Chemoprevention of murine urinary bladder carcinogenesis

小鼠膀胱癌的化学预防

• 批准号: 6829835
• 负责人: ASHISH M KAMAT
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829835
• 关键词: apoptosis; bladder neoplasm; carcinogenesis; cell growth regulation; cell line; cell proliferation; chemoprevention; ciprofloxacin; combination chemotherapy; disease /disorder model; drug interactions; drug screening /evaluation; genetically modified animals; laboratory mouse; magnetic resonance imaging; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer classification /staging; neoplastic cell; nonhuman therapy evaluation; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; pharmacokinetics; prostaglandin endoperoxide synthase; quinoline

DESCRIPTION (provided by applicant): The incidence of bladder cancer in the United States is increasing with 57,400 new cases projected for the year 2003. The majority of bladder tumors present as superficial papillary transitional cell carcinomas and recurrence rates approach 88% at 15 years. New approaches, including chemoprevention, are needed to reduce morbidity from this disease. Our study proposes to evaluate the hypothesis that two classes of agents - a cyclooxygenase-2 inhibitor and a quinolone antibiotic - either alone or in combination, have chemopreventive activity against superficial bladder cancer. Both these agents have been widely used with minimal toxicity, making them attractive for chemoprevention studies in humans. The first specific aim will study the in vitro effects of these agents on a panel of human bladder cancer cells with varying invasive and metastatic potential in order to obtain insights regarding activity against different grades of human bladder tumors. The second specific aim will evaluate the agents' chemopreventive efficacy in vivo. For these studies, we will use the transgenic mouse model in which development of papillary tumors in the bladder is driven by the presence of mutant Ha-ras. The tumors in this model mimic the tumors seen in patients who are considered candidates for chemoprevention studies. We will use MRI to image and monitor the tumors within the bladder of the animals since this will provide a rapid method to assess the efficacy of the chemopreventive agents. The third specific aim will determine the effects of the chemopreventive agents on tissue pathology and will address the hypothesis that the agents will prevent or inhibit the growth of tumors by inhibiting cell proliferation, inducing apoptosis, or both. We believe that this application will meet the stated goals of the program announcement to evaluate new chemopreventive agents, test strategies to prevent cancer in persons/animals at increased genetic risk, and to develop innovative animal models to mimic the human cancer process in order to expedite research in cancer prevention.

描述（由申请人提供）： 美国膀胱癌的发病率正在增加，预计2003年将有57，400例新病例。大多数膀胱肿瘤表现为浅表乳头状移行细胞癌，15年复发率接近88%。需要新的方法，包括化学预防，以减少这种疾病的发病率。我们的研究建议评估两类药物-环氧合酶-2抑制剂和喹诺酮类抗生素-单独或联合使用对浅表性膀胱癌具有化学预防活性的假设。这两种药物已被广泛使用，毒性最小，使它们对人类的化学预防研究具有吸引力。第一个具体目标将研究这些药物对一组具有不同侵袭和转移潜力的人膀胱癌细胞的体外作用，以获得关于对不同级别的人膀胱肿瘤的活性的见解。第二个具体目标是评估药物的体内化学预防功效。对于这些研究，我们将使用转基因小鼠模型，其中膀胱乳头状肿瘤的发展是由突变Ha-ras的存在驱动的。该模型中的肿瘤模拟了被认为是化学预防研究候选者的患者中观察到的肿瘤。我们将使用MRI成像和监测动物膀胱内的肿瘤，因为这将提供一种快速评估化学预防剂疗效的方法。第三个具体目标将确定化学预防剂对组织病理学的影响，并将解决该试剂将通过抑制细胞增殖、诱导细胞凋亡或两者来预防或抑制肿瘤生长的假设。我们相信，该应用程序将满足计划公告的既定目标，以评估新的化学预防剂，测试策略，以预防遗传风险增加的人/动物的癌症，并开发创新的动物模型来模拟人类癌症过程，以加快癌症预防研究。