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Anginex
A potent angiogenesis inhibitor and anti-tumor peptide

Antiangiogenic therapies in endometriosis
Oral contraceptives, androgenic agents, progestins and gonadotropin-releasing hormone analogues have all been successfully used in the treatment of endometriosis. However, none of these drugs can eradicate the disease. It is widely accepted that the growth of newly formed blood vessels is essential for the establishment and growth of endometriotic lesions; therefore, inhibition of angiogenesis may offer a new option for treatment of this disorder. In this paper, we reviewed anti-vascular endothelial growth factor agents and other angiostatic drugs (i.e., TNP470, endostatin, anginex, rapamycin) that have been studied in laboratory and animal models of endometriosis. Although preliminary results are interesting, further investigations are required before clinical trials can be planned in humans.
Ferrero S, Ragni N, Remorgida V. Br J Pharmacol. 2006 Aug 7; [Epub ahead of print]
 
Cloning an artificial gene encoding angiostatic anginex: From designed peptide to functional recombinant protein
Anginex, a designed peptide 33-mer, is a potent angiogenesis inhibitor and anti-tumor agent in vivo. Anginex functions by inhibiting endothelial cell (EC) proliferation and migration leading to detachment and apoptosis of activated EC's. To better understand tumor endothelium targeting properties of anginex and enable its use in gene therapy, we constructed an artificial gene encoding the biologically exogenous peptide and produced the protein recombinantly in Pichia pastoris. Mass spectrometry shows recombinant anginex to be a dimer and circular dichroism shows the recombinant protein folds with beta-strand structure like the synthetic peptide. Moreover, like parent anginex, the recombinant protein is active at inhibiting EC growth and migration, as well as inhibiting angiogenesis in vivo in the chorioallantoic membrane of the chick embryo. This study demonstrated that it is possible to produce a functionally active protein version of a rationally designed peptide, using an artificial gene and the recombinant protein approach.
Brandwijk RJ, et al. Biochem Biophys Res Commun. 2005 Aug 12;333(4):1261-8
 
Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors
Tumor escape from immunity, as well as the failure of several anti-cancer vaccination and cellular immunotherapy approaches, is suggested to be due to the angiogenesis-mediated suppression of endothelial cell (EC) adhesion molecules involved in leukocyte-vessel wall interactions. We hypothesized that inhibition of angiogenesis would overcome this escape from immunity. We investigated this in vivo by means of intravital microscopy and ex vivo by immunohistochemistry in two mouse tumor models. Angiogenesis inhibitors anginex, endostatin, and angiostatin, and the chemotherapeutic agent paclitaxel were found to significantly stimulate leukocyte-vessel wall interactions by circumvention of EC anergy in vivo, i.e., by the up-regulation of endothelial adhesion molecules in tumor vessels. This was confirmed by in vitro studies of cultured EC at the protein and mRNA levels. The new angiostatic designer peptide anginex was most potent at overcoming EC anergy; the enhanced leukocyte-vessel interactions led to an increase in the numbers of tumor infiltrating leukocytes. While anginex inhibited tumor growth and microvessel density significantly, the amount of infiltrated leukocytes (CD45), as well as the number of CD8+ cytotoxic T lymphocytes, was enhanced markedly. The current results suggest that immunotherapy strategies can be improved by combination with anti-angiogenesis.
Dirkx AE, et al. FASEB J. 2006 Apr;20(6):621-30.
 
