Annually, >66,000 new superficial bladder carcinomas and peritoneally- confined metastatic ovarian carcinomas tumors and some 20,000 disease- related deaths are reported. In their early stages, both tumors are amenable to intracavitary chemotherapy which, conceptually, affords a greater tumor exposure and lower toxicity than might achieved by systemic therapy and thereby offers the otherwise unattainable potential to overcome low levels of drug resistance. Unfortunately, current optimal therapeutic efficacy for these conditions may be compromised by: dose- limiting contact toxicity; inadequate penetration into larger (>0.5 cm) tumor masses; and reduced efficacy vs drug resistant tumors. Significant improvements in efficacy may result from the development of new agents particularly suited to intracavitary instillation. In this regard, four anthracycline analogues and a xanthene dyestuff-platinum complex, have been selected for evaluation based upon: antitumor activity; ease of penetration into cells; and activity in cells with known forms of drug resistance. Each selected intracavitary drug will be evaluated against its respective parental agent (doxorubicin or cisplatin) in a number of in vivo and in vitro models. Tissue contact toxicity will be determined in the rat bladder and peritoneal tissues following single or multiple intravesical (ive) or intraperitoneal (i.p.) drug exposures. Relative to the latter site, the selected agents will also be evaluated for effects upon wound healing, an important consideration for immediate post- operative adjunctive i.p. therapy. Likewise, potential systemic toxicity will be examined in the rat by comparing total systemic exposure following intravenous (i.v.) or intracavitary drug administration. These parameters both impact upon the ability to achieve an supra-optimal therapeutic drug concentration in the respective cavities. Drug penetration will be examined quantitatively by confocal microscopy and HPLC drug analysis) in dog and human urinary bladders and in tissues contained in the rat peritoneal cavity. The ability to effectively treat anatomically more deeply-seated tumors, such as those in advanced bladder cancer or ovarian tumor masses >0.5 cm in diameter, would represent major therapeutic advancements. In vitro antitumor activity (Clonogenic assay) will be examined in accepted drug sensitive and (doxorubicin or cisplatin) resistant bladder and ovarian cancer cell lines. Data will be interpreted in light of: parallel cellular pharmacology studies to provide a rationale for the observed antitumor activity in vitro and; intracavitary pharmacology profiles thereby demonstrating the viability of achieving cytotoxic intracavitary drug concentrations in vivo. The in vivo activity of systemically vs i.v. or i.p. administered drugs will be determined in accepted experimental models with parallel pharmacology and confocal laser scanning fluorescence microscopic studies of drug distribution and tumor penetration. In conclusion, the ultimate aim of this proposal is the clinical introduction of new intracavitary therapeutics which offer improved safety and efficacy.
