INHIBITORY EFFECTS OF FUMAGILLIN AND ITS ANALOG TNP-470 ON THE FUNCTION, MORPHOLOGY AND ANGIOGENESIS OF AN ESTROGEN-INDUCED PROLACTINOMA INFISCHER-344 RATS

The process of angiogenesis occurs in many physiological states, but i t is also essential for the growth of solid tumours and metastasis for mation. An abnormal arterial vascularization has been shown in prolact in-secreting pituitary adenomas induced by prolonged treatment with oe strogens in Fischer 344 (F344) rats. It is thought that antiangiogenic agents might be useful in therapy for these tumours. Fumagillin and i ts analogue TNP-470 are known to inhibit endothelial cell proliferatio n selectively, but their effect on lactotroph cell secretory function and prolactinoma formation has not yet been described. The aim of the present study was to examine the effects of fumagillin and TNP-470 on prolactin secretion, and morphological and vascular changes within the anterior pituitary in long-term oestrogen-treated male F344 rats in v ivo and in vitro. As expected, 7 weeks after s.c. implantation of Sila stic tubes containing 10 mg diethylstilboestrol (DES), a very high ris e in serum prolactin levels was found. Both angiogenesis inhibitors in jected s.c. at doses of 10 mg/kg body weight for 24 days attenuated th e stimulatory effect of DES on prolactin production and release. They also diminished prolactin cell density and inhibited cell proliferatio n expressed as the number of anterior pituitary cells labelled with br omodeoxyuridine (BrdU), but the effect of TNP-470 was minor compared w ith fumagillin. Both angioinhibitors suppressed neovascularization wit hin the anterior pituitary with similar potency but, on the other hand , they did not affect DES-induced increases in prolactin secretion fro m cultured rat pituitary cells and cell proliferation in vitro. In con clusion, our results provide strong evidence for the anti-tumour and a nti-prolactin activity of angiogenesis inhibitors in the experimentall y oestrogen-induced pituitary adenoma; this might be mediated indirect ly through the inhibition of angiogenesis.