Virchows Archiv

, Volume 450, Issue 3, pp 335–341 | Cite as

Inhibition of estrogen-induced pituitary tumor growth and angiogenesis in Fischer 344 rats by the matrix metalloproteinase inhibitor batimastat

  • Slawomir A. MuchaEmail author
  • Gabriela Meleń-Mucha
  • Andrzej Godlewski
  • Henryk Stepień
Original Article


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.


Pituitary Prolactinoma Proliferation Apoptosis Angiogenesis 



This study was supported by a grant from the State Committee for Scientific Research of Poland (KBN) to H. S. (No 4 P05A 04215). All experiments were performed according to our institutional and National Institutes of Health (NIH) guidelines for care and use of research animals.


  1. 1.
    Asa SL, Ezzat S (1998) The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev 19:798–827PubMedCrossRefGoogle Scholar
  2. 2.
    Beaulieu E, Kachra Z, Mousseau N, Delbecchi L, Hardy J, Beliveau R (1999) Matrix metalloproteinases and their inhibitors in human pituitary tumors. Neurosurgery 45:1432–1441PubMedCrossRefGoogle Scholar
  3. 3.
    Bevan JS, Webster J, Burke CW, Scanlon MF (1992) Dopamine agonists and pituitary tumor shrinkage. Endocr Rev 13:220–240PubMedCrossRefGoogle Scholar
  4. 4.
    Bravo R, Frank R, Blundell PA, MacDonald-Bravo H (1987) Cyclin/PCNA is the auxiliary protein of DNA polymerase-δ. Nature 326:515–517PubMedCrossRefGoogle Scholar
  5. 5.
    Brown PD, Giavazzi R (1995) Matrix metalloproteinase inhibition—a review of anti-tumor activity. Ann Oncol 6:967–974PubMedGoogle Scholar
  6. 6.
    Chirivi RGS, Garofalo A, Crimmin MJ, Bawden LJ, Stoppacciano A, Brown PD, Giavazzi R (1994) Inhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor. Int J Cancer 58:460–464PubMedCrossRefGoogle Scholar
  7. 7.
    Davies B, Brown P, East N, Crimmin MJ, Balkwill FR (1993) A synthetic matrix metalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts. Cancer Res 53:2087–2091. Erratum: Cancer Res 53:3652PubMedGoogle Scholar
  8. 8.
    DeLisser HM, Christofidou-Solomidou M, Strieter RM, Burdick MD, Robinson CS, Wexler RS, Kerr JS, Garlanda C, Merwin JR, Madri JA, Albelda SM (1997) Involvement of endothelial PECAM-1/CD31 in angiogenesis. Am J Pathol 151:671–677PubMedGoogle Scholar
  9. 9.
    Elias KA, Weiner RI (1984) Direct arterial vascularization of estrogen-induced prolactin-secreting anterior pituitary tumors. Proc Natl Acad Sci USA 81:4549–4553PubMedCrossRefGoogle Scholar
  10. 10.
    Farnoud MR, Farhadian F, Samuel JL, Derome P, Peillon F, Li JY (1995) Fibronectin isoforms are differentially expressed in normal and adenomatous human anterior pituitaries. Int J Cancer 61:27–34PubMedCrossRefGoogle Scholar
  11. 11.
    Farnoud MR, Veirana N, Derome P, Peillon F, Li JY (1996) Adenomatous transformation of the human anterior pituitary is associated with alterations in integrin expression. Int J Cancer 67:45–53PubMedCrossRefGoogle Scholar
  12. 12.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186PubMedCrossRefGoogle Scholar
  13. 13.
    Gastman BR, Atarshi Y, Reichert TE, Saito T, Balkir L, Rabinowich H, Whiteside TL (1999) Fas ligand is expressed on human squamous cell carcinomas of the head and neck, and it promotes apoptosis of T lymphocytes. Cancer Res 59:5356–5364PubMedGoogle Scholar
  14. 14.
    Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501PubMedCrossRefGoogle Scholar
  15. 15.
    Heath EI, Grochow LB (2000) Clinical potential of matrix metalloprotease inhibitors in cancer therapy. Drugs 59:1043–1055PubMedCrossRefGoogle Scholar
