CATIONIC COMPOUNDS FOR THERAPY OF BLADDER CANCER

用于治疗膀胱癌的阳离子化合物

• 批准号: 3175088
• 负责人: GERALD W CHODAK
• 金额: $ 8.85万
• 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/3175088
• 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，复发于 大约70%的患者。常规化疗治疗 无论是全身给药还是膀胱内给药都有一个缺点 对正常细胞和恶性细胞都有不良影响。最近， 对阳离子罗丹明染料的研究表明，恶性 过渡细胞吸收这种染料，并将其与线粒体结合，以 延长的一段时间。这具有干扰细胞的效果 并对癌细胞产生优先毒性。上一首 研究人员已经证明，腹膜腔内注射一种 罗丹明复合制剂对会膀胱癌动物的治疗作用 延长生存时间。 我们建议使用小鼠膀胱内肿瘤模型来评估 这些化合物是否仍然具有抗肿瘤活性 膀胱。这些研究是重要的，因为治疗和 对本病患者的诊断意义。这个肿瘤模型 是理想的，因为它接近于模拟人类的情况。长期的 目的是确定罗丹明染料是否将用于 系统性或全身性治疗人移行细胞癌 膀胱内途径。此外，这些阳离子和其他阳离子的能力 将确定用于定位膀胱癌区域的化合物 首先是在实验模型中，然后是在人类身上。 这项工作将主要使用膀胱内移行细胞肿瘤模型 这导致了可复制的肿瘤生长和相对恒定的 中位存活率。体内结合和组织学变化将是 经腹膜腔和腹膜腔给药后测定 行政管理。各种阳离子化合物将在体外和在 以确定哪种药物对这种肿瘤具有最大的活性。这个 最佳给药时间表将通过改变 给药的时间、剂量、持续时间、频率和地点。 各种阳离子化合物的比较将通过定量 肿瘤和正常尿路上皮细胞化学定位的相关性 生化组织化学和线粒体亚细胞分级 线粒体氧化磷酸化改变及其与肿瘤的关系 生长和寄主存活。在实验研究之后，一名飞行员 计划在人体内进行研究，以确定膀胱内给药是否 罗丹明或其他阳离子化合物可以帮助定位和 膀胱内肿瘤的治疗。