Project Details


DESCRIPTION (Applicant's Description)

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
Effective start/end date7/1/986/30/01


  • National Cancer Institute
  • National Cancer Institute


  • Oncology
  • Cancer Research


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