  16. 16.
    Jugenburg M, Kovacs K, Jugenburg I, Scheithauer BW (1998) Angiogenesis in endocrine neoplasms. Endocr Pathol 8:259–272Google Scholar
  17. 17.
    Katznelson L, Alexander JM, Klibanski A (1993) Clinically nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 76:1089–1094PubMedCrossRefGoogle Scholar
  18. 18.
    Knox JD, Bretton L, Lynch T, Bowden GT, Nagle RB (1998) Synthetic matrix metalloproteinase inhibitor, BB-94, inhibits the invasion of neoplastic human prostate cells in a mouse model. Prostate 35:248–254PubMedCrossRefGoogle Scholar
  19. 19.
    Lei H, Kalluri R, Furth EE, Baker AH, Strauss JF 3rd (1999) Rat amnion type IV collagen composition and metabolism: implications for membrane breakdown. Biol Reprod 60:176–182PubMedCrossRefGoogle Scholar
  20. 20.
    Lein M, Jung K, Le DK, Hasan T, Ortel B, Borchert D, Winkelmann B, Schnorr D, Loenings SA (2000) Synthetic inhibitor of matrix metalloproteinases (batimastat) reduces prostate cancer growth in an orthotopic rat model. Prostate 43:77–82PubMedCrossRefGoogle Scholar
  21. 21.
    Levy A (1999) Mitosis and apoptosis in anterior pituitary gland: tumour formation or hyperplasia? Baillieres Best Pract Res Clin Endocrinol Metab 13:353–365PubMedCrossRefGoogle Scholar
  22. 22.
    Meleń-Mucha G, Winczyk K, Pawlikowski M (1998) Somatostatin analogue octreotide and melatonin inhibit bromodeoxyuridine incorporation into cell nuclei and enhance apoptosis in the transplantable murine colon 38 cancer. Anticancer Res 18:3615–3620PubMedGoogle Scholar
  23. 23.
    Minderman T, Wilson CB (1994) Age-related and gender-related occurrence of pituitary adenomas. Clin Endocrinol 41:359–364Google Scholar
  24. 24.
    Murphy G, Docherty AJP (1992) The matrix metalloproteinases and their inhibitors. Am J Respir Cell Mol Biol 7:120–125PubMedGoogle Scholar
  25. 25.
    Páez Pereda M, Ledda MF, Goldberg V, Chervin A, Carrizo G, Molina H, Müller A, Renner U, Podhajcer O, Arzt E, Stalla GK (2000) High levels of matrix metalloproteinases regulate proliferation and hormone secretion in pituitary cells. J Clin Endocrinol Metab 85:263–269PubMedCrossRefGoogle Scholar
  26. 26.
    Pellegrini I, Rasolonjanahary R, Gunz G, Bertrand P, Delivet S, Jedynak CP, Kordon C, Peillon F, Jaquet P, Enjalbert A (1989) Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab 69:500–509PubMedGoogle Scholar
  27. 27.
    Pereda MP, Goldberg V, Chervin A, Carizzo G, Molina A, Andrada J, Sauer J, Renner U, Stalla GK, Arzt E (1996) Interleukin-2 (IL-2) and IL-6 regulate c-fos protooncogene expression in human pituitary adenoma explants. Mol Cell Endocrinol 124:33–42PubMedCrossRefGoogle Scholar
  28. 28.
    Phelps C, Hymer WC (1983) Characterization of oestrogen-induced adenohypophyseal tumors in the Fischer 344 rat. Neuroendocrinology 37:23–31PubMedGoogle Scholar
  29. 29.
    Sang QX (1998) Complex role of matrix metalloproteinases in angiogenesis. Cell Res 8:171–177PubMedGoogle Scholar
  30. 30.
    Schechter J, Ahmad N, Elias K, Weiner R (1987) Estrogen-induced tumors: changes in the vasculature in two strains of rat. Am J Anat 179:315–323PubMedCrossRefGoogle Scholar
  31. 31.
    Scheithauer BW, Kovacs KT, Laws ER, Randall RV (1986) Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg 65:733–744PubMedCrossRefGoogle Scholar
  32. 32.
    Sledge GW Jr, Qulali M, Goulet R, Bone EA, Fife R (1995) Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J Natl Cancer Inst 87:1546–1550PubMedCrossRefGoogle Scholar
