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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2002 Jul;93(7):834–841. doi: 10.1111/j.1349-7006.2002.tb01326.x

Matrix Metalloproteinase Inhibitor, Marimastat, Decreases Peritoneal Spread of Gastric Carcinoma in Nude Mice

Masaru Kimata 1, Yoshihide Otani 1,✉, Tetsuro Kubota 1, Naoki Igarashi 1, Takeyoshi Yokoyama 1, Norihito Wada 1, Nobunari Yoshimizu 1, Masato Fujii 2, Kaori Kameyama 3, Yasunori Okada 3, Koichiro Kumai 4, Masaki Kitajima ✉
PMCID: PMC5927074  PMID: 12149150

Abstract

Marimastat, a matrix metalloproteinese inhibitor, was examined for the ability to prevent peritoneal dissemination of a human gastric cancer xenograft, TMK–1. Even with novel approaches such as molecular targeting of cancer chemotherapy, peritoneal dissemination of gastric cancer has little sensitivity to anticancer drugs, and it is impossible to inhibit its growth completely. Intraperitoneal injection of TMK–1 into nude mice at 5 × 105 cells/body resulted in carcinomatous peritonitis that mimicked clinical cases. Continuous administration of marimastat (18 mg/kg/day) from 24 h after the tumor inoculation successfully inhibited the growth of peritoneal dissemination nodules. Combined administration of marimastat (18 mg/kg/day) and mitomycin C (MMC, 2 mg/kg) showed synergistic inhibition of growth of peritoneal dissemination, being superior to MMC alone (2 mg/kg). Although marimastat alone could not increase survival tune with statistical significance, combined administration of marimastat and MMC had a survival benefit with statistical significance. The combination of marimastat and MMC increased the preventive effect on peritoneal dissemination. Marimastat seems to be a candidate for the prevention of peritoneal spread of gastric carcinoma.

