The overall goal of the proposed studies in this project is to determine how radioimmunotherapy (RAIT) can be used together with chemotherapy to improve anti-tumor responses of colonic and pancreatic cancer and to establish biological principles that will guide the optimal combined use of these two therapeutic modalities. Studies will be done primarily on three colonic cancer lines (GW-39, LS174T, HT-29) and on one pancreatic line (CaPan-1) that vary in their sensitivity to RAIT and chemotherapy. Studies will be performed on tumors grown s.c., as well as in micrometastatic and orthotopic models. The GW-39 xenograft will be used as both a subcutaneous (sc) model and as an intrapulmonary micrometastatic model. The LS174T and HT-29 lines will be used as both sc and liver metastasis models. The responsiveness to RAIT or to chemotherapy alone of all 3 colonic sc models has already been determined. GW-39 is a good responder to RAIT and a moderate responder to chemotherapy. LS174T is a good responder to RAIT and a poor responder to chemotherapy and HT-29 exhibits a moderate response to each treatment. The well characterized sc xenograft and orthotopic models of CaPan-1 will be used. All four lines have already been used to evaluate antigen (Ag) expression, antibody (MAb) targeting, and growth kinetics in nude mice. Radiolabeled MN-14 anti-carcinoembryonic antigen (CEA) and PAM4 (anti-MUC-1 epitope) will be used for these studies. Chemotherapy will be done with 5-fluorouracil (5-FU) alone for pancreatic cancer and with 5-FU+leucovorin (LV) for colonic tumors. Four major aims will be examined: [1] the optimal approach for using chemotherapy and RAIT together will be examined, [2] the importance of (a) in vitro chemo- and radiosensitivity, and (b) in vivo chemo- and radiosensitivity (intratumor pH and pO2) on tumor responsiveness to chemotherapy and RAIT will be examined, [3] the expression of antigen, intratumor pH and pO2, and targetability and responsiveness of whole tumor that survive either RAIT, chemotherapy or the combination therapy will be determined, and [4] the deposition of antibody or cytotoxic drug as function of vascularization. tumor size and viability will be assessed using video image analysis of colonic and pancreatic xenograft sections, treated with a single cycle or multiple cycles of chemo- or radioantibody therapy.
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