The goal of this proposal is to develop improved marrow transplant preparative regimens for the treatment of malignant and nonmalignant diseases of the marrow. Marrow transplantation is a widely used form of therapy for diseases of the marrow; over 5,000 transplants were performed last year alone. The success of transplantation, as currently used, is limited primarily by inadequacies of the preparative regimens which are often incapable of eradicating the marrow-based disease, yet are frequently associated with severe or fatal nonhematopoietic toxicities. This project will explore whether improved preparative regimens can be developed by using radiotherapy targeted specifically to the marrow. Two approaches to targeting marrow will be taken. One approach is to use radionuclides linked to antibodies reactive with antigens expressed on cells of marrow origin. The second approach is to use radionuclides linked to boneseeking agents as a way of delivering radiotherapy specifically to the marrow cavity. A canine model will be used to explore these two approaches. For the antibody studies, initial experiments will involve murine monoclonal antibodies specifically reactive with canine myeloid cells labeled with trace amounts of radionuclide, administered intravenously to normal dogs. Using external gamma camera imaging and organ biopsies, specific experiments will determine the biodistribution over time of the radiolabeled antibody, and will explore those factors which influence biodistribution, including antibody dose, form, amount of antigen on target cells, mass of targeted cells, deiodination (in the case of radioiodinated antibody), and the use of alternative radionuclides. The actual radiobiologic effects of radiolabeled antibodies will be determined by labeling a nonbinding antibody and a specific antimyeloid antibody with high levels of activity and determining the effects of these reagents in dogs given no transplant support to determine the marrow ablative effects of these reagents, autologous transplant support to determine nonhematopoietic dose-limiting toxicities, or allogeneic transplantation to determine the immunosuppressive effects of these reagents. A similar series of experiments will be performed using an energetic beta emitter (166Ho) linked to the bone-seeking aminophosphonic acid EDTMP. Again using a canine model, the biodistribution of 166Ho-EDTMP will be determined and the actual radiobiologic effects of 166Ho-EDTMP will be measured by administering the agent to normal dogs given no marrow support, autologous marrow, or allogeneic marrow.
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