Keywords: MMP inhibitor, Gastric cancer, Peritoneal dissemination, Marimastat

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REFERENCES

  • 1. ) Liotta , L. A. , Stee , P. S. and Stetler‐Stevenson , W.Cancer metastasis and angiogenesis; an imbalance of positive and negative regulation . Cell , 64 , 327 – 336 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Steward , W. P.Marimastat (BB2516): current status of development . Cancer Chemother. Pharmacol. , 43 ( Suppl. ), S56 – S60 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Igarashi , N. , Kubota , T. , Otani , Y. , Matsuzaki , S. W. , Watanabe , M. , Teramoto , T. , Kumai , K. , Tamaki , K. , Tanzawa , K. , Kobayashi , T. and Kitajima , M.Preventive effect of matrix metalloproteinase inhibitor, R–94138, in combination with mitomycin C or cisplatin on peritoneal dissemination of human gastric cancer cell line TMK–1 in nude mice . Jpn. J. Cancer Res. , 90 , 116 – 121 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. ) Prontera , C. , Mariani , B. , Rossi , C. , Poggi , A. and Rotilio , D.Inhibition of gelatinase A (MMP–2) by batimastat and captopril reduces tumor growth and lung metastasis in mice bearing Lewis lung carcinoma . Int. J. Cancer , 81 , 761 – 766 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Giavazzi , R. , Gfarofalo , A. , Ferri , C. , Lucchini , V. , Bone , E. A. , Chiari , S. , Brown , P. D. , Nicoletti , M. I. and Taraboletti , G.Batimastat, a synthetic inhibitor of matrix metalloproteinases, potentiates the antitumor activity of cisplatin in ovarian carcinoma zenografts . Clin. Cancer Res. , 4 , 985 – 992 ( 1998. ). [PubMed] [Google Scholar]
  • 6. ) Eccles , S. A. , Box , G. M. , Court , W. J. , Bone , E. A. , Thomas , W. and Brown , P. D.Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by matrix metalloproteinase inhibitor batimastat . Cancer Res. , 56 , 2815 – 2822 ( 1996. ). [PubMed] [Google Scholar]
  • 7. ) Price , A. , Shi , Q. , Morris , D. , Wilcox , M. E. , Brasher , P. M. , Rewcastle , N. B. , Shalinsky , D. , Zou , H. , Appelt , K. , Johnson , R. N. , Yong , V. W. , Edwards , D. and Forsyth , P.Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340 . Clin. Cancer Res. , 5 , 845 – 854 ( 1999. ). [PubMed] [Google Scholar]
  • 8. ) Rowinsky , E. K. , Humphrey , R. , Hammond , L. A. , Aylesworth , C. , Smetzer , L. , Hidalgo , M. , Morrow , M. , Smith , L. , Garner , A. , Sorensen , J. M. , Van Hoff , D. D. and Eckhardt , S. G.Phase I and pharmacologic study of the specific matrix metalloproteinase inhibitor BAY 12–9566 on a protracted oral daily dosing schedule in patients with solid malignancies . J. Clin. Oncol. , 18 , 178 – 186 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Rudek , M. A. , Figg , W. D. , Dyer , V. , Dahut , W. , Turner , M. L. , Steinberg , S. M. , Liewehr , D. J. , Kohler , D. R. , Pluda , J. M. and Reed , E.Phase I clinical trial of oral COL–3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer . J. Clin. Oncol. , 19 , 584 – 592 ( 2001. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Cianfrocca , M. , Cooley , T. P. , Lee , J. Y. , Rudek , M. A. , Scadden , D. T. , Ratner , L. , Pluda , J. M. , William , D. F. , Krown , S. E. and Dezube , B. J.Matrix metalloproteinase inhibitor COL–3 in the treatment of AIDS‐related Kaposi's sarcoma: a phase I AIDS Malignancy Consortium study . J. Clin. Oncol. , 20 , 153 – 159 ( 2002. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Rasmussen , H. S. and McCann , P. P.Matrix metalloproteinase inhibition as a novel anticancer strategy: a review with special focus on Batimastat and Marimastat . Pharmacol. Ther. , 75 , 69 – 75 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Nemunaitis , J. , Poole , C. , Primrose , J. and Rosemurgy , A.Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer‐term studies . Clin. Cancer Res. , 4 , 1101 – 1109 ( 1998. ). [PubMed] [Google Scholar]
  • 13. ) Miller , A. W. , Brown , P. D. , Moor , J. , Galloway , W. A. , Cornish , A. G. and Lenehan , T. J.Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers . Br. J. Clin. Pharmacol. , 45 , 21 – 26 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Bramhall , S. R. , Rosemurgy , A. , Brown , P. D. , Bowry , C. and Buckels , J. A. C.for the Marimastat Pancreatic Cancer Study Group. Marimastat as first‐line therapy for patients with unresectable pancreatic cancer: a randomized traial . J. Clin. Oncol. , 19 , 3447 – 3455 ( 2001. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Tokuda , Y. , Nagura , H. , Maruo , K. , Uemura , Y. , Yoshimura , S. , Tamaoki , K. , Kondo , Y. , Ogoshi , Y. and Mitomi , T.An immunohistochemical study of human gastric carcinoma in nude mice and athymic rats with special reference to secretory component production . Jpn. J. Cancer Clin. , 27 , 1605 – 1612 ( 1981. ) (in Japanese with English abstract ). [Google Scholar]
  • 16. ) Ochiai , A. , Yasui , W. and Tahara , E.Growth‐promoting effect of gastrin on human gastric carcinoma cell line TMK–1 . Jpn. J. Cancer Res. (Gann) , 76 , 1064 – 1071 ( 1985. ). [PubMed] [Google Scholar]
