CATIONIC COMPOUNDS FOR THERAPY OF BLADDER CANCER

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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.