fibrin and Carcinoma--Transitional-Cell

Baseline cellular plasminogen activator (PA) activity, the cellular proteins responsible for variations in PA activity and the effect of cellular PA activity on cellular adherence to and lysis of fibrin substrate were evaluated in three human transitional carcinoma cell lines. Net PA activity in the cell lines 253J, 639V and 647V was measured using a chromogenic substrate assay. These lines were then analyzed to determine the specific protein(s) responsible for differences in PA activity. mRNA and protein levels of cellular uPA, tPA, PAI1 and PAI2 were measured using Northern blot analysis and ELISA assays. Intact cells were used in an in vitro fibrinolysis assay so as to correlate cell biology with protein and mRNA level observations. Net cellular PA activity in the three cell lines varied over a 20-fold range (253J > 639V > 647V). Net PA activity demonstrated a direct correlation with mRNA transcript and protein levels of uPA/low levels of tPA mRNA were detected in the 253J line. However, tPA protein was not detectable in any of the lines. Both PAI1 and PAI2 were detected in varying amounts in each of the three cell lines. In vitro assays demonstrated a direct correlation between net PA activity and plasminogen dependent fibrin substrate lysis. Cellular adherence to fibrin varied as an inverse function of net PA activity. These findings suggest that variations in cellular uPA levels are principally responsible for variations in PA activity between cell lines. Variations in net PA activity are in turn reflected at the cellular level by differences in ECMP substrate lysis and cellular adherence to fibrin.

Topics: Carcinoma, Transitional Cell; Fibrin; Humans; Plasminogen Activators; RNA, Messenger; Tumor Cells, Cultured

After transurethral resection (TUR) of superficial bladder tumors, intravesical instillations with BCG are successfully used to lower the recurrence rate. The mechanism of the antitumor activity of BCG is not completely understood. After TUR, a fibrin clot is formed on the damaged urothelium. Fibronectin (FN) is part of the clot. It has been demonstrated that binding of BCG to the bladder wall is mediated by FN, and therefore FN seems necessary for the antitumor activity of BCG. This binding can be inhibited by fibrin clot inhibitors, like aspirin and coumarin. A reduced efficacy of BCG in patients with superficial bladder cancer using these drugs has been described. We studied 183 patients with superficial bladder cancer, treated with one or two 6-week courses of intravesical BCG instillations. Of the 42 patients that used fibrin clot inhibitors, 13 (31%) experienced a recurrent tumor, as compared to 56 (40%) of 141 patients who did not use these drugs (p = 0.28). The mean time to recurrence was the same in both groups. These results did not depend on the BCG strain used (Tice or RIVM, p = 0.92) and were not influenced by the use of antibiotics against urinary tract infections. We conclude that in our study fibrin clot inhibitors have no adverse effect on the efficacy of BCG therapy for superficial bladder cancer.

Topics: Administration, Intravesical; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aspirin; BCG Vaccine; Carcinoma in Situ; Carcinoma, Transitional Cell; Coumarins; Dipyridamole; Fibrin; Humans; Male; Random Allocation; Urinary Bladder Neoplasms; Warfarin

Although intravesical bacillus Calmette-Guerin therapy has proved to be efficacious in the treatment and prophylaxis against tumor recurrence of superficial bladder tumors, its mechanism of action has not been fully elucidated. Previous work has suggested that bacillus Calmette-Guerin organisms attach to the matrix protein, fibronectin, during fibrin clot formation at sites of urothelial disruption and that this attachment was required for the antitumor effect of bacillus Calmette-Guerin to be expressed. Furthermore, drugs inhibiting clot formation were found to abrogate the antitumor effect of intravesical bacillus Calmette-Guerin therapy in a murine bladder tumor model. To examine the effect of inhibitors of fibrin clot formation on the results of intravesical bacillus Calmette-Guerin therapy, a retrospective analysis of 149 evaluable patients receiving intravesical bacillus Calmette-Guerin for superficial bladder tumors was performed. The over-all response rate free of tumor for 29 patients who concomitantly received inhibitors of fibrin clot formation with bacillus Calmette-Guerin therapy was 48%, as compared with 67% for 120 patients who were not receiving these medications (p = 0.0655, chi-square). The most striking difference was noted for patients who failed with recurrent superficial disease. Of the patients who received fibrin clot inhibitors during intravesical bacillus Calmette-Guerin therapy 35% had recurrent superficial tumors compared to only 8% of those who did not receive these drugs during a mean followup of 29.8 plus or minus 11 months (p = 0.005, chi-square). Our study suggests that inhibitors of fibrin clot formation may have an adverse influence on the results of intravesical bacillus Calmette-Guerin therapy for superficial bladder tumors.

Topics: Administration, Intravesical; BCG Vaccine; Carcinoma in Situ; Carcinoma, Transitional Cell; Fibrin; Fibronectins; Humans; Neoplasm Recurrence, Local; Platelet Aggregation Inhibitors; Retrospective Studies; Urinary Bladder Neoplasms; Warfarin

Topics: Adult; Aged; Blood Coagulation; Carcinoma, Transitional Cell; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Histocytochemistry; Humans; Male; Middle Aged; Urinary Bladder Neoplasms