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Matrix metalloproteinase inhibition improves survival in an orthotopic model of human pancreatic cancer

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Journal of Gastrointestinal Surgery

Abstract

Matrix metalloproteinases (MMPs) have been implicated in the growth and invasiveness of primary and metastatic tumors. Hypothesizing that MMP inhibition would slow cancer growth, the MMP inhibitor BB-94 (batimistat) was evaluated in an orthotopic animal model of human pancreatic carcinoma. Ten million human pancreatic cancer cells were surgically implanted into the pancreata of 30 athymic nu/nu mice. Intraperitoneal administration of 30 mg/kg BB-94 or vehicle control began 7 days after tumor implantation (13 mice with confirmed implantations in each group) and continued daily for 21 days, and then three times weekly until death or sacrifice at day 70. Representative tumors harvested from mice in each group were analyzed for presence and activity of MMP-2 and MMP-9. Animal weights were significantly higher in the BB-94-treated group at sacrifice (mean 58.4 ±7.9 g vs. 39.8 ±6.2 g; P<0.05, Student’s t test). The likelihood of survival to 70 days was significantly higher in the treated group (4 of 13 vs. 0 of 13, P <0.05, Z-test for end points) than in the control group as was overall survival (P = 0.03, Wilcoxon test). Nine mice in the control group developed metastases to the liver, peritoneum, abdominal wall, or local lymph nodes, whereas only two mice in the BB-94 group had evidence of metastatic disease (P <0.02, Fisher’s exact test), in both instances confined to the abdominal wall. Tumors from treated mice manifested lower MMP activity than those from control animals. These reports support the use of MMP inhibitors alone or as an adjunct in the treatment of pancreatic cancer.

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References

  1. Murr MM, Sarr MG, Oshi A, vanHeerden JA. Pancreatic can- cer. CA Cancer J Clin 1994;44:304–318.

    PubMed  CAS  Google Scholar 

  2. Lillemoe KD. Current management of pancreatic carcinoma. Ann Surg 1995;221:133–148.

    Article  PubMed  CAS  Google Scholar 

  3. Mauch C, Krieg T, Bauer EA. Role of the extracellular matrix in the degradation of connective tissue. Arch Dermatol Res 1994;287:107–114.

    Article  PubMed  CAS  Google Scholar 

  4. DeClerck YA, Imren S. Protease inhibitors: Role and potential therapeutic use in human cancers. Eur J Cancer 1994;30:2170–2180.

    Article  Google Scholar 

  5. Ray JM, Stetler-Stevenson WG. The role of matrix metallo- proteinases and their inhibitors in tumour invasion, metastasis, and angiogenesis. Eur Res J 1994;7:2062–2072.

    CAS  Google Scholar 

  6. Brown PD. Matrix metalloproteinase inhibitors: A novel class of anticancer agents. Adv Enzyme Regul 1995;35:293–30l.

    Article  PubMed  CAS  Google Scholar 

  7. Liabakk NB, Talbot I, Smith RA, Wilkinson K, Balkwill F. Matrix metalloproteinase 2 (MMP-2) and matrix metallopro- teinase 9 (MMP-9) type IV collagenase in colorectal cancer. Cancer Res 1996;56:190–196.

    PubMed  CAS  Google Scholar 

  8. Levy JT, Cioce V, Sobel M, Garbisa S, Grigioni WF, Liotta LA, Stetler-Stevenson WG. Increased expression to the Mr 72,000 type IV collagenase in human colonic adenocardnoma. Cancer Res 1991;51:439–444.

    PubMed  CAS  Google Scholar 

  9. Hoyhtya M, Fridman R, Komarek D, Porter-Jordan K, Stetler-Stevenson WG. Immunohistochemical localization of matrix metalloproteinase 2 and its specific inhibitor TIMP-2 in neoplastic tissues with monoclonal antibodies. Int J Cancer 1994;56:500–505.

    Article  PubMed  CAS  Google Scholar 

  10. Chenard MP, Rio MC, Chambon P, Bellocq J, Bassett P. StromeIysin-3 gene expression in human cancer: An overview. Invasion Metastasis 1994-95;14:269–275.

    Google Scholar 

  11. Yamamoto M, Mohanam S, Sawaya R, Fuller GN, Seiki M, Sato H, Gokaslan Z, Liotta L, Nicolson G, Rao J. Differential expression of membrane type matrix metalloproteinases and its correlation with gelatinase A activation in human malignant brain tumors in vivo and in vitro. Cancer Res 1996;56:384–392.

    PubMed  CAS  Google Scholar 

  12. Eccles SA, Box GM, Court WJ, Bone EA, Thomas W, Brown PD. Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase in- hibitor Batimastat BB-94. Cancer Res 1996;56:2815–2822.

    PubMed  CAS  Google Scholar 

  13. Wang X, Brown PD, Crimmin MJ, Hoffman RM. Matrix metalloproteinase inhibitor BB-94 (Batimastat) inhibits hu- man colon tumor growth and spread in a patient-like ortho- topic model in nude mice. Cancer Res 1994;54:4726–4728.

