Our previous studies have demonstrated a large pharmacologic advantage for the i.p. route of administration for tumors confined to extravascular cavities. The i.p. route permits a 1-3 log greater exposure for the peritoneal cavity than for plasma for several drugs, and very long duration exposure to S phase specific agents. In the case of cisplatin, i.v. infusion of a neutralizing agent (thiosulfate) selectively protects the kidneys and permits doses of 270 mg/m squared to be injected i.p. This in turn results in delivery of approximately 11-fold more reactive cisplatin to the systemic circulation than could be accomplished by i.v. injection of cisplatin without thiosulfate. This program will investigate use of the intracavitary route of drug administration to improve the treatment of ovarian carcinoma by: a) using combinations of drugs already shown to have a pharmacologic advantage when administered by this route; b) identifying other agents for which the i.p. route is pharmacologically advantageous, and developing non-cross-resistant combinations suitable for i.p. use; and c) defining the optimal way to use thiosulfate neutralization of cisplatin through elucidation of its pharmaco-kinetics and the mechanism by which it is producing selective protection of the kidneys. A pilot trial and pharmacokinetic studies of the 3 drug combination of CISplatin, Cytosine Arabinoside, and DOXorubicin (CISCADOX) will be performed in patients with intraperitoneal tumors, and based on the results a phase II trial of CISCADOX administered entirely by the i.p. route will be carried out in patients with ovarian carcinoma. A series of phase I and pharmacokinetic studies will be carried out of the i.p. instillation of other agents with established activity in ovarian carcinoma including bleomycin, vinblastine, and hexamethylmelamine. Based on the results, additional combinations of these combinations will be selected for i.p. use. We will perform detailed studies of the pharmacokinetics of thiosulfate, its effect on the pharmacokinetics of reactive cisplatin, and its effect on plasma and cellular thiols to define the mechanism of its selective protection of the kidneys.
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