Current Pharmaceutical Design - Volume 10, Issue 19, 2004

The histone deacetylase inhibitors (HDIs) are a new class of antineoplastic agents currently being evaluated in clinical trials. While these agents have been studied extensively in the laboratory, only recently has their mechanism of action begun to be elucidated. Several structural classes of compounds have been shown to exert histone deacetylase inhibition, including sodium n-butyrate, suberoylanilide hydroxamic acid, LAQ824, CI-994, MS-275, and depsipeptide. The HDIs have been shown to induce differentiation, to decrease cell proliferation, and to induce cell death. HDIs are thought to exert their anti-neoplastic effects by altering the expression of genes that play a role in the control of cell growth, and transformation. The HDIs have specific and well-defined effects on cancer cells. Preliminary results from clinical trials suggest that these agents are very promising. While there were sporadic case reports of activity using the early generation HDIs, dramatic responses have recently been observed in patients with T-cell lymphomas treated with depsipeptide, one of the newer agents. With the well-defined molecular effects on cancer cells, surrogate markers can be analyzed for evidence of activity and efficacy using either tumor samples or normal tissue. Presented in this review are details from clinical trials with both earlier and newer generations of HDIs. Toxicities specific to this class of agents are outlined and possibilities for rational combination therapies are discussed.

Membrane disrupting lytic peptides are abundant in nature and serve insects, invertebrates, vertebrates and humans as defense molecules. Initially, these peptides attracted attention as antimicrobial agents; later, the sensitivity of tumor cells to lytic peptides was discovered. In the last decade intensive research has been conducted to determine how lytic peptides lyse bacteria and tumor cells. A number of synthetic peptides have been designed to optimize their antibiotic and anti-tumor properties and improve their therapeutic capabilities. The sequences of α-helical cationic membrane disrupting peptides has been discussed, their proposed mechanisms of action reviewed, and their roles in cell selectivity and tumor cell destruction considered. Parameters important for the selection and design of lytic peptides for cancer treatments include increased activities against tumor cells, low cytolytic activities to normal mammalian cells and erythrocytes. The conjugation of lytic peptides with hormone ligands and the production of pro-peptides provide methods for targeting of cancer cells. The therapeutic possibilities in cancer treatment by targeted lytic peptides are broad and offer improvement to currently used chemotherapeutical drugs. Lytic peptides interact with the tumor cell membrane within minutes, and their activity is independent of multi-drug resistance. Lytic peptide-chorionic gonadotropin (CG) conjugates destroy primary tumors, prevent metastases and kill dormant and metastatic tumor cells. These conjugates do not destroy vital organs; they are not antigenic, and are more toxic to tumor cells than to non-malignant cells.

Targeting toxic therapeutics to tumors through receptors over expressed on the surface of cancer cells can reduce systemic toxicity and increase the effectiveness of the targeted compounds. Small molecule targeted therapeutics have a number of advantages over toxic immunoconjugates including better tumor penetration, lack of neutralizing host immune response and superior flexibility in selection of drug components with optimal specificity, potency and stability in circulation. Three major components of the targeted drug, the toxic warhead, tumor-specific ligand and the linker can influence the properties of each other and thus have to be optimized for each system. All receptor-targeted drugs are delivered inside the cells through endocytosis and undergo processing liberating the toxins in endosomes and lysosomes. Common delivery route defines a number of general requirements for each drug component. The review addresses currently known possible receptor targets and their ligands along with toxins that have been used and that have a potential to be successfully applied in tumor targeting. Linkers that are stable in circulation, but efficiently cleaved in lysosomes constitute an essential component of receptor-targeted drugs and are evaluated in greater detail.

Although monoclonal antibodies have demonstrated clinical potentials as tumor targeting agents, poor tumor penetration of the antibodies due to the size of molecules and liver / bone marrow toxicity by non-specific uptake of the antibodies are the two major limitations of antibody therapy. Peptidic targeting agents may ease the problems associated with antibody cancer therapy. Combinatorial libraries displayed on microorganisms have successfully been utilized to discover cell surface-binding peptides, which can be tumor-targeting agents. Among many molecular display techniques, phage display has been the most popular approach. Peptides can be used as targeting molecules of receptor-targeted toxins and gene therapy, imaging and / or therapeutic agents, and nano-medical technologies. Recent results from preclinical studies with various peptides support their targeting potential and suggest that the role of peptides as targeting molecules in drug development should be further exploited.