    PubMed  CAS  Google Scholar 

  14. Davies B, Brown PD, East N, Crimmin MJ, Balkwill FR. A synthetic matrix metalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian cancer xenografts. Cancer Res 1993;53:2087–2091.

    PubMed  CAS  Google Scholar 

  15. Marincola FM, Drucker BJ, Siao DY, Hough KL, Holder WG. The nude mouse as a model for the study of human pan- creatic cancer. J Surg Res 1989;47:520–529.

    Article  PubMed  CAS  Google Scholar 

  16. Furukawa T, Kubota T, Watanabe M, Kitajima M, Hoffman RM. A novel “patient-like” treatment model of human pan- creatic cancer constructed using orthotopic transplantation of histologically intact human tumor tissue in nude mice. Cancer Res 1993;53:3070–3072.

    PubMed  CAS  Google Scholar 

  17. Liu CD, Slice LW, Balasubramaniam A, Walsh JH, Newton TR, Saxton PE, McFadden DW. Y2 receptors decrease hu- man pancreatic cancer growth and intracellular cyclic adeno- sine monophosphate levels. Surgery 1995;118:229–236.

    Article  PubMed  CAS  Google Scholar 

  18. Mong H, Chu TM. Characterization of the tumorigenic and metastatic properties of a human pancreatic tumor cell line (ASPC-1) implanted orthotopically into nude mice. Tumor Biol 1985;6:89–98.

    Google Scholar 

  19. Vezeridis MP, Doremus CM, Tibbetts LM, Tzanakakis G, Jackson BT. Invasion and metastasis following orthotopic transplantation of human pancreatic cancer in the nude mouse. J Surg Oncol 1989;40:261–265.

    Article  PubMed  CAS  Google Scholar 

  20. Zervos EE, Norman JG, Gower WR, Franz M, Rosemurgy AS. Matrix metalloproteinase inhibition attenuates human pancreatic cancer growth in vitro and decreases mortality and tumorigenesis in vivo. J Surg Res 1997;69:601–605.

    Article  Google Scholar 

  21. Gower WR, Risch R, Godellas C, Fabri PJ. HPAC, a new hu- man glucocorticoid-sensitive pancreatic ductal adenocarci- noma cell line. In Vitro Cell Dev Biol 1994;30A:151–161.

    Article  CAS  Google Scholar 

  22. Brown PD, Bloxidge RE, Stuart NS, Gatter KC, Carmichael J. Association between expression of activated 72kD gelatinase and tumor spread in non-small cell lung cancer. J Natl Cancer Inst 1993;85:574–579.

    Article  PubMed  CAS  Google Scholar 

  23. Zervos EE, Shafii AE, Rosemurgy AS. Matrix metallopro- teinase inhibition selectively decreases type II MMP activity in a murine model of pancreatic cancer. J Surg Res 1999;81:65–68.

    Article  PubMed  CAS  Google Scholar 

  24. Zervos EE, Shafii AE, Haq M, Rosemurgy AS. Matrix metal- loproteinase inhibition suppresses MMP-2 activity and acti- vation of PANC-1 cells in vitro. J SurgRes 1999;84:162–167.

    CAS  Google Scholar 

  25. Matrisian L. Matrix metalloproteinase gene expression. Ann N Y Acad Sci 1994;732:42–50.

    Article  PubMed  CAS  Google Scholar 

  26. Saarialho-Kere UK, Chang ES, Welgus HG, Parks WC. Dis- tinct localization of collagenase and tissue inhibitor of metal- loproteinase expression in wound healing associated with ulcerative pyogenic granuloma. J Clin Invest 1992;90:1952–1957.

    Article  PubMed  CAS  Google Scholar 

  27. Tryggvason K, Hoyhtya M, Pyke C. Type IV collagenases in invasive tumors. Breast Cancer Res Treatm 1993;24:209–218.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgical Oncology, Ohio State University, Columbus, Ohio

    Emmanuel E. Zervos M.D.

  2. Departments of Surgery, University of South Florida, Tampa, Fla.

    Michael G. Franz M.D., Khaled F. Salhab B.S., Alexis E. Shafii B.S., Julian Menendez B.S. & Alexander S. Rosemurgy M.D.

  3. Departments of Biochemistry and Molecular Biology, University of South Florida, Tampa, Fla.

    William R. Gower Ph.D.

Authors
  1. Emmanuel E. Zervos M.D.
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  2. Michael G. Franz M.D.
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  3. Khaled F. Salhab B.S.
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  4. Alexis E. Shafii B.S.
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  5. Julian Menendez B.S.
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  6. William R. Gower Ph.D.
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  7. Alexander S. Rosemurgy M.D.
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Zervos, E.E., Franz, M.G., Salhab, K.F. et al. Matrix metalloproteinase inhibition improves survival in an orthotopic model of human pancreatic cancer. J Gastrointest Surg 4, 614–619 (2000). https://doi.org/10.1016/S1091-255X(00)80111-0

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  • DOI: https://doi.org/10.1016/S1091-255X(00)80111-0

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