2007 — 2008 |
Cao, Deliang |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Aldose Reductase-Like-1, a Novel Hepatocellular Carcinoma Drug Resistant Protein @ Southern Illinois University Sch of Med
[unreadable] DESCRIPTION (provided by applicant): Human hepatocellular carcinoma (HCC) is a rapidly increasing type of human cancer, ranked the eighth leading cause of cancer death in the United States. Although early diagnosis and surgical removal is a curative approach for some HCC cases, the majority are not resectable at the time of diagnosis due to lack of efficient early diagnosis and aggressive progression of the disease. Therefore, chemotherapy still remains the primary therapeutic choice for this disease. However, HCC is widely resistant to various cytotoxic antitumor agents, resulting in high patient mortality rates. Aldose reductase-like-1 (ARL-1), a novel protein overexpressed in 54% of human HCC tissues, can efficiently reduce the C13 methyl ketone group of daunorubicin to alcoholic form, daunorubicinol. Daunorubicinol possesses less antitumor activity, but stronger cardiomyopathic toxicity, compared to daunorubicin. Thus, we hypothesize that ARL-1 may represent a novel target to explore a new HCC chemotherapy strategy. This proposal is designed to answer the following questions: Does expression of ARL-1 within HCC tissues result in their drug resistance to anthracyclines? If so, how does this process occur? What is the pharmacokinetics of these agents in tumor tissues with high ARL-1 levels? Within tumors, what is the effect of high ARL-1 levels on the circulating metabolites with strong cardiovascular toxicity? These questions will be addressed through the following specific aims: (1) Determine the in vitro enzymatic activity of ARL-1 in catalyzing the reduction of the anthracyclines, with purified ARL-1 protein; (2) Determine the role of ARL-1 in the intracellular metabolism and antiproliferative activity of the anthracyclines, using ARL-1 gene targeting cell models; and (3) Evaluate the effect of tumor ARL-1 levels on the intratumoral metabolism and antitumor activity of the anthracyclines, using animal tumor models. Human hepatocellular carcinoma (HCC) is the most rapidly increasing type of human cancer in the United States. This disease carries high patient mortality rates, due to its wide resistance to current chemotherapy. Aldose reductase-like-1 (ARL-1) is a novel protein and a potential target for improved HCC chemotherapy treatment. This study will determine the role of ARL-1 in HCC drug resistance and its mechanisms of action, toward the pursuit of reducing HCC patient death. [unreadable] [unreadable] [unreadable]
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0.976 |
2008 — 2009 |
Cao, Deliang |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Role of Aldose Reductase-Like-1 in Colon Tumorigenesis @ Southern Illinois University Sch of Med
[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] This R21 resubmission details an exploratory study on the role of aldose reductase-like-1 (ARL-1) in preventing reactive carbonyl-induced chronic inflammation and malignancy in the colon. With greater than 106,680 new cases diagnosed annually, colorectal cancer accounts for more than 55,000 deaths each year in the United States, indicating a need for improved prevention, detection, and treatment of this disease. Chronic inflammatory bowel diseases (ulcerative and Crohn's disease), affecting up to two million Americans, is associated with the development of colorectal cancer. Electrophilic carbonyls pervade our daily environment and various diets and are produced constantly during cellular metabolism, being important pathogens of intestinal inflammation and tumorigenesis. ARL-1, a novel protein with specific expression in the normal colon, displays strong enzymatic activity toward reactive carbonyls, protecting cells from carbonyl lesions. Of particular interest, preliminary data from our laboratory indicates that ARL-1 protein is lost in tested inflammatory and malignant colon tissues. Therefore, we hypothesize that ARL-1 may block colon cells from dietary reactive carbonyls, protecting them from carbonyl lesions. The loss of ARL-1, via genetic or epigenetic factors, may leave colon cells vulnerable to carbonyl toxins, resulting in inflammatory and neoplastic lesions. This exploratory study will address the following questions: What is the role of ARL-1 in regulating cellular response to reactive carbonyls, particularly in DNA damage? What is the level of ARL-1 expression in malignant colon tissues? How does ARL-1 expression correlate with the type, grade, and differentiation of colon cancer? What is the level of ARL-1 expression in inflammatory colon tissues and cancer precursors, such as dysplasia? [unreadable] [unreadable] We will answer these questions through the following specific aims: (1) determine the effect of ARL-1 activity on DNA damage induced by electrophilic carbonyls, using ARL-1 gene targeted cells, and (2) evaluate the expression and function of ARL-1 gene in inflammatory and malignant colon tissues using real time reverse transcriptase polymerase chain reaction, Western blot, immunohistochemistry, and ARL-1 enzymatic activity/gene sequencing analysis. The resulting data will define the role of ARL-1 in protecting cells against reactive carbonyl lesions and validate ARL-1 as a novel target for prevention of colon cancer. Successful study results will support an extensive R01 study in the future, benefiting chronic inflammatory patients through improved chemoprevention, early diagnosis, and treatment of colon cancer.7. Project Narrative [unreadable] [unreadable] Chronic inflammatory bowel diseases (ulcerative and Crohn's disease) are strongly associated with colon cancer - the second leading cause of cancer deaths in the United States. Electrophilic carbonyls, present in diet or produced during cellular metabolism, are important pathogens of inflammatory and neoplastic bowel diseases. The proposed study will elucidate the role of a novel protein, ARL-1, in protecting colon cells from carbonyl lesions, validating ARL-1 as a novel target for the prevention of colon cancer. [unreadable] [unreadable] [unreadable]
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0.976 |