Accumulating evidence in literature suggests that amidated and non-amidated gastrins (gastrin precursors) may play an important role in the proliferation and carcinogenesis of gastrointestinal and pancreatic cancers, especially in the presence of DNA damaging agents and / or infectious agents. Amidated gastrins appear to have a protective role, while progastrins exert growth promoting effects in cancers. Several receptor subtypes and signal transduction pathways mediate the biological effects of the gastrin peptides. Progastrin and gastrins also exert anti-apoptotic effects, which may additionally contribute to the growth and co-carcinogenic effects of these peptides on GI mucosal cells in vivo. Amidated gastrins additionally play an important role in the migration of GI epithelial cells, and in glandular morphogenesis, while progastrins may play an important role in invasion and metastasis. Therefore, targeting progastrins, gastrins, and their cognate receptors may provide a therapeutic tool for treating GI and pancreatic cancers. Targeting CCK2-receptors has, so far, not provided optimal beneficial effects. However, targeting gastrins via a vaccine approach has provided some encouraging results for treating GI and pancreatic cancers. It is expected that targeting precursor gastrins (progastrins and gly-gastrins), exclusively rather than amidated gastrins, may be more effective for treating GI cancers. Since GI cancers at advanced stages are largely responsive to autocrine and intracrine progastrins, down-regulation of intracellular progastrins will likely be more effective at this stage.

The glycolipid-anchored receptor for urokinase-type plasminogen activator (uPAR) is essential for cell-surface associated plasminogen activation and is overexpressed at the invasive tumor-stromal microenvironment in many human cancers. In line with this, uPAR and uPA levels in both resected tumor tissue and plasma are of independent prognostic significance for patient survival in several types of human cancer. As the expression of both uPAR and its cognate protease ligand thus appears to be correlated with tumor malignancy, the uPA-uPAR interaction represents an attractive target for the development of either antagonists with possible anti-invasive effects or cytotoxic agents with anti-tumor effects. In this review we discuss recent achievements in the development of protein and peptide based drug candidates targeting uPAR. The majority of these compounds has been optimized for human uPAR and exhibits a pronounced species-specificity showing little or no reactivity with murine uPAR. This evidently complicates their application in preclinical intervention studies, since an intimate interplay between the tumor and its associated stroma is a distinct feature of the invasive phenotype of many human cancers. The virtues and drawbacks of various mouse tumor models as surrogates for human cancer are also discussed in relation to uPAR targeting.

The contribution of small molecular weight chemoattractant cytokines (chemokines) and their receptors in the trafficking of tumor, immune and vascular cells pertaining to the development and progression of cancer has begun to be investigated. The current literature indicates that interactions between the immune network, angiogenic and cell survival cascades are important for the trafficking and progression of human cancer and that chemokines and chemokine receptors play a central role in these complex inter-related pathways. Several therapeutic approaches have been reviewed and suggest that the most promising arise from the development of combinations of chemokine receptor antagonists.

Isoprenoids, a diverse group of compounds derived from the five-carbon building units isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), are essential for survival in all organisms. Animals synthesize their isoprenoids from mevalonic acid (MVA), whereas most pathogenic bacteria and the malaria parasites utilize a completely different pathway for IPP and DMAPP synthesis, the methylerythritol phosphate (MEP) pathway. Plants use both pathways for the synthesis of isoprenoid precursors. The recent elucidation of the MEP pathway has opened the possibility to develop new strategies against microbial pathogens. Novel immunotherapeutic agents can be developed based on the MEP pathway intermediates known to activate the proliferation of human V-delta-9V-gamma-2 T-cells after infection by many pathogenic bacteria and protozoa. Moreover, the design of specific inhibitors of MEP pathway enzymes (which are highly conserved but show no homology to mammalian proteins) should result in herbicides and drugs with broad-spectrum antimicrobial activity without mechanism-based toxicity to humans. A good example is the cure of bacterial infections and malaria with fosmidomycin, a highly stable inhibitor of the MEP pathway. The use of plants as test systems has led to the identification of additional inhibitors such as ketoclomazone. Biochemical, genetic and crystallographic approaches with the MEP pathway enzymes are now starting to characterize the inhibition kinetics and identify which residues play a structural or catalytic role. Current efforts should eventually contribute to an effective drug designed to fight against microbial pathogens that show resistance to currently available agents.

As a non-toxic endogenous antioxidant, the semi-essential amino acid taurine is a potential attenuator of oxidative damage such as that produced by ischaemia-reperfusion injury. Ischaemia-reperfusion injury is a well established if paradoxical phenomenon whereby ischaemic tissue, doomed to necrosis if it is not reperfused, is actually further damaged by oxidative attack when perfusion is restored. This paper is a review of the literature concerning therapeutic strategies in ischaemia-reperfusion injury, including nonpharmacological and pharmacological interventions. There is consistent experimental evidence of an important role of taurine in ischaemia-reperfusion injury, with a clinical role emerging in human trials of taurine administered prior to coronary artery bypass grafting and heart valve surgery.