Anti-tumor and anti-angiogenic effects in mice of heparin conjugated to angiostatic steroids.
Heparin-steroid conjugates have been prepared by linking a non-anti-coagulating derivative of heparin, which binds to endothelial cells, to an angiostatic steroid, which suppresses endothelial cell division. One such conjugate, heparin adipic hydrazide (HAH) linked to cortisol, has previously been shown to inhibit both angiogenesis and the growth of solid tumors in mice. In the present study, heparin hydrazide (HH) was linked to tetrahydro S, tetrahydrocortisone and tetrahydrocortisol, which are devoid of glucocorticoid and mineralocorticoid activity and hence were predicted to have low toxicity to animals. The tetrahydro steroid conjugates were compared with the cortisol conjugate for therapeutic effectiveness against solid Lewis lung carcinoma growing in mice. HAH-cortisol reduced tumor growth by up to 75% whereas a simple mixture of HAH and cortisol was not significantly inhibitory. In contrast to HAH-cortisol, the 3 tetrahydro steroid conjugates did not significantly inhibit tumor growth. The differences in anti-tumor properties of the conjugates correlated with their ability to inhibit angiogenesis in a Matrigel implant model in mice. The tetrahydro steroid conjugates did not significantly inhibit angiogenesis whereas HAH-cortisol inhibited angiogenesis by greater than 90%. Therefore, HAH-cortisol is the most effective heparin-steroid conjugate so far developed.
Derbyshire
E J
EJ
Department of Pharmacology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas 75235-8593, USA.
Comin
G A
GA
Yang
Y C
YC
Overholser
J
J
Watkins
L
L
Thorpe
P E
PE
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D003094:Collagen; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006493:Heparin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007797:Laminin; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011509:Proteoglycans; D014407:Tumor Cells, Cultured
D000925:Anticoagulants; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C081894:heparin adipic hydrazide-cortisol; C059485:matrigel; D006493:Heparin; D003094:Collagen; D006854:Hydrocortisone