In vitro and in vivo induction of antiangiogenic activity by plasminogen activators and captopril

Jaime R Merchan, Barden Chan, Sujata Kale, Lowell E. Schnipper, Vikas P. Sukhatme

Research output: Contribution to journalArticle

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Abstract

Background: Many antiangiogenic molecules are proteolytically cleaved from larger plasma proteins. For example, plasminogen activators cleave plasminogen into plasmin, and plasmin is converted into angiostatin in the presence of sulfhydryl donors. We thus investigated whether the antiangiogenic activity in plasma could be increased by treatment with recombinant tissue plasminogen activator (rt-PA) and the sulfhydryl donor captopril. Methods: Human plasma was treated with rt-PA (10 μg/mL) and/or captopril (1 μM). Angiogenesis was measured in vitro by human endothelial cell tube formation and endothelial cell proliferation and in vivo in mice with the Matrigel plug assay. Angiostatin was removed from treated plasma by affinity chromatography, immunoprecipitation, or ion-exchange chromatography, and the antiangiogenic activity of the depleted plasma was assessed by tube formation. Three cancer patients were treated with rt-PA and captopril, and their pretreatment and post-treatment plasmas were tested for antiangiogenic activity in vitro. Results: Angiogenesis in vitro was stimulated by untreated plasma and inhibited by plasma that had been treated with rt-PA and captopril but was not affected by treatment with rt-PA and/or captopril alone. In vivo angiogenesis in Matrigel plugs was substantially lower in mice treated with rt-PA and captopril than in untreated control mice. Antiangiogenic activity in treated plasma was largely retained after angiostatin was removed: treated plasma inhibited angiogenesis by 64.3% (95% confidence interval [CI] = 46.4% to 82.2%), relative to untreated plasma, and treated plasma depleted of angiostatin by affinity chromatography or immunoprecipitation inhibited angiogenesis by 65.1% (95% CI = 53.8% to 76.4%) or 63.7% (95% CI = 50.9% to 76.5%), respectively. Antiangiogenic activity of plasma from three cancer patients was higher after treatment with rt-PA and captopril than before such treatment. Conclusion: Treatment with rt-PA and captopril induced antiangiogenic activity in vitro and in vivo that appears to be independent of angiostatin.

Original languageEnglish
Pages (from-to)388-399
Number of pages12
JournalJournal of the National Cancer Institute
Volume95
Issue number5
StatePublished - Mar 5 2003
Externally publishedYes

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Plasminogen Activators
Captopril
Tissue Plasminogen Activator
Angiostatins
Fibrinolysin
Confidence Intervals
Affinity Chromatography
Immunoprecipitation
In Vitro Techniques
Therapeutics
Endothelial Cells
Plasminogen
Ion Exchange Chromatography
Blood Proteins
Neoplasms
Cell Proliferation
Tissue Donors

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

In vitro and in vivo induction of antiangiogenic activity by plasminogen activators and captopril. / Merchan, Jaime R; Chan, Barden; Kale, Sujata; Schnipper, Lowell E.; Sukhatme, Vikas P.

In: Journal of the National Cancer Institute, Vol. 95, No. 5, 05.03.2003, p. 388-399.

Research output: Contribution to journalArticle

Merchan, Jaime R ; Chan, Barden ; Kale, Sujata ; Schnipper, Lowell E. ; Sukhatme, Vikas P. / In vitro and in vivo induction of antiangiogenic activity by plasminogen activators and captopril. In: Journal of the National Cancer Institute. 2003 ; Vol. 95, No. 5. pp. 388-399.
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T1 - In vitro and in vivo induction of antiangiogenic activity by plasminogen activators and captopril

AU - Merchan, Jaime R

AU - Chan, Barden

AU - Kale, Sujata

AU - Schnipper, Lowell E.

AU - Sukhatme, Vikas P.

