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Arginine deiminase: a potential inhibitor of angiogenesis and tumour growth.

Park IS, Kang SW, Shin YJ, Chae KY, Park MO, Kim MY, Wheatley DN, Min BH - Br. J. Cancer (2003)

Bottom Line: Since arginine is the precursor of NO, and the latter modulates angiogenesis, we explored whether ADI treatment significantly affected tube-like (capillary) formation of human umbilical vein endothelial cells.Inhibition of angiogenesis by ADI was reversed when a surplus of exogenous arginine was provided, indicating that its antiangiogenic effect is primarily due to arginine depletion, although other pathways of interference are not entirely excluded.Thus, it could be highly beneficial in cancer therapy because of its two-pronged attack as both an antiproliferative and an antiangiogenic agent.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, College of Medicine, Inha University, Inchon 400-103, Korea.

ABSTRACT
Hydrolysis of plasma arginine to citrulline by arginine deiminase (ADI) was recently shown to suppress lipopolysaccharide-induced nitric oxide (NO) synthesis. Since arginine is the precursor of NO, and the latter modulates angiogenesis, we explored whether ADI treatment significantly affected tube-like (capillary) formation of human umbilical vein endothelial cells. Inhibition occurred in a dose-dependent manner, both in the chorioallantoic membrane and the murine Matrigel plug assay. Inhibition of angiogenesis by ADI was reversed when a surplus of exogenous arginine was provided, indicating that its antiangiogenic effect is primarily due to arginine depletion, although other pathways of interference are not entirely excluded. Arginine deiminase is also shown to be as a potent inhibitor of tumour growth in vitro as in vivo, being effective at nanogram quantities per millilitre in CHO and HeLa cells. Thus, it could be highly beneficial in cancer therapy because of its two-pronged attack as both an antiproliferative and an antiangiogenic agent.

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Inhibition of angiogenesis by ADI in vivo mouse Matrigel assay. Matrigel (0.4 ml) containing 50 ng ml−1 of bFGF and 60 U ml−1 of heparin in combination with or without 0.46 U ml−1 ADI was subcutaneously injected near the abdominal midline of the mice. (A) Histological analysis of Matrigel implants (for experimental procedures, see Materials and methods). Matrigel without ADI (A and B) showed formation of blood vessels with various sizes (arrows) forming in the Matrigel. Inside the vessel, red blood cells were observed (red colour in the vessel). However, ADI treatment clearly inhibited blood vessel formation (C and D). *Indicates connective tissues surrounding Matrigel implants. (A and C: haematoxylin–eosin staining, B and D: Masson-Trichrome staining). Original magnification x100. (B) Haemoglobin content in the Matrigel was measured with Drabkin reagent kit 525 to evaluate blood within the vessels formed 5 days after injection, calibrated against a known amount of haemoglobin in parallel. ADI potently inhibited growth factor-induced angiogenesis by 97%. Each value represents the mean±s.e.of five ADI-treated animals and seven per control group.
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fig5: Inhibition of angiogenesis by ADI in vivo mouse Matrigel assay. Matrigel (0.4 ml) containing 50 ng ml−1 of bFGF and 60 U ml−1 of heparin in combination with or without 0.46 U ml−1 ADI was subcutaneously injected near the abdominal midline of the mice. (A) Histological analysis of Matrigel implants (for experimental procedures, see Materials and methods). Matrigel without ADI (A and B) showed formation of blood vessels with various sizes (arrows) forming in the Matrigel. Inside the vessel, red blood cells were observed (red colour in the vessel). However, ADI treatment clearly inhibited blood vessel formation (C and D). *Indicates connective tissues surrounding Matrigel implants. (A and C: haematoxylin–eosin staining, B and D: Masson-Trichrome staining). Original magnification x100. (B) Haemoglobin content in the Matrigel was measured with Drabkin reagent kit 525 to evaluate blood within the vessels formed 5 days after injection, calibrated against a known amount of haemoglobin in parallel. ADI potently inhibited growth factor-induced angiogenesis by 97%. Each value represents the mean±s.e.of five ADI-treated animals and seven per control group.

Mentions: Antiangiogenic effect of ADI on the chick CAM. Arginine deiminase (0.046 U) was loaded in Thermanox coverslips, air-dried and applied to the CAM surface of fertilised eggs (Materials and methods). An avascular zone of the CAM beneath the disk (surrounded by arrows) was produced 2 days after treatment of ADI, but not in control disk. At least 20 eggs were used for each assay.


