Radioimmunotherapy (RAIT) was shown to decrease vascular permeability (VP) in the GW-39 human colonic carcinoma xenograft model. Changes in VP were characterized as a function of tumor size, radiation dose, antibody (Ab) penetration, radionuclide, single versus fractionated dosing and time post treatment. The use of another 10 xenografts revealed that a similar change in tumor VP post RAIT could be found in three of these 10 cell lines. However, four tumor cell lines exhibited a RAIT-induced increase in VP and three cell lines exhibited no change in VP post RAIT. Since tumor VP is an important factor in regulating accretion of therapeutic agents, understanding the biochemical regulation of tumor VP and elucidating other effects of RAIT on tumor physiology, e.g. induction of hypoxia, might permit to manipulate tumor VP and/or take advantage of changes in tumor physiology and thus develop rational multimodal therapy approaches using RAIT and vascular directed agents. Two key biochemical mechanisms, nitric oxide synthase (NOS) activity and expression of vascular permeability factor (VEGF), have been implicated in the literature as having influential roles in regulating VP both in tumor and normal tissues. The studies in this continuing renewal application are directed at testing the hypothesis that NOS and VEGF are key regulators maintaining baseline tumor permeability and regulating RAIT-induced changes in permeability. These studies will form the basis of efforts to manipulate these two mechanisms towards creating combination therapy approaches using RAIT with either a hypoxic cytoxin, since RAIT induces a significant hypoxia, and/or a VEGF-directed reagent, VEGF antibody or radiolabeled VEGF, or a NOS stimulator or inhibitor. The 2nd hypothesis to be tested is that optimal timing of each modality, based on tumor physiological changes post RAIT, will result in multimodal therapy protocols that are more efficacious than either modality alone. These long-term goals will be accomplished in four aims: 1) Establish the amount of tumor NOS activity, VEGF production and VEGF-receptor (VEGF-R) expression in tumor extracts taken from untreated and RAIT-treated tumors and correlate the results with tumor VP; 2) Establish the temporal relationship between intratumor hypoxia and RAIT administration; 3) Utilize the results on RAIT-induced changes in intratumor hypoxia and/or VEGF/VEGFR expression to optimize multimodal therapy of RAIT with the hypoxic cytoxin SR4233 and/or anti-VEGF Ab or VEGF radioconjugate administration; and 4) Modify tumor VP by altering tumor nitric oxide (NO) production using a NOS substrate or inhibitor, and thus enhance uptake, dosimetry and therapeutic efficacy of radioantibody.
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