Controlling tumor angiogenesis and metastasis of C26 murine colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB-R7785, in two tumor models

Experimental evidence has directly implicated matrix metalloproteinases (MM Ps) in the remodeling of the stromal tissue surrounding tumors. Thus, MMP i nhibitors could limit the expansion of both neoplastic cell compartment and endothelial cell compartment of a tumor. Much of the work on the role of M MP inhibitors has concentrated on their inhibitory effects on tumor cell in vasion. We have examined the effects of a new MMP inhibitor, KB-R7785 (acti ng an MMP-1, MMP-3, and MMP-9), on tumor angiogenesis and metastasis of mur ine colon adenocarcinoma (C-26) in two tumor models in BALB/c mice (transpa rent chamber model and lung: colonization model). KB-R7785 has not shown in hibitory effects on in vitro growth of either C-26 or KOP2.16 murine endoth elial cells. In vivo, KB-R7785 administrated twice daily for 15 days (100 m g/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, co mpared with that in vehicle-administered mice (controls). Tumors grown in c ontrols have doubled their area in 3.3 days, whereas those treated by KB-R7 785 progressed almost four times slower (tumor area doubling time, 12 days) . KB-R7785 rendered centrally avascular tumors with only a rim of periphera l neovasculature, which had significant lower functional vascular density a nd vascular area than the corresponding parameters in control tumors 10 day s after inoculation [79.9 +/- 6.7 cm/cm(2) versus 164.1 +/- 10.1 cm/cm(2) ( 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 ce lls), 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 tum or 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 wi th von Willebrand factor antibody revealed few, if any, positive cells with in the metastatic foci from MMP inhibitor-treated lungs, whereas terminal d eoxynucleotidyl transferase-mediated nick end labeling showed a 4-fold incr ease in the rate of tumor cell apoptosis compared with controls, The fact t hat KB-R7785 interferes with early steps of angiogenesis and cancer spread suggests that MMP inhibitors may control both primary and secondary tumor g rowths by limiting the expansion of endothelial cells, as well as cancer ce lls, composing the tumors.