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An Antiangiogenic Urokinase-derived Peptide Combined with Tamoxifen Decreases Tumor Growth and Metastasis in a Syngeneic Model of Breast Cancer¹

Department of Medicine, McGill University Health Centre, Montreal, Quebec, H3A 1A1 Canada [Y. J. G., J. J. L., S. A.R.] and Ångstrom Pharmaceuticals Inc., San Diego, California 92121 [A. P. M.]

Expression of urokinase (uPA) and its receptor (uPAR) is associated with increased tumor-cellinvasion and metastasis in several malignancies including breast cancer.An 8-mer peptide derived from the nonreceptor-binding domain of urokinase (Å6) has been shown to have antiangiogenic and proapoptotic effects to block the progression of breast cancer in vivo. In the present study, we evaluated the effects of Å6 and the antiestrogen tamoxifen (TAM) alone and in combination on estrogen-receptor-positive Mat B-III rat breast cancer cells in vitro and in vivo. Treatment of Mat B-III cells with Å6 and TAM resulted in a dose-dependent decrease in tumor-cell invasion through Matrigel; these effects were more marked when Å6 and TAM were tested in combination. In addition, treatment of Mat B-III cells with either Å6 or TAM resulted in a significant reduction of vascular endothelial growth factor receptor (flk-1) expression and in transforming growth factor ß activity, effects that were significantly higher after combined treatment with Å6 and TAM. For in vivo studies, female Fischer rats were inoculated with Mat B-III cells (1 x 10⁶) into the mammary fat pad. These orthotopic tumors were staged to 30–40 mm³ in volume and then treatment was initiated with Å6 (75 mg/kg/day) and TAM (3 mg/kg/day) alone or in combination. Both Å6 and TAM caused a significant reduction in tumor volume; however, these antitumor effects were significantly greater in animals receiving both Å6 and TAM, which demonstrated a 75% reduction in tumor growth as compared with control animals. The number of macroscopic tumor foci was significantly reduced in Å6-treated animals, whereas TAM failed to exhibit any antimetastatic effects. Histological analysis of primary tumors from different groups showed a decrease in new blood-vessel density and increased tumor-cell death in Å6- and TAM-treated animals, and these effects were greater in experimental animals receiving Å6 and TAM in combination. Collectively, these studies demonstrate that the addition of novel antiangiogenic/antimetastatic agents like Å6 to hormone therapy can enhance the antitumor effects of hormone therapy through increased inhibition of angiogenesis and induction of tumor-cell death.

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