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• W1443108546 abstract "Proc Amer Assoc Cancer Res, Volume 45, 20044102 Alphastatin is a peptide derived from fibrinogen E fragment, a component of the mammalian clotting cascade. It consists of 24 amino acid residues, with the N- and C-termini modified by acetyl and carboxamide groups respectively. Alphastatin is active in assays of in vitro angiogenesis, and can disrupt endothelial cell migration, proliferation and differentiation. Here, we describe the in vivo effects of Alphastatin when given at increasing doses, and by different routes of administration, to mice bearing the 4T1 syngeneic breast tumor. Groups of female Balb/c mice were administered Alphastatin (in PBS) by one of three routes, intraperitoneally (ip), orally (po) or intravenously (iv), and at three doses, 0.0025, 0.025 or 0.25 mg/kg; control mice received PBS alone. Oral and ip dosing was performed daily, with iv dosing every two days. Tumor volume was determined regularly and expressed as the relative tumor volume (RTV %); at necropsy, the tumor was removed for blinded histological examination. Alphastatin was non-toxic at all doses and routes used. When administered ip or po, tumor RTV % was not affected. However, when administered iv, a dose of 0.25mg/kg caused a significant (p<0.05) decrease in the RTV % of the treated group compared to controls: at day 7, the RTV % of the controls was 310±41.4 (mean±sem, n = 5), while that of the treated group was 195.6±29.9 (n = 6); at day 11, the corresponding figures were: 402.9±34.6 and 243.9±41.1 (40% inhibition). This dose also caused a non-significant increase in tumor necrosis and thrombosis, compared to controls. To test for any effect of a higher iv dose, tumor-bearing mice received iv Alphastatin at 0.25 or 2.5 mg/kg, or PBS, every two days. Initially (days 0-7), the mean RTV % of the two groups did not differ significantly; from day 7 onwards, the RTV % of the high dose group increased more rapidly; by day 11, the RTV % of the two groups were 228.2±52.8 (n = 6) and 314.7±26.2 (n = 6) respectively. To test iv Alphastatin dosing schedule, tumor-bearing mice were dosed every day for 5 consecutive days, followed by no further treatment, with PBS, or Alphastatin at 0.025, 0.25 or 2.5 mg/kg. Initially (days 0-7), the latter two dose levels caused a non-significant decrease in RTV % compared to controls; once treatment ceased, the tumors in both groups returned to control tumor size. To determine Alphastatin efficacy towards a human tumor xenograft, nude mice bearing the HT29 human colon tumor xenograft received iv Alphastatin at 0.25 or 2.5 mg/kg, or PBS, every two days; after ten days, the control RTV % was 326.6±53.9 (n = 7), while that of the treated groups was 251.1±13.6 (n = 6) and 235.6±15.2 (n = 7) (23% and 28% inhibition respectively). Alphastatin therefore demonstrates in vivo efficacy, with a dose of 0.25mg/kg and an iv route of administration being the optimum for antitumor activity. The efficacy in orthotopic and metastatic tumor models, and in combination with existing anti cancer drugs, is currently being studied." @default.
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• W1443108546 date "2004-04-01" @default.
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• W1443108546 title "The in vivo efficacy of the potential antiangiogenic peptide Alphastatin" @default.
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