DIFFERENTIAL-EFFECTS OF ANGIOSTATIC STEROIDS AND DEXAMETHASONE ON ANGIOGENESIS AND CYTOKINE LEVELS IN RAT SPONGE IMPLANTS

1 Subcutaneous implantation of sterile polyether sponges elicited a re producible neovascular response in rats, as determined by blood flow m easurement with a Xe-133 clearance technique and confirmed histologica lly. This model was used to monitor the levels of two cytokines during angiogenesis and to compare the activities of angiostatic steroids an d anti-inflammatory steroids. 2 Initial experiments followed the neova scular development over a 20-day period. Daily local injection of hydr ocortisone caused a dose-dependent (0.5, 5 and 50 mu g per sponge) inh ibition of the basal sponge-induced angiogenesis. However, daily syste mic treatment of hydrocortisone (2, 10 and 50 mg kg(-1), s.c.) was les s effective at inhibiting angiogenesis, and this inhibition was not su stained by day 20 after sponge implantation. 3 To investigate the invo lvement of cytokines during the course of angiogenesis, we measured th e endogenous levels of tumour necrosis factor-alpha (TNF-alpha) and in terleukin 6 (IL-6) in sponge implants. Levels of IL-6 and TNF-alpha pe aked at day 7 and day 11 after implantation, respectively. These cytok ine levels subsided through the completion of angiogenesis by day 20. 4 Subsequent experiments were carried out over a 14-day period. Among the three angiostatic steroids tested, U-24067 (6 alpha-fluoro-17,21-d ihydroxy-16 -methylpregna-4,9(11)-diene-3,20-dione-21-acetate) showed a dose-dependent inhibition (0.5, 5 and 50 mu g per sponge per day) of sponge-induced angiogenesis. Tetrahydro-S was also effective at 5 mu g doses, but medroxyprogesterone failed to affect the angiogenic respo nse. None of these steroids caused atrophies of the spleen and thymus. 5 Daily local injection of dexamethasone (0.5 mu g per sponge) inhibi ted the basal sponge-induced angiogenesis almost completely. Although higher doses of dexamethasone (5 and 50 mu g per sponge) did not produ ce further inhibition of angiogenesis, they caused severe spleen and t hymus weight losses, indicative of immunosuppression. 6 At the daily d ose of 5 mu g per sponge, dexamethasone inhibited angiogenesis and pro duced a marked reduction in the levels of TNF-alpha and IL-6 at day 14 . In contrast, hydrocortisone, U-24067 and tetrahydro-S did not influe nce the levels of TNF-alpha and IL-6. 7 We concluded that the anti-ang iogenic activity of angiostatic steroids and anti-inflammatory steroid s in the rat sponge model is independent of their ability to reduce th e production of TNF-alpha and IL-6. The differential effects of angios tatic and anti-inflammatory steroids suggest that U-24067 and its deri vatives may have therapeutic potential in the management of angiogenic diseases such as rheumatoid arthritis.