Cj. Ren et al., IRSOGLADINE MALEATE INHIBITS ANGIOGENESIS IN WILD-TYPE AND PLASMINOGEN ACTIVATOR-DEFICIENT MICE, The Journal of surgical research (Print), 77(2), 1998, pp. 126-131
Background. The activation of the zymogen plasminogen to the serine pr
otease plasmin by urokinase-type (uPA) and tissue-type (tPA) plasminog
en activators (PA) is an important event in a variety of physiologic a
nd pathophysiologic processes in mammals. Enhanced PA activity occurs
during angiogenesis and has been correlated in vitro and in vivo with
increased tumor aggressiveness and is an indicator of poor prognosis i
n a variety of tumors in humans. Preliminary studies suggest that the
antiulcer drug irsogladine maleate (IM) diminishes PA activity in vitr
o and may inhibit angiogenesis in vivo. To define the precise mechanis
m of angiogenesis inhibition by IRI in vivo we tested the ability of I
RI to blunt angiogenesis in a mouse cornea neovascularization model pe
rformed in wild-type and PA-knockout mice. Methods. Three days prior t
o pellet implantation, groups of C57Bl/6 wild-type, uPA-deficient (upA
-/-), and tPA-deficient (tPA-/-) mice received IR I (300 mg/kg), IM (5
00 mg/kg), or vehicle (0.5% carboxymethylcellulose) via oral gavage, A
fter 3 days of treatment, hydron polymer-coated pellets of sucrose alu
minum sulfate containing 100 ng of basic fibroblast growth factor (bFG
F) were inserted into surgically created pockets in the cornea of each
mouse. On postoperative day 6, the neovascularization of each cornea
was evaluated by a blinded observer using slit lamp microscopy and pho
tographed. Angiogenesis was quantified by calculating vascular area (m
m(2)) +/- SEM using a modified formula for a half ellipse that incorpo
rates calibrated vessel measurements [Vessel length (mm) x Clock hours
x pi x 0.2]. Results. IM treatment (300 and 500 mg/kg/day) resulted i
n a dose-dependent reduction of angiogenesis in wild-type mice by 21 a
nd 45.3% (P < 0.02, P < 0.001), in tPA-deficient mice by 42.6 and 46%
(P < 0.001, P < 0.001), and in uPA-deficient mice by 27.2 and 46% (P <
0.05, p < 0.001), respectively. No quantitative differences in neovas
cularization were observed in either treatment group between transgeni
c mouse strains. No toxicity was noted in any group. Conclusion. IM in
hibits bFGF-induced angiogenesis in wild-type, tPA-knockout, and uPA-k
nockout mice. The observation that IM significantly diminishes angioge
nesis in both PA-deficient mice and wild-type mice suggests that the m
echanism of action of IM may be independent of plasminogen activation.
(C) 1998 Academic Press.