In the United States 75% of patients with gastric cancer have disseminated disease at diagnosis; chemotherapy remains the main modality of treatment for metastatic disease. Recent reports suggest that FAMTX chemotherapy (a combination of 5-Fluorouracil, doxorubicin, and methotrexate with leucovorin rescue) has a superior response rate and associated median survival than FAM chemotherapy (5-Fluorouracil, doxorubicin, and mitomycin- C). The purpose of this grant application is to describe correlations between pharmacodynamic parameters and clinical antitumor responses in patients receiving FAMTX chemotherapy for gastric cancer. The pharmacodynamic parameters can be divided into measurements obtained by invasive or non-invasive methods. The invasive methods involve obtaining tumor specimens for histologic diagnosis, measurement of proliferative index, and measurement of various biochemical pharmacology parameters [5- Fluorodeoxyuridine monophosphate (FdUMP), phosphoribosyl pyrophosphate (PRPP) and thymidylate synthetase (TS) activity and structure]. The non- invasive methods involve magnetic resonance spectroscopy (MRS) to assess 5- FU trapping and metabolism within tumors. A total of 40 evaluable patients will be studied; patients will have advanced or locally resectable disease. Thirty evaluable patients will undergo two serial MRS measurements, one following 5-FU alone, and the second following MTX and 5-FU. At least 10 patients will undergo two serial biopsies following 5-FU alone, and one following MTX and 5-FU. Biopsies will be used for histologic assessment, proliferative index measurement and biochemical pharmacology assessment. It is anticipated that approximately 12 of the 40 patients will be candidates for an attempt at curative resection following induction chemotherapy. This surgery will be performed within 24 hours of MTX and 5- FU chemotherapy to facilitate obtaining biochemical pharmacology measurements. Correlations between histology, proliferative index, biochemical pharmacology parameters and MRS parameters will be described.
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