  • 17. ) Aaronson , S. A. and Todaro , G. J.Development of 3T3–like lines from Balb‐c mouse embryo cultures: transformation susceptibility to SV40 . J. Cell. Physiol. , 72 , 141 – 148 ( 1968. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Wojtowicz‐Praga , S. M. , Dickson , R. B. and Hawkins , M. J.Matrix metalloproteinase inhibitors . Invest. New Drugs , 15 , 61 – 75 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Mosmann , T.Rapid calorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays . J. Immunol. Methods , 65 , 55 – 63 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Suto , A. , Kubota , T. , Shimoyama , Y. , Ishibiki , K. and Abe , O.MTT assay with reference to clinical effect of chemotherapy . J. Surg. Oncol. , 42 , 28 – 32 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Furukawa , T. , Kubota , T. , Suto , A. , Takahara , T. , Yamaguchi , H. , Takeuchi , T. , Kase , S. , Kodaira , S. , Ishibiki , K. and Kitajima , M.Clinical usefulness of chemotherapy testing using the MTT assay . J. Surg. Oncol. , 48 , 188 – 193 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Otani , Y. , Okazaki , I. , Arai , M. , Kameyama , K. , Wada , N. , Maruyama , K. , Yoshino , K. , Kitajima , M. , Hosoda , Y. and Tsuchiya , M.Gene expression of interstitial collagenase (matrix metalloproteinase 1) in gastrointestinal tract cancers . J. Gastroenterol. , 29 , 391 – 397 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Sakurai , Y. , Otani , Y. , Kameyama , K. , Hosoda , Y. , Okazaki , I. , Kubota , T. , Kumai , K. and Kitajima , M.Expression of interstitial collagenase (matrix metallopro‐teinase–1) in gastric cancers . Jpn. J. Cancer Res. , 88 , 401 – 406 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Okada , Y. , Nagase , H. and Harris , E. D. , Jr.A metalloproteinase from human rheumatoid synovial fibroblasts that digests connective tissue matrix components . J. Biol. Chem. , 261 , 14245 – 14255 ( 1986. ). [PubMed] [Google Scholar]
  • 25. ) Tolnay , E. , Wiethege , T. , Kuhnen , C. , Wulf , M. , Voss , B. and Muller , K. M.Expression of type IV collagenase correlates with the expression of vascular endothelial growth factor in primary non‐small cell lung cancer . J. Cancer Res. Clin. Oncol. , 123 , 652 – 658 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Kurizaki , T. , Toi , M. and Tominaga , T.Relationship between matrix metalloproteinase expression and tumor angiogenesis in human breast carcinoma . Oncol. Rep. , 5 , 673 – 677 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Ito , T. , Tanioka , M. , Yoshida , H. , Yoshioka , T. , Nishimoto , H. and Itohara , S.Reduced angiogenesis and tumor progression in gelatinase A‐deficient mice . Cancer Res. , 58 , 1048 – 1051 ( 1998. ). [PubMed] [Google Scholar]
  • 28. ) Charvat , S. , Le Griel , C. , Chignol , M. C. , Schmitt , D. and Serres , M.Ras‐transfection up‐regulated HaCaT cell migration inhibition by Marimastat . Clin. Exp. Metastasis , 17 , 677 – 685 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Peterson , M. , Porter , K. E. , Loftus , I. M. , Thompson , M. M. and London , N. J.Marimastat inhibits neointimal thickening in a model of human arterial intimal hyperplasia . Eur. J. Vasc. Endovasc. Surg. , 19 , 461 – 467 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Zhu , W. H. , Guo , X. , Villaschi , S. and Francesco , N. R.Regulation of vascular growth and regression by matrix metalloproteinases in the rat aorta model of angiogenesis . Lab. Invest. , 80 , 545 – 555 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Lozonschi , L. , Sunamura , M. , Kobori , M. , Egawa , S. , Ding , L. and Matsuno , S.Controlling tumor angiogenesis and metastasis of C26 murine colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB‐R7785, in two tumor models . Cancer Res. , 59 , 1252 – 1258 ( 1999. ). [PubMed] [Google Scholar]
  • 32. ) Taraboletti , G. , Garofalo , A. , Beloti , D. , Drudis , T. , Borsotti , P. , Scanziani , E. , Brown , P. D. and Giavazzi , R.Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases . J. Natl. Cancer Inst. , 87 , 293 – 298 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Minagawa , A. , Otani , Y. , Kubota , T. , Wada , N. , Furukawa , T. , Kumai , K. , Kameyama , K. , Okada , Y. , Fujii , M. , Yano , M. , Sato , T. , Ito , A. and Kitajima , A.The citrus flavonoid, nobiletin, inhibits peritoneal dissemination of human gastric carcinoma in SCID mice . Jpn. J. Cancer Res. , 92 , 1322 – 1328 ( 2001. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. ) Murakami , A. , Nakamura , Y. , Torikai , K. , Tanaka , T. , Koshiba , T. , Koshimizu , K. , Kuwahara , S. , Takahashi , Y. , Ogawa , K. , Yano , M. , Tokuda , H. , Nishino , H. , Mimaki , Y. , Sashida , Y. , Kitanaka , S. and Ohigashi , H.Inhibitory effect of citrus nobiletin on phorbol ester‐induced skin inflammation, oxidative stress, and tumor promotion in mice . Cancer Res. , 60 , 5059 – 5066 ( 2000. ). [PubMed] [Google Scholar]

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