© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 5, 388-399,
March 5, 2003
© 2003 Oxford University Press
ARTICLE |
In Vitro and In Vivo Induction of Antiangiogenic Activity by Plasminogen Activators and Captopril
Affiliations of authors: J. R. Merchan, Division of Hematology-Oncology, Department of Medicine and the Center for Study of the Tumor Microenvironment, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, and The Clinical Investigator Training Program, Beth Israel Deaconess Medical Center–Harvard/Massachusetts Institute of Technology Health Sciences and Technology, in collaboration with Pfizer Inc.; B. Chan, S. Kale, Division of Nephrology, Department of Medicine and the Center for Study of the Tumor Microenvironment, Beth Israel Deaconess Medical Center and Harvard Medical School; L. E. Schnipper, Division of Hematology-Oncology, Department of Medicine and the Center for Study of the Tumor Microenvironment, Beth Israel Deaconess Medical Center and Harvard Medical School; V. P. Sukhatme, Divisions of Hematology-Oncology and Nephrology, Department of Medicine and the Center for Study of the Tumor Microenvironment, Beth Israel Deaconess Medical Center and Harvard Medical School.
Correspondence to: Vikas P. Sukhatme, M.D., Ph.D., Beth Israel Deaconess Medical Center, 330 Brookline Ave., Dana 517, Boston, MA 02215 (e-mail: vsukhatm{at}caregroup.harvard.edu).
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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