Aldose Reductase-Like-1, a Novel Hepatocellular Carcinoma Drug Resistant Protein

醛糖还原酶样-1，一种新型肝细胞癌耐药蛋白

• 批准号: 7261164
• 负责人: Deliang Cao
• 金额: $ 14.45万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261164
• 关键词: Address; Alcohols; Aldehyde Reductase; Animals; Anthracycline Antibiotics; Anthracyclines; Blood; Cancer Etiology; Cardiovascular system; Cell model; Cells; Cessation of life; Chemical Structure; Cytotoxic agent; Daunorubicin; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Doxorubicin; Drug Kinetics; Drug resistance; Duborimycin; Early Diagnosis; Epirubicin; Event; Excision; Future; Gene Expression; Gene Targeting; Gene Transfer; Growth; Human; Idarubicin; In Vitro; Investigation; Ketones; Life; Malignant Neoplasms; Measures; Messenger RNA; Metabolism; Modeling; Molecular; Mus; Neoplasm Metastasis; Numbers; Operative Surgical Procedures; Patients; Primary carcinoma of the liver cells; Process; Prognostic Marker; Protein Overexpression; Proteins; Rate; Recipe; Recording of previous events; Resectable; Resistance; Role; Site; Technology; Tetracycline; Tetracyclines; Therapeutic; Time; Tissues; Toxic effect; Tumor Tissue; United States; antitumor agent; chemotherapy; cytotoxic; data management; design; improved; inhibitor/antagonist; liquid chromatography mass spectrometry; mortality; novel; problem drinker; promoter; response; success; tumor

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.

描述（由申请人提供）：人类肝细胞癌（HCC）是一种迅速增加的人类癌症类型，是美国癌症死亡的第八个主要原因。尽管早期诊断和手术去除是某些HCC病例的一种治愈方法，但由于缺乏有效的早期诊断和疾病的侵略性进展，大多数在诊断时无法切除。因此，化学疗法仍然是该疾病的主要治疗选择。但是，HCC对各种细胞毒性抗肿瘤剂具有广泛的抗性，导致患者死亡率较高。醛糖还原酶样-1（ARL-1）是一种在54％的人类HCC组织中过表达的新型蛋白，可以有效地将daunorubicin的C13甲基酮基团降低至酒精形式，即daunorubicinol。与多诺比霉素相比，daunorubicinol具有较少的抗肿瘤活性，但心肌病的毒性较强。因此，我们假设ARL-1可能代表了探索新的HCC化学疗法策略的新目标。该提案旨在回答以下问题：ARL-1在HCC组织中的表达是否会导致其对蒽环类药物的耐药性？如果是这样，这个过程是如何发生的？这些药物在ARL-1水平高的肿瘤组织中的药代动力学是什么？在肿瘤中，高ARL-1水平对具有强心血管毒性的循环代谢产物有什么影响？这些问题将通过以下特定目的解决：（1）用纯化的ARL-1蛋白来确定ARL-1的体外酶促活性； （2）使用ARL-1基因靶向细胞模型，确定ARL-1在蒽环类药物的细胞内代谢和抗增殖活性中的作用； （3）使用动物肿瘤模型，评估肿瘤ARL-1水平对蒽环类药物的肿瘤内代谢和抗肿瘤活性的影响。人类肝细胞癌（HCC）是美国人类癌症类型最快的人。由于对当前化疗的广泛抵抗力，该疾病的患者死亡率很高。醛糖还原酶样-1（ARL-1）是一种新型蛋白质，也是改善HCC化学疗法治疗的潜在靶标。这项研究将确定ARL-1在HCC耐药性及其作用机理中的作用，以追求减少HCC患者死亡。