Experimental evidence has directly implicated
matrix metalloproteinases (
MMPs) in the remodeling of the stromal tissue surrounding
tumors. Thus,
MMP inhibitors could limit the expansion of both neoplastic cell compartment and endothelial cell compartment of a
tumor. Much of the work on the role of
MMP inhibitors has concentrated on their inhibitory effects on
tumor cell invasion. We have examined the effects of a new
MMP inhibitor,
KB-R7785 (acting on
MMP-1,
MMP-3, and
MMP-9), on
tumor angiogenesis and
metastasis of murine
colon adenocarcinoma (C-26) in two
tumor models in BALB/c mice (transparent chamber model and lung colonization model).
KB-R7785 has not shown inhibitory effects on in vitro growth of either C-26 or KOP2.16 murine endothelial cells. In vivo,
KB-R7785 administrated twice daily for 15 days (100 mg/kg, i.p.), starting the day of
tumor inoculation (5 x 10(5) C26 cells) in transparent chamber, has resulted in 88.2% suppression of
tumor growth, compared with that in vehicle-administered mice (controls).
Tumors grown in controls have doubled their area in 3.3 days, whereas those treated by
KB-R7785 progressed almost four times slower (
tumor area doubling time, 12 days).
KB-R7785 rendered centrally avascular
tumors with only a rim of peripheral neovasculature, which had significant lower functional vascular density and vascular area than the corresponding parameters in control
tumors 10 days after inoculation [79.9+/-6.7 cm/cm2 versus 164.1+/-10.1 cm/cm2 (P < 0.01) and 19.8+/-1.5% versus 42.6+/-2.7% (P < 0.01), respectively]. In the lung colonization model (tail vein inoculation of 5 x 10(5) C-26 cells), administration of
KB-R7785 (100 mg/kg, i.p.) twice daily for 20 days has reduced the number of surface
metastasis by 85.8% and abolished the
tumor burden, as compared with controls. The few metastatic colonies found in the lungs of
KB-R7785 treated mice appeared to be dormant (i.e., staining with
von Willebrand factor antibody revealed few, if any, positive cells within the metastatic foci from
MMP inhibitor-treated lungs, whereas
terminal deoxynucleotidyl transferase-mediated nick end labeling showed a 4-fold increase in the rate of
tumor cell apoptosis compared with controls. The fact that
KB-R7785 interferes with early steps of angiogenesis and
cancer spread suggests that
MMP inhibitors may control both primary and secondary
tumor growths by limiting the expansion of endothelial cells, as well as
cancer cells, composing the
tumors.