Inhibition of estrogen-induced pituitary tumor growth and angiogenesis in Fischer 344 rats by the matrix metalloproteinase inhibitor batimastat.
The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. Based on the significance of matrix metalloproteinases (MMPs) for tumor growth and angiogenesis, we have studied the effect of batimastat (BB-94), a synthetic MMPs inhibitor (MMPI) on the progression of prolactin-secreting pituitary adenoma in rats. Pituitary tumors were induced in male F344 rats by s.c. implantation of Silastic tubes containing diethylstilbestrol (DES). The effects of chronic treatment with BB-94 (30 mg/kg b.w.) on pituitary weight, cell proliferation, apoptosis and vascular density were evaluated. We have stated that chronic treatment with batimastat caused a significant reduction in the pituitary weight. Batimastat has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. A marked increase in the apoptotic index within the pituitary was observed in the study group. Moreover, the density of microvessels identified by CD31 was reduced in the group treated with BB-94. The results of our study provide evidence for an inhibitory effect of batimastat, a synthetic MMPI, on the growth and angiogenesis in an experimental model of human prolactinoma. The ability of BB-94 to suppress established pituitary tumor growth suggests a possible application of MMPIs in the treatment of pituitary adenomas.
Mucha
Slawomir A
SA
Department of Clinical Endocrinology, Medical University of Lodz, Sterling Street 3, 91-425, Lodz, Poland. mucha.sla@wp.pl
Meleń-Mucha
Gabriela
G
Godlewski
Andrzej
A
Stepień
Henryk
H
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004054:Diethylstilbestrol / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D004967:Estrogens / Q000633:toxicity; D007091:Image Processing, Computer-Assisted; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009929:Organ Size / Q000187:drug effects; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010903:Pituitary Gland, Anterior / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D010911:Pituitary Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D015175:Prolactinoma / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D013876:Thiophenes / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D004967:Estrogens; D018809:Proliferating Cell Nuclear Antigen; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; D004054:Diethylstilbestrol; C080985:batimastat; D008666:Metalloendopeptidases