TY - JOUR
T1 - Anti‐tumor and anti‐angiogenic effects in mice of heparin conjugated to angiostatic steroids
AU - Derbyshire, E. J.
AU - Comin, G. A.
AU - Yang, Y. C.
AU - Overholser, J.
AU - Watkins, L.
AU - Thorpe, P. E.
PY - 1995/11/27
Y1 - 1995/11/27
N2 - 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. © 1995 Wiley‐Liss, Inc.
AB - 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. © 1995 Wiley‐Liss, Inc.
UR - http://www.scopus.com/inward/record.url?scp=0028824321&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028824321&partnerID=8YFLogxK
U2 - 10.1002/ijc.2910630515
DO - 10.1002/ijc.2910630515
M3 - Article
C2 - 7591287
AN - SCOPUS:0028824321
SN - 0020-7136
VL - 63
SP - 694
EP - 701
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 5
ER -