THE MODULATION OF GRANULOMATOUS TISSUE AND TUMOR ANGIOGENESIS BY DICLOFENAC IN COMBINATION WITH HYALURONAN (HYAL EX-0001)

In a novel application, hyaluronan has been utilized as a deiivery sys tem for topical and i.v. therapeutics. Clinical trials and case report s show that topical diclofenac delivered in hyaluronan (HYAL CT-1101) is effective against basal-cell carcinoma and actinic keratosis. The e ffect of this drug formulation on tumour growth and angiogenesis, as w ell as granulomatous tissue angiogenesis, has been investigated experi mentally. The evidence that hyaluronan has a permissive effect on the inhibition of granulomatous tissue angiogenesis by diclofenac (as asse ssed by the carminel/gelatin vascular casting method) when injected in to the lesion or applied topically is reviewed. Topical diclofenac in hyaluronan also induces a regression of the existing neo-vasculature o f granulomatous tissue when applied therapeutically, The diclofenac fo rmulated in hyaluronan was also found to be profoundly effective again st the development of subcutaneous Colon-26 tumours in syngeneic balb/ c mice (T/C ratio after 12 days topical application of 0.174, p < 0.00 01). Analysis of the tumour vasculature showed that vascular developme nt was retarded by 12 days. This was shown by the reduction in the tum our density of carmine in the vascular casts, as well as reduced blood -vessel density visualized by rat anti-mouse CD31 immunohistology. Hya luronan alone had a significant effect on tumour development with a 53 % inhibition of tumour growth and only a transient reduction in vascul arity The effects noted when diclofenac is formulated in hyaluronan, a nd applied topically, could be related to trans-dermal delivery and de position properties of hyaluronan, and to the binding properties of hy aluronan to areas of pathology with high expression of hyaluronan rece ptors such as RHAMM, ICAM-1, and CD44.