) The proposed investigation is designed to provide clinical and pharmacologic data to determine the efficacy of IP gemcitabine therapy. Gemcitabine is a relatively new cytidine analog that has been approved for the treatment of metastatic pancreatic cancer and has shown promising activity in breast, lung, ovarian and bladder cancer. The potential advantage of IP chemotherapy is the ability to provide high regional drug concentrations for tumors confined to the peritoneal cavity. The pharmacokinetic advantage' of this regional therapy is primarily dependent on hepatic metabolism leading to clearance of the drug before systemic exposure. Gemcitabine appears to be an ideal candidate for IP therapy since approximately 98% of the dose is deaminated to the inactive dFdU by cytidine deaminase, which is present in high concentra-tions in the liver. Thus, by virtue of its high 'first-pass' metabolism, systemic exposure following IP gemcitabine should be minimal. High peritoneal gemcitabine concentrations may be effective in the treatment of peritoneal carcinomatosis arising from ovary and pancreas cancer, primary peritoneal carcinomatosis, or possibly mesothelioma.
The specific aims of the proposed investigation are: (1) To determine the MTD of IP gemcitabine, when given weekly, in patients with refractory intra-abdominal malignancies. (2) To evaluate the pharmacokinetic advantage of IP gemcitabine by quantitation gemcitabine, the active intracellular metabolite dFdCTP and the deaminated metabolite dFdU in peritoneal fluid and plasma. (3) To identify mechanisms of clinical resistance to gemcitabine. There are currently few drugs that are effective in the therapy of primary intra-abdominal malignancies. The results from the proposed trial should allow development of gemcitabine as an effective therapeutic strategy. Moreover, the proposed pharmacodynamic studies will provide important new data with regard to possible mechanisms of resistance to gemcitabine that are operative in patients.
