-Galectin Compounds as Potential Anti-Cancer Drugs
Laurent Ingrassia, Isabelle Camby, Florence Lefranc, Véronique Mathieu, Prosper Nshimyumukiza, Francis Darro and Robert Kiss

Galectins form a family of carbohydrate-binding proteins defined by their affinity for β-galactosides containing glycoconjugates. The carbohydrate recognition domain (CRD) is responsible for the specificity of galectins for saccharides. This binding may result in modulated cell proliferation, cell death and cell migration, three processes that are intimately involved in cancer initiation and progression. Galectins can also display protein-protein types of interactions with their binding partners. Certain galectins directly involved in cancer progression seem to be promising targets for the development of novel therapeutic strategies to combat cancer. Indeed, migrating cancer cells resistant to apoptosis still constitute the principal target for the cytotoxic drugs used to treat cancer patients. Reducing the levels of migration in apoptosis-resistant cancer cells can restore certain levels of sensitivity to apoptosis (and so to pro-apoptotic drugs) in restricted-migration cancer cells. Anti-galectin agents can restrict the levels of migration of several types of cancer cell and should therefore be used in association with cytotoxic drugs to combat metastatic cancer. We provide experimental proof in support of this concept. While the present review focuses on various experimental strategies to impair cancer progression by targeting certain types of galectins, it pays particular attention to glioblastomas, which constitute the ultimate level of malignancy in primary brain tumors. Glioblastomas form the most common type of malignant brain tumor in children and adults, and no glioblastoma patient has been cured to date.


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Antiviral Properties of Deazaadenine Nucleoside Derivatives
S. Vittori, D. Dal Ben, C. Lambertucci, G. Marucci, R. Volpini and G. Cristalli

Viral infections have menaced human beings since time immemorial, and even today new viral strains that cause lethal diseases are being discovered with alarming frequency. One major example is HIV, the etiological agent of AIDS, which spread up in the last two decades. Very recently, other virus based diseases such as avian flu have spread fear around the world, and hemorrhagic fevers from central Africa serious threaten human health because of their very deadly effects. New antiviral agents are still greatly needed to counter these menaces. Many scientists are involved in this field of research, and many of the recently discovered effective antiviral compounds are nucleoside analogues. Among those derivatives, deazapurine nucleoside analogues have demonstrated potent inhibitory effect of viral replication.

This review reports on recently generated data from preparing and testing deazapurine nucleoside derivatives as inhibitors in virus replication systems. Although most of the reported data have been produced in antiHIV, antiHCMV, and antiHSV biological testing, very recently other new important fields of application have been discovered, all in topical subjects of strong interest. In fact, deazapurine nucleosides have been found to be active as chemotherapeutics for some veterinary systemic viral infections, for which no antiviral drugs are licensed yet. Furthermore, they demonstrated efficacy in the inhibition of Hepatitis C virus replication. Finally, these compounds showed high potency as virucides against Ebola Virus, curing Ebola infected mice with a single dose administration.


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Nuclear Retinoic Acid Receptor Beta as a Tool in Chemoprevention Trials
B. Pavan, C. Biondi and A. Dalpiaz

Retinoic acid (RA) and its natural and synthetic derivatives (retinoids) are important dietary factors which regulate cellular differentiation and growth, so that they are thought to be particularly effective at preventing the development of several tumours. They play this role as ligands of the RAR and RXR nuclear retinoic acid receptors, including the RA receptor isoforms alpha, beta, and gamma. These ligand-activated nuclear receptors induce the transcription of target genes by binding to RA-responsive elements in the promoter regions. Among these target genes, the RARβ gene is of great interest, being able to encode a potential tumour suppressor. It should be emphasized that most breast carcinomas and breast cancer cell lines show loss or down-regulation of RARβ receptor expression, whereas RARα and γ, as well as retinoid X receptors, appear to be variably expressed in both normal and tumour cells. It is also interesting to note that basal and RA-induced RARβ mRNA levels tend to increase with senescence of normal cells. This information provides further support for the hypothesis that genetic events involved in cellular senescence may also play a significant role in tumour suppression in humans. The aim of this review is to clarify whether expression of RARβ could be modulated by chemopreventive intervention and may therefore serve as an intermediate biomarker in chemoprevention trials for some cancers.


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Current Concepts in Adult Stem Cell Therapy for Stroke
Dah-Ching Ding, Woei-Cherng Shyu, Shinn-Zong Lin and Hung Li

Acute ischemic stroke causes a disturbance of neuronal circuitry and disruption of the blood-brain-barrier that can lead to functional disabilities. At present, thrombolytic therapy inducing recanalization of the occluded vessels in the cerebral infarcted area is a commonly used therapeutic strategy. However, only a minority of patients have timely access to this kind of therapy. Therefore, finding other techniques to effectively treat stroke patients is an important research goal. Stem cell therapies, such as adult stem cell transplantation, are promising strategies for the treatment of stroke. Preclinical experimental studies have included the application of human stem cells from various sources including the brain, bone marrow, umbilical cord, and adipose tissue. This review provides an update on current preclinical cell-therapies for stroke, focusing on stem cells derived from adult sources.


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Effects of Progesterone on Sleep: A Possible Pharmacological Treatment for Sleep-Breathing Disorders?
M.L. Andersen, L.R.A. Bittencourt, I.B. Antunes and S. Tufik

Progesterone is present in a wide spectrum of biological activity within a variety of tissues. This hormone is also known to affect reproduction, sleep quality, respiration, mood, appetite, learning, memory and sexual activity. Progesterone exerts a sleep induction or hypnotic effect and is a potent respiratory stimulant that has been associated to a decrease in the number of central and obstructive sleep apnea episodes in men. The literature also contains a substantial amount of data on the effect of apnea in women with obesity-hypoventilation during menopause. This review attempts to outline the specific role of progesterone in normal sleep and breathing as well as its possible therapeutic effects in the treatment of sleep-disordered breathing.


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Towards Predictive Ligand Design With Free-Energy Based Computational Methods?
N. Foloppe and R. Hubbard

The accurate prediction of ligand-biopolymer binding affinities is of general interest to medicinal chemistry, as well as to the broader field of molecular recognition. The ability to predict computationally the thermodynamics of these molecular recognition processes has been relatively weak until recently, however, continued developments on several fronts are extending the scope of applicability of these methods.

The rapid growth in the number of protein-ligand structures has initially led to the development of a range of empirical scoring functions based on relatively simple descriptions of intermolecular interactions. These methods have had some success in ranking binding affinities when tuned to particular protein systems or in rather qualitative estimates of molecular fit in fast docking calculations. However, they are too unreliable for more detailed, quantitative, assessment and comparison of binding affinities.

Physics-based free energy calculations are in principle more general and have the potential to be significantly more accurate. These approaches have seen steady development over many years and rely on carefully calibrated molecular energy functions (force-fields), simulations of the systems with explicit solvent, and the coming-of-age of continuum solvation models. In addition to the initially developped Free Energy Perturbation (FEP) and Thermodynamic Integration (TI) methods, new approaches include the Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) and the Linear Interaction Energy (LIE) approaches. This review concentrates on MM-PBSA and LIE, and their variants. The routine application of these calculations is becoming possible because of enhanced computational hardware and the development of a range of computational chemistry tools.

This review addresses: i) the basic principles behind free energy calculations ii) recent methodological advances iii) comparisons of predicted and experimentally determined affinities iv) the uncertainties and limitations of both the computational and experimental data v) areas where progress can be made vi) the practicality of applying the methods at the different stages of the drug discovery and optimization process.