The Study Of The Depressant Effect By Gleevec Combines With Docetaxel And Capecitabine In Breast Cancer

Malignant tumor is a kind of common disease that threatens our healthy. The therapeutic tool of malignant tumor includes operation, chemotherapy, radiotherapy, immunization, and chemotherapy is the most general tool. In clinical using at present, the bulk of the anti-tumor drugs are cytotoxic drugs, which can not discriminate the tumor cell and the normal cell, so these kinds of drugs kill the tumor cell and the normal cell at the same time. These drugs can cause serious adverse reactions in clinical therapy, which can affect the quality of life and treatment plan of the patients, even the toxicity of the drugs can lead the patients to death.Gleevec is the most successful molecule targeted anti-cancer drug, which is the first anti-cancer drug of targeting molecular change. So, Gleevec dose not cause the serious adverse reactions. Presently, the confirmed targets of Gleevec include Bcr-Abl, c-Kit and platelet-derived growth factor receptor (PDGFR).In the prophase study, the direct interaction between Galectin-3 and c-Abl was demonstrated by co-immunoprecipiation, in vitro binding assay and Far-Western blot. It is also shown that Galectin-3 is the phosphorylation substrate of c-Abl by kinase assay and phosphorylated analysis. Futher, found that treated with Gleevec, Galectin-3 aggregated and degradated in lysosome accompanied by Hsc70. A consequence of phosphorylation is a significantly compromised chaperone-mediated autophagy of Galectin-3. The biological significance of c-Abl-mediated Galectin-3 phosphorylation is highlighted by the finding that Galectin-3 expressing cells treated with c-Abl specific inhibitor Gleevec, display much more sensitivity to the apoptosis inducing agents, and tumor cells expressing the mutants showed impaired tumorigenicity.In order to investigate the effect of Galectin-3 expressing tumors treated with c-Abl specific inhibitor Gleevec, this study will investigate these from celluar level, animal level and molecular level.On celluar level, MCF-7 cells are treated with Gleevec and/or Docetaxel. Cell cycle and apoptosis are accessed by SubG1 measured with FACS, find Gleevec and Docetaxel show significant synergy effect in inducing MCF-7 tumor cell apoptosis. This result can provide important data for the advance study.On animal level, nude mice xenograft models are established with MCF-7 human breast cancer cells and the nude mice are treated with Gleevec, Docetaxel and/or Capecitabine. Docetaxel and Capecitabine can cause serious adverse reaction in clinical. Then, this thesis demonstrates that add or synergia effect is observed when Gleevec is administered with Docetaxel and/or Capecitabine in the treatment of xenograft in nude mice. These results indicate that the dosage of Docetaxel and Capecitabine can be reduced when Gleevec combines with them, and can provide significant data for breast cancer therapy.Finally, on molecular level, Use Western blot to detect the anti-apoptosis protein Galectin-3, find that Galectin-3 of the xenografts decreases heavily when Gleevec is administered with Docetaxel and/or Capecitabine in the treatment of xenograft in nude mice. These result prove that anti-apoptosis protein Galectin-3 plays important role on the tumor therapy.