Summary
Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. Batimastat inhibits at least 50% of MMP activity at concentrations less than or equal to 10 ng/ml in vitro. Batimastat retarded ascites accumulation and increased survival in mice with human ovarian tumor xenografts. Acute and long-term toxicological studies revealed no major toxicity in animals. Batimastat is poorly soluble and was administered intraperitoneally (i.p.) as a suspension. Previous studies in patients with malignant ascites have shown no major toxicities at doses as high as 1350 mg/m2.
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References
Birkedal-Hansen H, Moore WGI, Bodden MK, Windsor LJ, Birkedal-Hansen B, DeCarlo A, Engler JA: Matrix metalloproteinases: a review. Critical Rev in Oral Biol Med 4:197–250, 1993
Stetler-Stevenson WG, Liotta LA, Kleiner DE Jr: Extra-cellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J 7:1434–1441, 1993
Matrisian LM: Metalloproteinases and their inhibitors in matrix remodeling. Trends in Genetics 6:121–125, 1990
Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64:327–336, 1991
Zucker S, Lysik RM, Zarrabi MH, Moll U: Mr 92,000 Type IV collagenase is increased in plasma of patients with colon and breast cancer. Cancer Res 53:140–146, 1993
Brown PD, Bloxidge RE, Stuart NSA, Garter KC, Carmichael J: Association between expression of activated 72-kilodalton gelatinase and tumor spread in non-small cell lung carcinoma. J Natl Cancer Inst 85:574–578, 1993
Khokha R, Zimmer MJ, Graham CH, Lala PK, Waterhouse P: Suppression of invasion by inducible expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in B16-F10 melanoma cells. J Natl Cancer Inst 84:1017–1022, 1992
DeClerck YA, Perez N, Shimada H, Boone TC, Langley KE, Taylor SM: Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res 52:701–708, 1992
Khokha R, Waterhouse P, Yagel S, Lala PK, Overall CM, Norton G, Denhardt DT: Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells. Science 243:947–950, 1989
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 carcinoma xenografts. Cancer Res 53:2087–2091, 1993
Wang X, Fu X, Brown PD, Crimmin MJ, Hoffman RM: Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. Cancer Res 54:4726–4728, 1994
Taraboletti G, Garofalo A, Belotti D, Drudis T, Borsotti P, Scanziani E, Brown PD, 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
Low JA, Johnson MD, Bone E, Dickson RB: Matrix metalloproteinase inhibitor batimastat (BB-94) retards human breast cancer solid tumor growth but not ascites formation in nude mice. Submitted.
Chirivi RGS, Garofalo A, Crimmin MJ, Bawden LJ, Stoppacciafo A, Brown PD, Giavazzi R: Inhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor. Int J Cancer 58:460–464, 1994
Watson SA, Morris TM, Robinson G, Crimmin MJ, Brown PD, Hardcastle JD: Inhibition of organ invasion by matrix metalloproteinase inhibitor batimastat (BB-94) in two human colon carcinoma metastasis models. Cancer Res 55:3629–3633, 1995
Heussen C, Dowdle EB: Electrophoretic analysis of plasminogen activators in polyacrylamide gels containing sodium dodecyl sulfate and copolymerized substrates. Analyt Biochem 102:196–202, 1980
Hurewitz AN, Wu CL, Mancuso P, Zucker S: Tetracycline and doxycycline inhibit pleural fluid metalloproteinases. A possible mechanism for chemical pleurodesis. Chest 103:1113–1117, 1993
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Wojtowicz-Praga, S., Low, J., Marshall, J. et al. Phase I trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer. Invest New Drugs 14, 193–202 (1996). https://doi.org/10.1007/BF00210790
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DOI: https://doi.org/10.1007/BF00210790