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Methods are disclosed for screening compounds for use in the treatment of, or the identification of a clinical or biological target for, a disease. The method comprises determining the ability of the compound to influence interactions involving alpha-methylacyl-CoA racemase.
This invention relates to methods for screening compounds to ascertain the effectiveness of such compounds in the treatment of, or the identification of a clinical or biological target for, a disease state in a subject. The i nvention further relates to compounds effective in the treatment of a d isease s uch as neoplastic disease, inflammation, inflammatory disease, pain, cystic fibrosis, dementia, and the like.
Neoplastic diseases are conditions in which abnormal proliferation of cells results in a mass of tissue called a neoplasm or tumor. Neoplasms have varying d egrees of a bnormalities in structure and behavior. S ome n eoplasms are benign while others are malignant or cancerous. An effective treatment intervention in the pathophysiologic progression of neoplastic disease would be considered a valuable contribution to the search for cancer preventive or curative procedures.
For example, the gastrointestinal tract, including the rectum and colon, is lined with epithelial cells, which have a high proliferation rate. The lining of the colon, in particular, made up of columnar rows of epithelial cells, is characterized by a series of indentations or crypts. Epithelial cells in the bottom regions of the crypts proliferate and move upward toward the tops of the crypts. In the normal colon, the proliferation region of the large intestine normally occupies the basal or deeper t hree-quarters of the crypts. A relationship has been observed between the expansion of cell proliferation zones to the upper regions of the crypts and colon cancer. See M. Lipkin, «Biomarkers of Increased Susceptibility to Gastrointestinal Cancer: New Application to Studies of Cancer Prevention in Human Subjects,» Cancer Research, Vol. 48, pp. 235-245.
Cancer of the colon is common in the western world and is an important cause of morbidity and mortality, having an incidence of about 5% in the U.S. population. As with other types of cancers, cancers of the gastrointestinal tract, including colon cancer, are characterized by development abnormalities in cell proliferation and differentiation in the gastrointestinal tract.
Another disease for which effective treatment is needed is cystic fibrosis. Cystic fibrosis (CF) is a heritable disease that follows an autosomal recessive pattern of transmittance. It i s the most common lethal genetic disease i n the United States. The approximate frequency in Caucasians is 1 in 2000. Cystic fibrosis is characterized by abnormal eccrine and exocrine gland function. In particular, mucous glands produce viscous secretions that lead to chronic pulmonary disease, insufficient pancreatic and digestive function and abnormally concentrated sweat.
The most prominent theories of CF etiology focus on alterations in physiochemical properties of exocrine secretions, the regulation of exocrine gland secretions, electrolyte transport and abnormalities in serum. Typical presentations include early onset of respiratory symptoms such as colds, and recurrent respiratory infections later in life. CF patients show evidence of decreasing pulmonary function with time, and their sputum cultures often display S. aureus, P. aeruginosa and P. capacia.
The major source of CF morbidity is pulmonary disease. More than 98% of CF patients die of either respiratory failure or pulmonary complications. Antibiotics are the key element in increasing survival. Prior to the 1950's, when modern antibiotics began to become available, patients typically survived for only a few years. At present, the median survival age is 32 years of age. Consequently, stimulation of neutrophil function as a means of clearing bacterial foci is thought to be an appropriate focus of treatment. Still another disease for which effective treatment is needed is dementia including Alzheimer's Disease (AD), which is a degenerative brain disorder associated with extensive loss of specific neuronal subpopuiations and characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in varied races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect up to four million individuals in the United States alone. To date, AD has proven to be incurable, and presently causes up to 100,000 deaths yearly.
The brains of individuals with AD exhibit neuronal degeneration and characteristic lesions variously referred to as amyloidogenic plaques, vascular amyloid angiopathy, and neurofibrillary tangles. Large numbers of these lesions, particularly amyloidogenic plaques and neurofibrillary tangles, are generally found in several areas of the human brain. Smaller numbers of these lesions in a more restricted anatomical distribution a re found in the b rains of most aged humans who do not have clinical AD, as well as patients suffering from Down's Syndrome and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.
Alpha-methylacyl-CoA racemase (AMACR) is a mitochondrial and peroxisomal enzyme that catalyzes the racemization of alpha-methyl, branched carboxylic coenzyme A thioesters. It is i important i n the oxidation of bile a cid intermediates such as di- and trihydroxycholestanoic acid (DHCA and THCA) and branched chain fatty a cids such as p ristanic acid. AMACR catalyzes the conversion of several (2R)-methyl-branched chain fatty acyl-CoA's to their (S)- stereoisomers. Patients with a deficiency of AMACR accumulate in their plasma pristanic acid and the aforementioned bile acid intermediates. According to expressed sequence tag (EST) information, AMACR is expressed in most human tissues (uterus, kidney, brain, colon, prostate, lung, lymph node, connective tissue, pancreas). AMACR expression is consistently up-regulated in tumors, e.g., prostate, colon, breast, ovarian, colorectal, bladder, lung, renal, lymphoma and melanoma. Western Blot and immunohistochemical analysis confirms the up-regulation at the protein level and localizes the enzyme predominantly to the peroxisomal compartment of several tumors. A detailed immunohistochemical analysis of samples from prostate cancer cases using both standard slides and tissue microarray demonstrates that both prostate cancer and the High PIN lesions consistently score significantly higher than matching normal tissue.
A continuing need exists for compositions that are useful in the treatment of diseases and illnesses such as, by way of illustration and not limitation, neoplastic d isease, inflammation, pain, cystic fibrosis, d ementia, and the like. The compositions should be effective for preventing, delaying, and/or treating a disease, preferably, without some or all of the disadvantages of known treatments.
SUMMARY OF THE INVENTION
One e mbodiment of the present invention is a method for screening compound for use in the treatment of, or in the identification of a clinical or biological target for, a disease. The method comprises determining the ability of the compound to influence interactions involving alpha-methylacyl-CoA racemase.
Another embodiment of the present invention is a method for screening a small organic compound for use in the treatment (intervention in the pathophysiological process) of a disease. An analysis system is formed comprising the compound a nd alpha-methylacyl-CoA racemase. The analysis system is used under conditions for an interaction involving alpha-methylacyl- CoA racemase to occur. The amount or activity of alpha-methylacyl-CoA racemase in the system is measured and related to the effectiveness of the compound in the treatment of a disease or illness.