PY - 2003/3/5

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N2 - Background: Many antiangiogenic molecules are proteolytically cleaved from larger plasma proteins. For example, plasminogen activators cleave plasminogen into plasmin, and plasmin is converted into angiostatin in the presence of sulfhydryl donors. We thus investigated whether the antiangiogenic activity in plasma could be increased by treatment with recombinant tissue plasminogen activator (rt-PA) and the sulfhydryl donor captopril. Methods: Human plasma was treated with rt-PA (10 μg/mL) and/or captopril (1 μM). Angiogenesis was measured in vitro by human endothelial cell tube formation and endothelial cell proliferation and in vivo in mice with the Matrigel plug assay. Angiostatin was removed from treated plasma by affinity chromatography, immunoprecipitation, or ion-exchange chromatography, and the antiangiogenic activity of the depleted plasma was assessed by tube formation. Three cancer patients were treated with rt-PA and captopril, and their pretreatment and post-treatment plasmas were tested for antiangiogenic activity in vitro. Results: Angiogenesis in vitro was stimulated by untreated plasma and inhibited by plasma that had been treated with rt-PA and captopril but was not affected by treatment with rt-PA and/or captopril alone. In vivo angiogenesis in Matrigel plugs was substantially lower in mice treated with rt-PA and captopril than in untreated control mice. Antiangiogenic activity in treated plasma was largely retained after angiostatin was removed: treated plasma inhibited angiogenesis by 64.3% (95% confidence interval [CI] = 46.4% to 82.2%), relative to untreated plasma, and treated plasma depleted of angiostatin by affinity chromatography or immunoprecipitation inhibited angiogenesis by 65.1% (95% CI = 53.8% to 76.4%) or 63.7% (95% CI = 50.9% to 76.5%), respectively. Antiangiogenic activity of plasma from three cancer patients was higher after treatment with rt-PA and captopril than before such treatment. Conclusion: Treatment with rt-PA and captopril induced antiangiogenic activity in vitro and in vivo that appears to be independent of angiostatin.

AB - Background: Many antiangiogenic molecules are proteolytically cleaved from larger plasma proteins. For example, plasminogen activators cleave plasminogen into plasmin, and plasmin is converted into angiostatin in the presence of sulfhydryl donors. We thus investigated whether the antiangiogenic activity in plasma could be increased by treatment with recombinant tissue plasminogen activator (rt-PA) and the sulfhydryl donor captopril. Methods: Human plasma was treated with rt-PA (10 μg/mL) and/or captopril (1 μM). Angiogenesis was measured in vitro by human endothelial cell tube formation and endothelial cell proliferation and in vivo in mice with the Matrigel plug assay. Angiostatin was removed from treated plasma by affinity chromatography, immunoprecipitation, or ion-exchange chromatography, and the antiangiogenic activity of the depleted plasma was assessed by tube formation. Three cancer patients were treated with rt-PA and captopril, and their pretreatment and post-treatment plasmas were tested for antiangiogenic activity in vitro. Results: Angiogenesis in vitro was stimulated by untreated plasma and inhibited by plasma that had been treated with rt-PA and captopril but was not affected by treatment with rt-PA and/or captopril alone. In vivo angiogenesis in Matrigel plugs was substantially lower in mice treated with rt-PA and captopril than in untreated control mice. Antiangiogenic activity in treated plasma was largely retained after angiostatin was removed: treated plasma inhibited angiogenesis by 64.3% (95% confidence interval [CI] = 46.4% to 82.2%), relative to untreated plasma, and treated plasma depleted of angiostatin by affinity chromatography or immunoprecipitation inhibited angiogenesis by 65.1% (95% CI = 53.8% to 76.4%) or 63.7% (95% CI = 50.9% to 76.5%), respectively. Antiangiogenic activity of plasma from three cancer patients was higher after treatment with rt-PA and captopril than before such treatment. Conclusion: Treatment with rt-PA and captopril induced antiangiogenic activity in vitro and in vivo that appears to be independent of angiostatin.

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