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.