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Prevention of breast tumor angiogenesis and metastasis by cytostatic molecules in relevant mouse models

Human breast cancer cells are capable of secreting a variety of growth factors which have autocrine and paracrine functions such as fibroblast growth factor 2, platelet-derived growth factor and transforming growth factor beta. Modulations of the synthesis of these paracrine growth factors by non-toxic therapeutic agents has not been fully investigated. Sodium phenylacetate (NaPa), a physiological metabolite of phenylalanine, has an antiproliferative effect against several human cancer cell lines. We have previously shown that NaPa exhibits powerful anti-tumor activity against breast cancer MCF7-ras xenografts in nude mice. Moreover, in this model, we have observed that NaPa can prevent tumor recurrence after tamoxifen treatment. Although glutamine depletion was proposed as a mechanism underlying NaPa growth inhibition, protein prenylation, regulating cellular function of p21/ras, may also be inhibited by NaPa. We showed that NaPa modifies the synthesis of growth factors secreted by MCF-7 and MCF-7ras tumor cells leading to cell proliferation inhibitions. This could explain in vitro and in vivo NaPa inhibition of MCF-7ras cells, which secreted higher levels of these growth factors. It was hypothesized that inhibiting tumor angiogenesis will halt tumor growth and decrease metastatic potential. Anti-angiogenic agents targeting the tumor vasculature are expected to block the neovascularization and thereby prevent metastasis. We previously showed that carbomethyl benzylamide dextran (CMDB7) prevents tumor growth and tumor angiogenesis by binding to angiogenic growth factors, thereby preventing them from reaching their receptors on tumor or stromal cells. We showed that CMDB7 inhibited neovessel formation within the fibroblast growth factor 2-enriched matrigel in mice, and its anticancer effect was then tested in a metastatic breast cancer model. Human MDA-MB435 cells were injected into the mammary fat pad of nude mice, and breast tumors developed within 1 week; all the mice had lung metastases at 12 weeks. CMDB7 treatment for 10 weeks reduced the incidence of the lung metastases to 12%. Histological analysis showed markedly less tumor neovascularization in the CMDB7-treated mice. We studied the uptake of CMDB7 labeled with 99mTc in MCF-7ras-tumor-bearing mice. The blood clearance of 99mTcCMDB7is rapid and the liver, speen and kidney uptakes are weak. Our results confirm the non-toxicity of CMDB7 and the usefulness of CMDB7 in cancer therapy by targeting breast tumors. Associations of CMDB and NaPa show a synergestic antiproliferative effect on the MCF-7ras cell line. We have synthesized new molecule esters of CMDB with phenyl-acetic acid. These new molecules, called NaPaC, are 100-fold more efficient on the in vitro growth of these cells. NaPaC inhibits the MCF-7ras tumor growth in nude mice 10-fold more than the parental molecules. Moreover, NaPaC have a strong anti-angiogenic effect on the MCF-7ras tumors. This anti-angiogenic effect is associated with a strong necro-apoptotic effect both in vitro and in vivo. Taken together, these results show that new cytostatic atoxic molecules, in associations, can be used as anti-tumoral, anti-angiogenic and anti-metastatic therapies in breast cancer.


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Crépin, M., DiBenedetto, M., Bagheri-Yarmand, R. et al. Prevention of breast tumor angiogenesis and metastasis by cytostatic molecules in relevant mouse models. Breast Cancer Res 5 (Suppl 1), 52 (2003).

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