batimastat and Pituitary-Neoplasms

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.

Topics: Angiogenesis Inhibitors; Animals; Cell Proliferation; Diethylstilbestrol; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Estrogens; Image Processing, Computer-Assisted; Male; Metalloendopeptidases; Neovascularization, Pathologic; Organ Size; Phenylalanine; Pituitary Gland, Anterior; Pituitary Neoplasms; Prolactinoma; Proliferating Cell Nuclear Antigen; Protease Inhibitors; Rats; Rats, Inbred F344; Thiophenes

Beside the digestion of the extracellular matrix during tumor invasion and metastasis, more recently, new functions for matrix metalloproteinases (MMPs) have been proposed. We studied the expression and function of these enzymes in pituitary cells. We observed the activities of MMP-2 and MMP-9 together with expression of membrane-type MMP and tissue inhibitor of metalloproteinase-1 in all types of human pituitary adenomas. We found surprisingly high levels of MMP activity and low levels of tissue inhibitor of metalloproteinases, indicating a high level of extracellular matrix-degrading activity in pituitary adenomas. To examine the function of metalloproteinase activity in pituitary cells we used the synthetic MMP inhibitor batimastat. These studies demonstrate that MMPs secreted by pituitary cells can release growth factors anchored to the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. These results define a new additional mechanism for the control of pituitary hormone secretion and indicate new potential therapeutic targets for pituitary adenomas.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Animals; Blotting, Northern; Cell Division; Female; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Middle Aged; Neoplastic Stem Cells; Phenylalanine; Pituitary Gland; Pituitary Hormones; Pituitary Neoplasms; Protease Inhibitors; Rats; Thiophenes; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tumor Cells, Cultured