CATIONIC COMPOUNDS FOR THERAPY OF BLADDER CANCER

用于治疗膀胱癌的阳离子化合物

• 批准号: 3175087
• 负责人: GERALD W CHODAK
• 金额: $ 8.84万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 1987-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3175087
• 关键词: bladder neoplasm; carcinoma; cations; cell growth regulation; drug administration rate /duration; drug adverse effect; dyes; histochemistry /cytochemistry; mitochondria; neoplasm /cancer chemotherapy; urinary bladder epithelium

Carcinoma of the bladder is a multifocal disease which recurs in approximately 70% of patients. Treatment with conventional chemotherapy administered either systemically or intravesically has a disadvantage of causing adverse effects for normal, as well as, malignant cells. Recently, studies with cationic rhodamine dyes have revealed that malignant transitional cells absorb this dye and bind it to the mitochondria for prolonged periods of time. This has the effect of interferring with cell growth and causes a preferential toxicity to the cancer cells. Previous investigators have demonstrated that intraperitoneal administration of a rhodamine compound to animals with an intrapertineal bladder tumor can prolong survival. We propose to use an intravesical bladder tumor model in mice to assess whether these compounds are still active against a tumor growing in the bladder. These studies are important because of the therapeutic and diagnostic implications for patients with this disease. This tumor model is ideal because it closely mimics the human situation. The long-term objective is to determine whether rhodamine dyes will be useful for treating human transitional cell carcinoma by either the systemic or intravesical route. In addition, the ability of these and other cationic compounds to localize malignant areas of the bladder will be determined first in an experimental model and then in humans. The work will promarily use an intravesical transitional cell tumor model which results in reproducible tumor growth and in relatively constant median survival. In vivo binding and histological changes will be determined following intraperitoneal and intraversical drug administration. Various cationic compounds will be tested in vitro and in vivo to determine which drug has maximum activity against this tumor. The optimum schedule of drug administration will be assessed by varying the time, dose, duration, frequency and location of drug administration. Comparisons of various cationic compounds will be made by quantitative correlations of chemical localization in tumor and normal urothelium by histochemistry and mitochondrial subcellular fractionation with biochemical alterations in mitochondrial oxidative phosphorylation and with tumor growth and host survival. Following the experimental studies, a pilot study is planned in humans to determine if intravesical administration of rhodamine or other cationic compounds can assist in the localization and therapy of intravesical bladder tumors.

膀胱癌是一种多灶性疾病， 约70%的患者。 常规化疗治疗 全身或膀胱内给药的缺点是 对正常细胞以及恶性细胞造成不利影响。 最近， 阳离子罗丹明染料的研究表明， 移行细胞吸收这种染料并将其结合到线粒体上， 长时间的。 这会干扰细胞 生长并对癌细胞产生优先毒性。 先前 研究者已经证明，腹膜内施用 罗丹明化合物对患有腹膜内膀胱肿瘤的动物的作用可 延长生存期 我们建议使用小鼠膀胱内膀胱肿瘤模型来评估 这些化合物是否仍然对生长在肿瘤中的肿瘤有活性， 膀胱 这些研究是重要的，因为治疗和 对这种疾病的诊断意义。 该肿瘤模型 是理想的，因为它非常接近人类的情况。 长期 目的是确定罗丹明染料是否可用于 通过全身性或全身性化疗治疗人移行细胞癌 膀胱内途径。 此外，这些和其他阳离子的能力 将确定定位膀胱恶性区域的化合物 首先是在实验模型中，然后是在人类中。 这项工作将使用膀胱内移行细胞肿瘤模型 这导致肿瘤生长的可重复性和相对恒定的 中位生存率 将研究体内结合和组织学变化。 腹腔内和膀胱内给药后确定 局 将在体外和体内测试各种阳离子化合物。 以确定哪种药物对这种肿瘤具有最大的活性。 的 最佳给药时间表将通过改变 给药时间、剂量、持续时间、频率和部位。 各种阳离子化合物的比较将通过定量分析来进行。 肿瘤与正常尿路上皮化学定位的相关性 组织化学和线粒体亚细胞分级与生化 线粒体氧化磷酸化的改变与肿瘤 生长和宿主生存。 在实验研究之后， 计划在人类中进行研究以确定膀胱内施用 若丹明或其它阳离子化合物可有助于定位， 膀胱内膀胱肿瘤的治疗。