Control of metastatic cancer remains one of the most important goals of cancer therapy. Human cancers frequently metastasize to the lung and many are refractory to conventional modes of chemotherapy. We reported previously that native human C-Reactive Protein (CRP) (a nontoxic endogenous acute phase plasma protein) reduced metastases and prolonged survival of tumor-bearing mice in three different models of established tumor metastasis: fibrosarcoma T241, B16 melanoma, and MCA 38 colon carcinoma. In vitro, CRP enhanced tumoricidal activity of murine and human macrophages. More recently, we have observed that a synthetic CRP peptide can mimic these effects of native CRP and that a combination of synthetic CRP peptide with Interleukin 2 (IL2) has a greater anti-metastatic effect than either agent alone. These data suggest that synthetic CRP peptide represents a novel biological response modifier with anti-metastatic and macrophage activating properties, and the potential to enhance existing cytokine therapy. We propose to evaluate the therapeutic effects of synthetic CRP-peptide alone and in combination with IL2 against established pulmonary metastases of murine fibrosarcoma T241, a malignant, spontaneously metastasizing tumor. Further, we propose to identify and characterize immunologic mechanisms of pulmonary tumor destruction evoked by such therapy.
Our specific aims are to: (1) Establish conditions for obtaining the optimal therapeutic effects of synthetic CRP peptides as a single treatment and in combination with IL2; (2) Evaluate the nature and kinetics of pulmonary immunopathologic changes occurring in situ after treatment with synthetic CRP peptide alone and with IL2, including the characterization of inflammatory leukocytes or mediators; and (3) Using in vitro techniques, characterize the pulmonary immune cells and/or soluble factors responsible for anti-tumor activity and the kinetics of such activity. These studies will enable us to evaluate the potential of synthetic CRP peptide alone and in combination with Interleukin 2 for the treatment of human metastatic cancer.
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