| Autor: |
P E, Thorpe, E J, Derbyshire, S P, Andrade, N, Press, P P, Knowles, S, King, G J, Watson, Y C, Yang, M, Rao-Betté |
| Rok vydání: |
1993 |
| Předmět: |
|
| Zdroj: |
Cancer research. 53(13) |
| ISSN: |
0008-5472 |
| Popis: |
Inhibitors of angiogenesis hold potential in the treatment of cancer and other diseases where the disease is caused or maintained by the inappropriate growth of blood vessels. In the present study, a novel inhibitor of angiogenesis was synthesized by covalently linking a nonanticoagulating derivative of heparin, heparin adipic hydrazide (HAH), by an acid-labile bond to the antiangiogenic steroid, cortisol. The rationale was that the heparin derivative, which binds to sulfated polyanion receptors on endothelial cells, should concentrate the steroid on the surface of vascular endothelial cells. Endocytosis of the conjugate and decomposition of the acid-labile linkage inside lysosomes and other acidic intracellular compartments should then lead to release of the cortisol and expression of its antiproliferative activity. Analysis of the stability of HAH-cortisol showed that it was stable at pH 7.4 and broke down rapidly (t1/2 15 min) at pH 4.8 at 37 degrees C. Treatment of murine pulmonary capillary endothelial cells with HAH-cortisol at 10(-5) M (with respect to cortisol) suppressed their DNA synthesis by 50% and inhibited their migration into wounded areas of confluent monolayers. HAH-cortisol at 10(-4) M (with respect to cortisol) did not suppress the DNA synthesis of Lewis lung carcinoma cells. Daily i.p. injections of HAH-cortisol into mice bearing s.c. sponge implants retarded vascularization of the sponge, and injections directly into the sponge abolished vascularization for as long as the injections were continued. Daily i.v. injections of HAH-cortisol at doses causing no apparent toxicity retarded the growth of solid s.c. Lewis lung carcinomas in mice by up to 65%. In all of these assays, equivalent treatments with a mixture of the HAH plus cortisol was significantly less effective. The antiproliferative effect of HAH-cortisol on endothelial cells appeared independent of the glucocorticoid activity of the steroid since HAH conjugated to 5 beta-pregnane-3 alpha,17 alpha,21-triol-20-one, a steroid lacking glucocorticoid or mineralocorticoid activity, was even more effective at inhibiting DNA synthesis by murine pulmonary capillary endothelial cells than was HAH-cortisol. In conclusion, HAH-cortisol represents the prototype of a new class of angiogenesis inhibitors for the treatment of cancer and other angiogenic diseases. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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