Heparin-steroid conjugates lacking glucocorticoid or mineralocorticoid activities inhibit the proliferation of vascular endothelial cells

Elaine J. Derbyshire, Yong Ching Yang, Shuzhen Li, Georgina A. Comin, Julian Belloir, Philip E. Thorpe

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

A new class of angiogenesis inhibitors consist of a non-anticoagulating derivative of heparin, which binds to vascular endothelial cells, coupled to a steroid (e.g., cortisol) which suppresses endothelial cell division. We linked heparin to a further 10 steroids in an effort to identify ones which would yield more effective or safer angiogenesis inhibitors. Steroids having a C3 ketone group were linked by reaction with a hydrazide derivative of heparin. Steroids having a C20 ketone group and lacking a C3 ketone could not be prepared by this method, necessitating the development of alternative methods. The most efficient was to convert the steroid into a derivative having a hydrazone group at C20 and then link the steroid hydrazone to heparin. Conjugates prepared from steroids having C3 ketones were at most 6-fold more inhibitory than the free steroids to endothelial cells in tissue culture. In contrast, steroids having a C20 ketone but lacking a C3 ketone (tetrahydrocortisone, tetrahydrocortisol and tetrahydro S) became highly inhibitory to endothelial cells only after conjugation to heparin. They inhibited [3H]thymidine incorporation by 50% at a steroid concentration of 18-30 μM and by 95% at 300 μM. Since tetrahydrocortisone, tetrahydrocortisol and tetrahydro S lack glucocorticoid and mineralocorticoid activity, they may prove safer alternatives to cortisol for prolonged administration, as is likely to be necessary with anti-angiogenic therapies.

Original languageEnglish (US)
Pages (from-to)86-96
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1310
Issue number1
DOIs
StatePublished - Jan 10 1996

Keywords

  • Angiogenesis inhibitor
  • Angiostatic steroid
  • Heparin-steroid conjugate
  • Vascular endothelial cell

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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