The mechanism by which intravesical recombinant
tissue plasminogen activator (rTPA) prevents
tumor cell adherence to injured bladder surfaces, and the optimal parameters for the in vivo use of rTPA for adherence prevention, were evaluated. Intravesical rTPA decreased
tumor cell adherence to sites of urothelial injury as a direct function of
drug concentration in the intravesical fluid. Recombinant TPA concentrations of 1 mg/ml and 0.1 mg/ml significantly decreased
tumor cell adherence relative to the control group. The efficacy of rTPA in removing adherent cells was time-dependent with maximal activity occurring at 15 min or later following
intravesical administration. Intravesical rTPA effectively reduced the size of the
tumor inoculum when administered either concomitant with, or subsequent to,
tumor cell exposure. The relative efficacy of these two approaches was dependent upon the presence of serum in the intravesical fluid. Administration of rTPA concomitant with
tumor cell exposure proved more effective in the absence of serum, while postadherence administration was more effective in the presence of 10%
fetal calf serum. The addition of exogenous
plasminogen to the rTPA
solution did not increase anti-adherence activity relative to rTPA alone. However, blockade of endogenous
plasminogen conversion with systemically administered epsilon-amino-
caproic acid reversed the anti-adherence activity of exogenous rTPA. In vitro experiments evaluating cellular adherence to
fibrin substrate confirmed that rTPA's anti-adherence activity was dependent on the presence of
plasminogen. Exogenous rTPA administered immediately following
tumor cell adherence decreased
tumor cell implantation in animals receiving low to moderate
tumor inoculums. These data suggest that rTPA prevents cellular adherence as a result of
plasminogen activation and subsequent fibrinolysis. Intravesical rTPA administered in sufficient concentration for relatively short periods of time effectively reduces the adherent
tumor inoculum and alters implantation as an inverse function of the
tumor inoculum. This approach represents a novel strategy which may prove applicable for the prevention of implantation-mediated
tumor recurrence at sites of surgical
trauma.