Anginex synergizes with radiation therapy to inhibit tumor growth by radiosensitizing endothelial cells
We have demonstrated that the designed peptide anginex displays potent antiangiogenic activity. The aim of our study was to investigate the effect of anginex on established tumor vasculature as an adjuvant to radiation therapy of solid tumors. In the MA148 human ovarian carcinoma athymic mouse model, anginex (10 mg/kg) in combination with a suboptimal dose of radiation (5 Gy once weekly for 4 weeks) caused tumors to regress to an impalpable state. In the more aggressive SCK murine mammary carcinoma model, combination of anginex and a single radiation dose of 25 Gy synergistically increased the delay in tumor growth compared to the tumor growth delay caused by either treatment alone. Immunohistochemical analysis also demonstrated significantly enhanced effects of combined treatment on tumor microvessel density and tumor or endothelial cell proliferation and viability. In assessing physiologic effects of anginex, we observed a reduction in tumor perfusion and tumor oxygenation in SCK tumors after 5-7 daily treatments with anginex with no reduction in blood pressure. To test anginex as a radiosensitizer, additional studies using SCK tumors were performed. Three daily i.p. injections of anginex were able to enhance the effect of 2 radiation doses of 10 Gy, resulting in 50% complete responses, whereas the known antiangiogenic agent angiostatin did not enhance the radiation response of SCK tumors. Mechanistically, it appears that anginex functions as an endothelial cell-specific radiosensitizer because anginex showed no effect on in vitro radiosensitivity of SCK or MA148 tumor cells, whereas anginex significantly enhanced the in vitro radiosensitivity of 2 endothelial cell types. This work supports the idea that the combination of the antiangiogenic agent anginex and radiation may lead to improved clinical outcome in treating cancer patients.
Dings RP, et al. Int J Cancer. 2005 Jun 10;115(2):312-9.
anginex

Figure 1 amino acid sequence and structure of anginex and CP analogues

The amino acid sequence of anginex is shown conformed as an anti-parallel b-sheet on the left-hand side of the Figure. The N-terminus is at the right bottom as labelled. CP analogues have only the first 27 residues and therefore are devoid of C-terminal residues Arg-Glu-Lys-Ser-Lys-Asp. The new C-terminal residue has its backbone carboxylate group amidated. The amino acid sequence for the control linear peptide 27mer (no cysteine residues) CP-1 is given on the right-hand side of the Figure. CP-2 to CP-6 [i.e. CP-2 (Cys6–Cys25), CP-3 (Cys8–Cys23), CP-4 (Cys10–Cys21), CP-5 (Cys12–Cys19), CP-6 (Cys13–Cys18)] have the same sequence as CP-1, with disulphide bridges positioned between b-strand 1 and b-strand 2 as indicated. CP-7 [Cys13–Cys19] and CP-8 [Cys6–Cys26] are control peptides that alter the alignment of b-strands 1 and 2. Single-letter amino-acid notation is used. Ruud P. M. DINGS et al. Biochem. J. (2003) 373 (281–288)

 

Anginex causes significant tumor growth inhibition. The mean tumor growth of human epithelial ovarian carcinoma cell line MA148 is shown in athymic mice treated with a dose range of anginex administered by minipumps implanted in the left flank of animals (, 5 mg/kg/day, n = 14; , 10 mg/kg/day, n = 16; , 20 mg/kg/day, n = 8). Controls () contained PBS with BSA (n = 13) and PBS with 5 mg/kg/day ▀pep28 (, n = 8) and 10 mg/kg/day ▀pep28 (, n = 4), which did not differ from each other. The treatment period was initiated on the day of tumor inoculation (day 0) and lasted for 28 days as indicated by the arrow. Data from three independent studies are shown and represent the mean tumor volume in mm3 (▒SE).
Ruud P. M. Dings et al. Cancer Research 63, 382-385, January 15, 2003

 

The mean tumor growth curves in a human ovarian carcinoma model treated with anginex, carboplatin, angiostatin, or a combination treatment. A, groups shown are defined as follows: , vehicle containing BSA (n = 11); , anginex (10 mg/kg/day, n = 11); x, carboplatin (n = 12); , a combination group (n = 12). Carboplatin was given in a suboptimal dosage (32.5 mg/kg) once every 3 days i.p. B, groups shown are defined as follows: , vehicle containing BSA (n = 11); , angiostatin (20 mg/kg/day, n = 11); , anginex (10 mg/kg/day, n = 11); , a combination group (n = 12). In both experiments, treatment was given for 28 days starting on day 7 postinoculation. The vehicle and anginex were given by osmotic minipump implanted s.c. in the flank, and angiostatin was given daily by s.c. injections in the neck (9) . The data are shown as means of tumor burden. Error bars, SEs. The tumor volumes were determined three times a week. The insets in both A and B show body weights of mice during treatment as an indirect measurement of toxicity.
Ruud P. M. Dings et al. Cancer Research 63, 382-385, January 15, 2003

 

 

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