Intravesical recombinant tissue plasminogen activator for the prevention of implantation-mediated bladder tumor recurrence.
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.
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Department of Urology, University of Iowa, Iowa City 52242-1089.
D000283:Administration, Intravesical; D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D008748:Methylcholanthrene; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009366:Neoplasm Seeding; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000517:prevention & control*
D011994:Recombinant Proteins; D008748:Methylcholanthrene; D010959:Tissue Plasminogen Activator