Bladder carcinoma is generally highly refractory to systemic antitumor therapy, presumably as a result of poor drug-delivery to the tumor site. However, certain bladder tumors may respond clinically to therapy involving intravesical drug administration. Based on laboratory studies, three adriamycin analogues have been identified with excellent potential for use in intravesical therapy by virtue of their high lipophilicity, low toxicity, and mechanistic differences relative to adriamycin. Another agent, rhodamine-123, a xanthene dye derivative, appears to have similar advantages. It is believed that these drugs offer the potential for (a) better penetration into deeply-seated invasive tumors and (b) circumvention of drug resistance, two parameters with a significant effect upon disease prognosis. A series of studies is proposed to evaluate the experimental agents relative to these parameters. Drug and metabolite levels will be quantified by hplc analyses and cellular localization by fluorescence microscopy/autoradiography. Absorption of experimental drugs from the bladder will be examined in rats and the significance of resulting plasma drug-levels determined relative to the systemic toxicities of these agents. Established murine bladder tumor systems of varying growth fraction and response to adriamycin will be used to determine the antitumor efficacy of the selected agents. Parallel drug metabolism/disposition studies will be conducted in tumor-bearing animals. With respect to human disease, urothelial drug penetration will be studied in a limited series of patients undergoing total cystectomy for advanced bladder carcinoma, with results compared to data obtained in animal studies. Established in vitro human bladder tumor cell lines with varying inherent adriamycin sensitivity will be used to examine the potential human antitumor efficacy of the agents in paraallel with cellular pharmacology and tumor colony=forming assay studies. Results will be compared with antitumor data obtainecd in the murine test system. Current intravesical therapy relies upon a limited number of drugs which have evolved from systemic administration. The proposed work is significant in that it seeks to evaluate and develop new agents, based upon sound rationale, with superiority to those presently used in intravesical treatment of bladder cancer.
