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The Inhibition of colon-26 Adenocarcinoma Development and Angiogenesis by Topical Diclofenac in 2.5% Hyaluronan¹

Departments of Experimental Pathology [M. P. S., J. R. B., C. N. F., J. L. P., P. R. C-N., D. W., D. A. W.], and Environmental and Preventive Medicine, [K. W. S.] Saint Bartholomew's Hospital and the Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, United Kingdom and Hyal Pharmaceutical Corporation, Mississauga, Toronto, Ontario, Canada [S. A.]

Topical diclofenac in 2.5% hyaluronan inhibits basal cell carcinoma, actinic keratosis, and murine colon-26 growth in vivo. colon-26 tumor growth was preceded by angiogenesis and reduced apoptotic and mitotic indices. Diclofenac reduced proliferation and viability in vitro, and stimulated apoptosis. Hyaluronan inhibited proliferation and viability at 1 mg/ml but was inactive below this level. Topical application of diclofenac inhibited tumor prostaglandin synthesis and retarded angiogenesis and tumor growth (ratio of treatment:control, 0.174). The mitotic index remained unaltered in vivo, whereas the apoptotic index and necrosis were increased. Topical vehicle exhibited slight antitumor and antiangiogenesis activity. The substantial quantities of diclofenac delivered locally in hyaluronan may exhibit antitumor activity in similar fashion to those seen in vitro and explain its clinical efficacy.

¹ This work was supported by Hyal Research Foundation Charity (Toronto, Ontario, Canada). D. W. is funded by a grant from the ONO Pharmaceutical Company (Osaka, Japan) and J. R. B. through a Saint Bartholomew's and Royal London Medical School scholarship.

² To whom requests for reprints should be addressed. Phone: 44 171 982 6030; Fax: 44 171 982 6095; E-mail: m.p.seed@mds.qmw.ac.uk.

Received 1/30/97. Accepted 3/20/97.

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