title: Metastasis is strongly reduced by the matrix metalloproteinase inhibitor Galardin in the MMTV-PymT transgenic breast cancer model.
abstract: Matrix metalloproteinases (MMP) have several roles that influence cancer progression and dissemination. However, low molecular weight metalloproteinase inhibitors (MPI) have not yet been tested in transgenic/spontaneous metastasis models. We have tested Galardin/GM6001, a potent MPI that reacts with most MMPs, in the MMTV-PymT transgenic breast cancer model. We followed a cohort of 81 MMTV-PymT transgenic mice that received Galardin, placebo, or no treatment. Galardin treatment was started at age 6 weeks with 100 mg/kg/d, and all mice were killed at age 13.5 weeks. Galardin treatment significantly reduced primary tumor growth. Final tumor burden in Galardin-treated mice was 1.69 cm3 compared with 3.29 cm3 in placebo-treated mice (t test, P = 0.0014). We quantified the total lung metastasis volume in the same cohort of mice. The median metastasis volume was 0.003 mm(3) in Galardin-treated mice compared with 0.56 mm(3) in placebo-treated mice (t test, P < 0.0001). Thus, metastasis burden was reduced more than 100-fold, whereas primary tumor size was reduced only 2-fold. We also found that primary tumors from Galardin-treated mice exhibited a lower histopathologic tumor grade, increased collagen deposition, and increased MMP-2 activity. MMPs are known to have tumor-promoting and tumor-inhibitory effects, and several clinical trials of broad-spectrum MPIs have failed to show promising effects. The very potent antimetastatic effect of Galardin in the MMTV-PymT model does, however, show that it may be possible to find broad-spectrum MPIs with favorable inhibition profiles, or perhaps combinations of monospecific MPIs, for future clinical application.
authors.affiliation: Finsen Laboratory, Rigshospitalet 3735, Copenhagen Biocenter, Ole Maaløes Vej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Almholt
authors.forename: Anna
authors.initials: A
authors.lastname: Juncker-Jensen
authors.forename: Ole Didrik
authors.initials: OD
authors.lastname: Laerum
authors.forename: Keld
authors.initials: K
authors.lastname: Danø
authors.forename: Morten
authors.initials: M
authors.lastname: Johnsen
authors.forename: Leif Røge
authors.initials: LR
authors.lastname: Lund
authors.forename: John
authors.initials: J
authors.lastname: Rømer
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D008207:Lymphatic Metastasis / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D047368:Tumor Burden
chemical_list: D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D003094:Collagen; D020782:Matrix Metalloproteinases