Arginine deiminase: a potential inhibitor of angiogenesis and tumour growth.

Park IS, Kang SW, Shin YJ, Chae KY, Park MO, Kim MY, Wheatley DN, Min BH - Br. J. Cancer (2003)

Inhibition of angiogenesis by ADI in vivo mouse Matrigel assay. Matrigel (0.4 ml) containing 50 ng ml−1 of bFGF and 60 U ml−1 of heparin in combination with or without 0.46 U ml−1 ADI was subcutaneously injected near the abdominal midline of the mice. (A) Histological analysis of Matrigel implants (for experimental procedures, see Materials and methods). Matrigel without ADI (A and B) showed formation of blood vessels with various sizes (arrows) forming in the Matrigel. Inside the vessel, red blood cells were observed (red colour in the vessel). However, ADI treatment clearly inhibited blood vessel formation (C and D). *Indicates connective tissues surrounding Matrigel implants. (A and C: haematoxylin–eosin staining, B and D: Masson-Trichrome staining). Original magnification x100. (B) Haemoglobin content in the Matrigel was measured with Drabkin reagent kit 525 to evaluate blood within the vessels formed 5 days after injection, calibrated against a known amount of haemoglobin in parallel. ADI potently inhibited growth factor-induced angiogenesis by 97%. Each value represents the mean±s.e.of five ADI-treated animals and seven per control group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2394481&req=5

fig5: Inhibition of angiogenesis by ADI in vivo mouse Matrigel assay. Matrigel (0.4 ml) containing 50 ng ml−1 of bFGF and 60 U ml−1 of heparin in combination with or without 0.46 U ml−1 ADI was subcutaneously injected near the abdominal midline of the mice. (A) Histological analysis of Matrigel implants (for experimental procedures, see Materials and methods). Matrigel without ADI (A and B) showed formation of blood vessels with various sizes (arrows) forming in the Matrigel. Inside the vessel, red blood cells were observed (red colour in the vessel). However, ADI treatment clearly inhibited blood vessel formation (C and D). *Indicates connective tissues surrounding Matrigel implants. (A and C: haematoxylin–eosin staining, B and D: Masson-Trichrome staining). Original magnification x100. (B) Haemoglobin content in the Matrigel was measured with Drabkin reagent kit 525 to evaluate blood within the vessels formed 5 days after injection, calibrated against a known amount of haemoglobin in parallel. ADI potently inhibited growth factor-induced angiogenesis by 97%. Each value represents the mean±s.e.of five ADI-treated animals and seven per control group.
Mentions: Antiangiogenic effect of ADI on the chick CAM. Arginine deiminase (0.046 U) was loaded in Thermanox coverslips, air-dried and applied to the CAM surface of fertilised eggs (Materials and methods). An avascular zone of the CAM beneath the disk (surrounded by arrows) was produced 2 days after treatment of ADI, but not in control disk. At least 20 eggs were used for each assay.

Bottom Line: Since arginine is the precursor of NO, and the latter modulates angiogenesis, we explored whether ADI treatment significantly affected tube-like (capillary) formation of human umbilical vein endothelial cells.Inhibition of angiogenesis by ADI was reversed when a surplus of exogenous arginine was provided, indicating that its antiangiogenic effect is primarily due to arginine depletion, although other pathways of interference are not entirely excluded.Thus, it could be highly beneficial in cancer therapy because of its two-pronged attack as both an antiproliferative and an antiangiogenic agent.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, College of Medicine, Inha University, Inchon 400-103, Korea.

ABSTRACT
Hydrolysis of plasma arginine to citrulline by arginine deiminase (ADI) was recently shown to suppress lipopolysaccharide-induced nitric oxide (NO) synthesis. Since arginine is the precursor of NO, and the latter modulates angiogenesis, we explored whether ADI treatment significantly affected tube-like (capillary) formation of human umbilical vein endothelial cells. Inhibition occurred in a dose-dependent manner, both in the chorioallantoic membrane and the murine Matrigel plug assay. Inhibition of angiogenesis by ADI was reversed when a surplus of exogenous arginine was provided, indicating that its antiangiogenic effect is primarily due to arginine depletion, although other pathways of interference are not entirely excluded. Arginine deiminase is also shown to be as a potent inhibitor of tumour growth in vitro as in vivo, being effective at nanogram quantities per millilitre in CHO and HeLa cells. Thus, it could be highly beneficial in cancer therapy because of its two-pronged attack as both an antiproliferative and an antiangiogenic agent.

Show MeSH
Related in: MedlinePlus