o-(chloroacetylcarbamoyl)fumagillol and Pituitary-Neoplasms

The process of angiogenesis occurs in many physiological states, but it is also essential for the growth of solid tumours and metastasis formation. An abnormal arterial vascularization has been shown in prolactin-secreting pituitary adenomas induced by prolonged treatment with oestrogens in Fischer 344 (F344) rats. It is thought that anti-angiogenic agents might be useful in therapy for these tumours. Fumagillin and its analogue TNP-470 are known to inhibit endothelial cell proliferation 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 vivo and in vitro. As expected, 7 weeks after s.c. implantation of Silastic tubes containing 10 mg diethyl-stilboestrol (DES), a very high rise in serum prolactin levels was found. Both angiogenesis inhibitors injected s.c. at doses of 10 mg/kg body weight for 24 days attenuated the stimulatory effect of DES on prolactin production and release. They also diminished prolactin cell density and inhibited cell proliferation expressed as the number of anterior pituitary cells labelled with bromodeoxyuridine (BrdU), but the effect of TNP-470 was minor compared with fumagillin. Both angioinhibitors suppressed neo-vascularization within the anterior pituitary with similar potency but, on the other hand, they did not affect DES-induced increases in prolactin secretion from cultured rat pituitary cells and cell proliferation in vitro. In conclusion, our results provide strong evidence for the anti-tumour and anti-prolactin activity of angiogenesis inhibitors in the experimentally oestrogen-induced pituitary adenoma; this might be mediated indirectly through the inhibition of angiogenesis.

Topics: Animals; Antibiotics, Antineoplastic; Cell Division; Cells, Cultured; Cyclohexanes; Diethylstilbestrol; Fatty Acids, Unsaturated; Injections, Subcutaneous; Male; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Pituitary Gland, Anterior; Pituitary Neoplasms; Prolactin; Prolactinoma; Rats; Rats, Inbred F344; Sesquiterpenes

TNP-470 (TNP), an analog of fumagillin, inhibits cell proliferation and tumorigenesis in estrogen-induced pituitary tumors in rats. This study found that treatment with TNP or TNP and bromocriptine suppressed vascular formation in these pituitary tumors more than bromocriptine alone. TNP had a greater suppressive effect on vascular formation in pituitary tumors than in normal pituitary gland. Laminin and basic fibroblast growth factor (FGF) were detected around new blood vessels in normal pituitary gland and pituitary tumor. TNP did not completely suppress laminin or basic FGF expression. The effect of TNP on pituitary tumor may involve inhibition of vascular formation by mechanisms mediated by other factors in addition to basic FGF. Treatment with bromocriptine and TNP acts indirectly and directly on vascular formation and may provide a useful chemotherapeutic modality for pituitary tumors.

Topics: Animals; Bromocriptine; Cyclohexanes; Estradiol; Female; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Pituitary Neoplasms; Rats; Rats, Inbred F344; Sesquiterpenes