RADIOIMMUNOTHERAPY AND TUMOR VASCULAR PHYSIOLOGY

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Control of tumor growth has been reported for several human tumor xenograft models and for a few clinical trials using radionuclides coupled to tumor-associated antibodies. These radioimmunoconjugates accrete and are retained in tumor tissue for many days, thereby delivering a continuous low dose of radiation. The cytocidal and physiological changes in target tissue associated with short duration- high dose ionizing radiation are well understood. However, the effects of low dose rate irradiation, such as from radioimmunotherapy (RAIT), remain unknown. Autoradiographic analysis has demonstrated that radioantibodies distribute in the perivascular space, and preliminary results indicate that this localized radiation dose alters tumor vascular physiology and the ability to retarget these tumors with additional doses of RAIT. These radiation-induced changes in vascular function may in turn influence intratumoral pH and pO2. The disruption in cell density may also affect intratumoral interstitial pressure. The net effect of these changes may not only impact on the accretion of additional doses of radioantibody in a multiple cycle scheme, but may also affect accretion of radioantibody in a fractionated dose scheme and may influence the uptake of other smaller anti-tumor agents (e.g. drugs, BRMs). This proposal has three broad goals: (a) To determine the effects of low- dose rate radiation on tumor vascular structure and function on the whole tumor and on the microscopic level, (b) To determine how RAIT affects intratumoral interstitial pressure, pH, and pO2, and (c) To assess how these changes influence accretion and therapeutic potential of multiple doses of radioantibody or lower molecular weight therapeutics. We will use an anti-colon-specific antigen-p (CSAp) antibody (Mu-9) labeled with I-131, a radionuclide that deposits its energy within a 1-mm range, or Re-186, an intermediate range beta-emitter, or two high-energy beta- emitters, Re-188 and Y-90, with longer path lengths, to address these issues. Specifically we will: (1) establish a dose-response relationship between rad dose and vascular change, (2) determine whether RAIT with other nuclide-labeled antibodies alters vascular function of tumors, (3) determine whether vascular changes occur in tumors if the radioantibody distributes away from the perivascular space, (4) determine whether vascular changes occur if the total dose of RAIT is fractionated, ed tumors. (5) assess the effect of RAIT on pH, and pO2, and interstitial pressure (6) assess whether surviving cell populations are accessible and responsive to a 2nd dose of RAIT after the tumor vasculature is disrupted, and (7) determine whether the disruption in the tumor vasculature impedes uptake and therapeutic efficacy of small molecular weight substances. Overall, the hypothesis that low dose rate radiation derived from the perivascular distribution of radioantibodies damages tumor vessels either directly by disrupting radiosensitive endothelial cells and/or indirectly by influencing the production of endogenous vascular stimulating agents like VEGF/VPF. The proposal also addresses two other hypotheses: [a] once vessels are damaged, the ability to target tumor with additional therapeutics (immunoconjugates, BRMS, or cytotoxic drugs) may be limited, and [b] damaged vessels will effect the internal milieu of the tumor and thereby influence the distribution and the cytotoxic potential of additional therapeutics that are dependent on factors like intestinal pressure, pO2, and pH.