The overall objective of Project 0006 is to improve the response and therapeutic ratio of radioimmunotherapy (RIT) by: 1) determining how tumor, antibody, and radioisotope related factors are important in antibody targeting and cell killing and 2) developing treatment strategies that can further improve the efficacy of RIT. There are four specific aims:
Aim 1) To understand the importance of antibody distribution and dose heterogeneity within the tumor in the optimization of RIT response. Using antibody constructs of different sizes and affinities radiolabeled with beta emitters with different particle path lengths, we will assess how different patterns of antibody and radiation dose distribution within the tumor influence response in vivo. By the addition of lymphokines, we will further modulate and improve the pattern of dose distribution, by increasing tumor vascular permeability (interleukin-2) and increasing antigen expression (gamma-interferon). Three dimensional reconstruction of autoradiographic studies, will allow us to estimate regional differences in tumor dose at a histologic level and will provide a better understanding of how tumor dose and dose heterogeneity correlate with tumor response.
Aim 2) To determine in vivo whether appropriately timed cyclic RIT can result in a greater therapeutic ratio. For clinically promising antibody constructs, we will compare and rationally design various cyclic RIT dosing regimens based on differences in clearance rates, recovery times, and antibody uptake between tumor and normal tissue. For each regimen changes in a) antibody uptake, b) antibody pharmacokinetics, c) tumor antigen expression, d) tumor dose and response, and e) normal organ dose and toxicity with each cycle will be assessed. These studies will determine what tumor and antibody factors are best suited for each dosing regimen.
Aim 3) To develop the measurement of stable chromosome translocations as an indicator of cumulative radiation damage. Fluorescence in situ hybridization (FISH) will be used to rapidly and accurately assess stable chromosome translocations. In vitro and in vivo studies with low dose rate irradiation will be used to evaluate the utility of this technique to estimate radiation dose from RIT for comparison with dose calculations made in Core A. The goal of this effort is the application of this technique to clinical biopsy material to improve theoretical dose calculations, particularly in the bone marrow.
Aim 4) To determine the optimum use of 5-fluorouracil (5-FU) as an adjunct to RIT. Specifically, we will determine how 5-FU augments RIT by investigating the following mechanisms: a) direct radiosensitization of 90Y cell kill, b) induction of increased tumor CEA expression and antibody targeting and c) reduced radiosensitization of normal organ toxicity.
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