  33. 33.
    Spady TJ, McComb RD, Shull JD (1999) Estrogen action in the regulation of cell proliferation, cell survival, and tumorigenesis in the rat anterior pituitary gland. Endocrine 11:217–233PubMedCrossRefGoogle Scholar
  34. 34.
    Stefaneanu L, Kovacs K, Scheithauer BW, Kontogeorgos G, Riehle DL, Sebo TJ, Murray D, Vidal S, Tran A, Buchfelder M, Fahlbusch R (2000) Effect of dopamine agonists on lactotroph adenomas of the human pituitary. Endocr Pathol 11:341–352PubMedCrossRefGoogle Scholar
  35. 35.
    Stepień H, Grochal M, Zieliński KW, Mucha S, Kunert-Radek J, Kulig A, Stawowy A, Pisarek H (1996) Inhibitory effects of fumagillin and its analogue TNP-470 on the function, morphology and angiogenesis of an oestrogen-induced prolactinoma in Fischer 344 rats. J Endocrinol 150:99–106PubMedCrossRefGoogle Scholar
  36. 36.
    Talbot DC, Brown PD (1996) Experimental and clinical studies on the use of matrix metalloproteinase inhibitors for the treatment of cancer. Eur J Cancer 32:2528–2533CrossRefGoogle Scholar
  37. 37.
    Taraboletti G, Garofalo A, Belotti D, Drudis T, Borsotti P, Scanziani E, Brown PD, Giavazzi R (1995) Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases. J Natl Cancer Inst 87:293–298PubMedCrossRefGoogle Scholar
  38. 38.
    Turner HE, Nagy Z, Esiri MM, Harris AL, Wass JAH (2000) Role of matrix metalloproteinase 9 in pituitary tumor behavior. J Clin Endocrinol Metab 85:2931–2935PubMedCrossRefGoogle Scholar
  39. 39.
    Turner HE (2001) Pituitary tumor angiogenesis. Endocrinologist 11:465–469Google Scholar
  40. 40.
    Wang X, Fu X, Brown PD, Crimmin MJ, Hoffman RM (1994) Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. Cancer Res 54:4726–4728PubMedGoogle Scholar
  41. 41.
    Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl J Med 324:1–8PubMedCrossRefGoogle Scholar
  42. 42.
    Weidner N (1995) Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors. Breast Cancer Res Treat 36:169–180PubMedCrossRefGoogle Scholar
  43. 43.
    Wiklund J, Wertz N, Gorski J (1981) A comparison of estrogen effects on uterine and pituitary growth and prolactin synthesis in F344 and Holtzman rats. Endocrinology 109:1700–1707PubMedCrossRefGoogle Scholar
  44. 44.
    Woessner JF Jr (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 5:2145–2154PubMedGoogle Scholar
  45. 45.
    Wojtowicz-Praga S, Low J, Marshall J, Ness E, Dickson R, Barter J, Sale M, McCann P, Moore J, Cole A, Hawkins MJ (1996) Phase I trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer. Invest New Drugs 14:193–202PubMedCrossRefGoogle Scholar
  46. 46.
    Wyllie AH (1993) Apoptosis (The 1992 Frank Rose Memorial Lecture). Br J Cancer 67:205–208PubMedGoogle Scholar
  47. 47.
    Zervos EE, Norman JG, Gower WR, Franz MG, Rosemurgy AS (1997) Matrix metalloproteinase inhibition attenuates human pancreatic cancer growth in vitro and decreases mortality and tumorigenesis in vivo. J Surg Res 69:367–371PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Slawomir A. Mucha
    • 1
    Email author
  • Gabriela Meleń-Mucha
    • 2
  • Andrzej Godlewski
    • 3
  • Henryk Stepień
    • 4
  1. 1.Department of Clinical EndocrinologyMedical University of LodzLodzPoland
  2. 2.Department of ImmunoendocrinologyMedical University of LodzLodzPoland
  3. 3.Department of Cytology, Histology and EmbryologyMedical University of LodzLodzPoland
  4. 4.Department of ImmunoendocrinologyMedical University of LodzLodzPoland

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