Current Pharmaceutical Design - Volume 9, Issue 6, 2003

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD is defined pathologically by extracellular neuritic plaques comprised of fibrillar deposits of β-amyloid peptide (Aβ) and neurofibrillary tangles comprised of paired helical filaments of hyperphosphorylated tau. Current therapies for AD, such as cholinesterase inhibitors, treat the symptoms but do not modify the progression of the disease. The etiology of AD is unclear. However, data from familial AD mutations (FAD) strongly support the “amyloid cascade hypothesis” of AD, i.e. that neurodegeneration in AD is initiated by the formation of neurotoxic β-amyloid (Aβ) aggregates, all FAD mutations increase levels of Aβ peptide or density of Aβ deposits. The likely link between Aβ aggregation and AD pathology emphasizes the need for a better understanding of the mechanisms of Aβ production. This review summarizes current therapeutic strategies directed at lowering Aβ levels and decreasing levels of toxic Aβ aggregates through (1) inhibition of the processing of amyloid precursor protein (APP) to Aβ peptide, (2) inhibition, reversal or clearance of Aβ aggregation, (3) cholesterol reduction and (4) Aβ immunization.

The formation of senile plaques containing amyloid β peptides (Aβ peptides) as a major constituent plays a significant role in development of Alzheimer's disease. The concentration of Aβ peptides in the brain is determined by a combination of their rate of synthesis and their rate of clearance. Considerable effort has been expended in producing inhibitors of the β and γ secretases involved in the synthesis of the Aβ peptides. More recently interest in the mechanism of clearance of the Aβ peptides has emerged, as promoting Aβ peptide clearance represents an alternative therapeutic approach. It now appears that cleavage of Aβpeptide by peptidases and proteases represents the major mechanism of clearance. This review describes those peptidases and proteases implicated in Aβ peptide clearance, the evidence that these enzymes function in vivo, and how they may represent new therapeutic targets.

Prostate cancer is the most frequently diagnosed cancer in North American men and accounts for 10% of cancer-related deaths in men. Despite advances in early detection and aggressive treatment of early disease, the overall mortality rate has not appear to have fallen, indicating that the current therapies are not beneficial for life expectancy and new strategies are required. Prostate cancer is a dynamic evolving process that develops in distinct steps, with each step liable to additional genetic hits that change the cancer cell phenotype and alter the patterns of gene expression. The molecular events in prostate cancer are beginning to be understood, including altered expression of tumor suppressor genes, pro- and anti-apoptotic genes, and oncogenes associated with the progression of the disease, and specific genes that are expressed predominantly or exclusively in prostate cells, prostate cancer cells, and prostate metastasis cells. These latter genes on the level of DNA, RNA and protein products are the targets of several new approaches to prostate cancer therapy and are the focus of this review.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a novel member of the secretin / glucagon / vasoactive intestinal peptide (VIP) superfamily. In vertebrates, including avians, it occurs in two forms: PACAP38 and PACAP27. PACAP structure is well conserved during evolution, being identical in mammals, and showing one amino acid dfifference in avians (chick, turkey). PACAP is widely distributed in the central nervous system and peripheral tissues and displays a pleiotropic activity, including functions as a hypophysiotropic hormone, neuromodulator, and neurotrophic factor. PACAP exerts its biological actions through three types of receptors designated PAC1, VPAC1 and VPAC2. This review (1) presents the current knowledge on PACAP origin, distribution and function, (2) compares the avian findings with those found in mammals, and (3) describes receptor-linked mechanisms in avians, including recent data on receptor-related signal transduction pathways, with a special emphasis on receptor pharmacology and function.

The following review outlines the physiological outcome of VIP and VIP gene manipulations. Previously, we reviewed the various VIP receptors associated with biological functions ranging from growth regulation, sexual function, bronchodilation, vasodilation and immune interactions to neurotrophism. VIP-based drug design is discussed below.

Neuropeptides can function as autocrine growth factors in cancer cells. High levels of bombesin (BB) and neurotensin (NT)-like immunoreactivity are present in small cell lung cancer (SCLC), a neuroendocrine tumor. Vasoactive intestinal peptide (VIP) stimulates and somatostatin (SST) inhibits the release of BB-like peptides from SCLC cells. BB-like peptides bind to BB2 receptors, which are present on the cell surface. BB-like peptides stimulate the mitogen activated protein kinase (MAPK) cascade leading to increased expression of nuclear oncogenes and growth factors in SCLC cells. Due to the high density of neuropeptide receptors present on the cell surface, SST analogs have been radiolabeled to image neuroendocrine tumors. VIP receptors are present in many epithelial cancers including breast, colon, non-small cell lung cancer (NSCLC), pancreatic and prostate cancers. Due to the high density of VIP receptors on lung cancer cells, radiolabeled VIP agonists may be used to image these tumors. VIP receptor antagonists, such as VIPhybrid, inhibit the growth of cancer cell lines in vitro and in vivo. VIPhybrid and SR48692, a NT receptor antagonist, potentiate the cytotoxicity of chemotherapeutic drugs. These results suggest that neuropeptide receptor antagonists may be useful in the treatment of cancer.