The overall objective of this project is to increase the potential clinical efficacy of radiolabeled monoclonal antibodies (MoAbs) to carcinoembryonic antigen (CEA) or a gastrointestinal cancer associated with antigen (GICA). Radiolabeled MoAbs offer the possibility that radiation can be targeted preferentially toward cancer cells, which could yield a higher therapeutic index than external beam radiation alone. The chief stumbling block is the low dose of radiation that can be delivered to the tumor without causing systemic toxicity. The use of autologous bone marrow transplantation (ABMT) to increase the tolerable dose that can be delivered and of the halogenated pyrimidines to increase tumor sensitivity will likely increase the delivered radiation dose to bring it within the range of external beam doses shown to control gross tumor. The goal of this proposal is to determine the conditions for producing a significant increase in effective dose delivered to the tumor with acceptable toxicity, which will form the basis for subsequent clinical trials. MoAbs 35 and 17-IA which are well characterized have been used in clinical immunodetection and immunotherapy trials of human colorectal cancer will be utilized.
The Specific Aim of this application is to evaluate the therapeutic efficacy of 131I-and 90Y- labeled MoAbs with reactivities against human gastrointestinal tumor associated antigens in vivo human colon and pancreatic cancer experimental tumor models. Increased emphasis will be placed on therapy and dosimetry studies in this revised application Radiolabeled antibody induced cytotox- icity will be quantified for human colon and pancreatic cancer cell lines, as well as for control cells. The radiosensitizing effects of IdUrd an FdUrd will be assessed. These data will be correlated with those obtained from eternal beam radiation. Therapy studies will also be carried out in athymic nude mice bearing subcutaneous human colon or pancreatic cancer xenografts. Subsequent studies will determine the effect of ABMT on the dose and frequency of radiolabeled MoAb that can be safely administered. In addition, the effect of IdUrd and FdUrd on the effectiveness of radiola- beled MoAb therapy will be determined. Finally, a combination of ABMT and radiosensitizer would be used.
