title: Heparin-steroid conjugates lacking glucocorticoid or mineralocorticoid activities inhibit the proliferation of vascular endothelial cells.
abstract: A new class of angiogenesis inhibitors consist of a non-anticoagulating derivative of heparin, which binds to vascular endothelial cells, coupled to a steriod (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 microM and by 95% at 300 microM. 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.
authors.affiliation: Department of Pharmacology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas 75235-8593, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Derbyshire
authors.forename: Y C
authors.initials: YC
authors.lastname: Yang
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: G A
authors.initials: GA
authors.lastname: Comin
authors.forename: J
authors.initials: J
authors.lastname: Belloir
authors.forename: P E
authors.initials: PE
authors.lastname: Thorpe
mesh_terms: D000305:Adrenal Cortex Hormones; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D003350:Cortodoxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects*; D006493:Heparin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D013761:Tetrahydrocortisone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000305:Adrenal Cortex Hormones; D000925:Anticoagulants; C081894:heparin adipic hydrazide-cortisol; D013761:Tetrahydrocortisone; C009412:tetrahydro-11-deoxycortisol; D006493:Heparin; D003350:Cortodoxone; D006854:Hydrocortisone