Radiolabeled immunoconjugates against tumor-associated antigens have shown promise as both diagnostic and therapeutic agents in-vitro, in human tumor implants in animals, and in selected groups of cancer patients with metastatic lesions. When a large activity of radiolabeled immunoconjugate is administered to a patient for therapeutic purposes, it is mandatory to be able to calculate as accurately as possible the radiation doses to both neoplastic and normal tissues. Recent experimental data have shown that the distribution of radioimmunoconjugates in tumors is highly inhomogeneous and that bone marrow toxicity is a key issue to the success of this new modality. The Medical Internal Radiation Dosimetry system fails to provide accurate enough dose estimates to these tissues. The present proposal, consisting of 4 inter-related projects, will provide (a) new distribution data of the radioimmunoconjugates in micrometastases and bone marrow, and (b) new validated methods of dose calculation for these tissues. The projects are: 1. Experimental determination and mathematical modeling of uptake kinetics of immunoconjugates in human multicell spheroid model of avascular tumor metastases. 2. Determination of rates of exchange of immunoconjugates between bone marrow parenchyma and bone marrow sinusoids in dogs by positron emission tomography. 3. Development of computer programs to evaluate dose distributions of any extended electron or beta sources in a homogeneous volume of soft tissue of arbitrary shape using Fast Fourier Transform method. 4. Development of an effective surface source concept which may explain quantitatively the perturbation of electron dose distributions heterogeneous media from their respective homogeneous media. The end product of the proposal will be validated computer programs which may eventually be used for routine treatment planning of radioimmunotherapy.
