Inhibitory effect of thalidomide on the growth, secretory function and angiogenesis of estrogen-induced prolactinoma in Fischer 344 rats.
The process of angiogenesis has been found to be essential for the development of estrogen-induced pituitary prolactinoma in Fischer 344 rats. Thalidomide [(alpha-(N-phthalimido)-glutarimide] is known to be a potent immunomodulatory drug with antiangiogenic properties, but its effect on lactotroph cell secretory function and pituitary prolactinoma formation has not been described yet. The purpose of this study was to examine the effects of thalidomide on secretion of prolactin (PRL) and vascular endothelial growth factor (VEGF), cell proliferation, apoptosis and angiogenesis within the anterior pituitary gland in long-term diethylstilboestrol (DES)-treated male F344 rats in vivo and in vitro. It was found that DES sharply increased serum PRL and VEGF levels. On the other hand, simultaneous treatment of F344 rats with thalidomide for the last 15 days of the experiment attenuated the stimulatory effect of DES on PRL and VEGF secretion. It also diminished prolactin cell proliferation evaluated as the number of proliferating cell nuclear antigen (PCNA)-positive stained cell nuclei and increased the number of apoptotic bodies determined by the terminal deoxynucleotidyl-mediated dUTP nick-end labeling (TUNEL) method in sections of the DES-induced pituitary prolactinoma. The density of pituitary microvessels evaluated by microscopic counting of CD-31-positive blood vessels was also diminished by the tested drug. In addition, thalidomide (10(-4) to 10(-6) M) inhibited cell proliferation, prolactin and VEGF secretion from rat pituitary prolactinoma cells cultured in vitro. In conclusion, our results provide strong evidence for the antiprolactin and antitumor activity of thalidomide in experimentally DES-induced pituitary adenoma.
Stepień
Henryk
H
Department of Immunoendocrinology, Medical University of Lodz, Dr Sterling 3 Street, 91-425 Lodz, Poland. hstep@csk.umed.lodz.pl
Lawnicka
Hanna
H
Mucha
Sławomir
S
Wagrowska-Danilewicz
Małgorzata
M
Stepień
Bartłomiej
B
Siejka
Agnieszka
A
Komorowski
Jan
J
D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D004054:Diethylstilbestrol / Q000633:toxicity; D004967:Estrogens / Q000633:toxicity; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D010902:Pituitary Gland / Q000737:chemistry / Q000473:pathology; D010911:Pituitary Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011388:Prolactin / Q000097:blood / Q000378:metabolism*; D015175:Prolactinoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D013792:Thalidomide / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A
D020533:Angiogenesis Inhibitors; D004967:Estrogens; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide; D004054:Diethylstilbestrol; D011388:Prolactin