Many botanicals advocated or researched for the treatment of cancer are thought to act via an immune mechanism. Their interaction with antibody-mediated cytotoxicity has not been previously explored. Tumor-specific antibodies now play major roles in the standard treatment of several human cancers, including trastuzumab (Herceptin) for breast cancer, rituximab (Rituxan) and alemtuzumab (Campath) for lymphorina and Cetuximab (Erbitux) for colon cancer. Natural or induced anti-tumor antibodies have also been correlated with favorable clinical outcomes in a number of human cancers. Through antibody, both complement mediated cytotoxicity (CMC) and cell-mediated cytotoxicity (ADCC) have played key roles. Besides Fc receptors, complement receptor 3 (CR3) is now found to be essential for ADCC in both in vitro and in vivo models. Beta-glucan is a major ingredient in many botanicals and when orally administered is transported by gut macrophages to the marrow where the processed carbohydrate is released to allow activation of the CR3 on leukocytes. In the presence of anti-tumor antibodies, this increased avidity of CR3 translates into highly efficient tumor kill. Therapies designed rationally on the basis of this mechanistic knowledge have been highly effective in animal models and early clinical trials. In this grant application, we hypothesize that botanicals can impact on these anti-tumor mechanisms by enhancing effector functions of leukocytes in ADCC through modulation of FcR, CR3 as well as other critical adhesion molecules. We propose to study oral administration of botanicals in combination with intravenous intravenous injection of anti-tumor antibodies in human xenograft models. Botanicals will also be tested for binding to CR3, and in vivo activation of CR3, FcR and integrins on leukocytes, as well as in vivo activation of neutrophil and .macrophage mediated tumor cytotoxicity. CR3-dependent tumor cytotoxicity for both IgM (innate) or IgG (induced) anti-tumor antibodies will be examined. For those botanicals with significant anti-tumor effects, the importance of CR3 will be confirmed using knockout mice. Although initial experiments will be carried out on five botanicals, we expect to screen a total of 46. Our findings will: a) suggest candidate botanicals for clinical trial in combination with antibodies or vaccines; b) form the basis of a general screening tool and quality control; c) provide leads for further research in the other projects that focus on vaccines, dendritic cells, T-cells and NK cells in different disease models.
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