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Modulation of Fibronectin-mediated Bacillus Calmette-Guérin Attachment to Murine Bladder Mucosa by Drugs Influencing the Coagulation Pathways¹

Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030 [M. A. H.], and Division of Urological Surgery, Departments of Medicine, Microbiology and Immunology, Washington University School of Medicine and the Jewish Hospital of St. Louis, St. Louis, Missouri 63110 [E. J. B., J. K. R., T. L. R.]

Adjuvant intravesical Bacillus Calmette-Guérin (BCG) has proved to be an effective treatment for superficial bladder cancer. Intraluminal attachment of BCG organisms via binding to the extracellular matrix protein, fibronectin (FN), appears to be required for expression of the antitumor efficacy of BCG against a murine bladder tumor. Initial studies demonstrated that radiolabeled FN localized to the acutely injured urothelium but not to intact urothelium. These studies also demonstrated that exogenous administration of FN enhanced BCG attachment to the injured but not to the intact urothelium. Because FN has been shown to be an integral part of clot formation at sites of urothelial injury, drugs known to affect fibrin clot formation were tested for their effects on BCG attachment and antitumor efficacy in a murine bladder tumor model. A stabilizer of fibrin clot formation was shown to enhance both BCG attachment and antitumor efficacy in the same model. An increased number of BCG organisms were also retained in the lymph nodes and spleens of mice receiving fibrin clot stabilizers, suggesting indirectly that immunological mechanisms are involved in the antitumor efficacy of BCG.

The data presented herein provide further support for the hypothesis that BCG attachment to the injured bladder is mediated by FN. Furthermore, modulation of BCG-FN attachment is demonstrated to be possible with drugs influencing the coagulation pathway. This attachment is shown to be required for the antitumor efficacy in a murine bladder tumor model, and thus modulation of BCG-FN attachment appears to have significant influence on the antitumor efficacy of BCG in the murine bladder tumor model.

¹ This work was supported by USPHS Grants CA37926-04, CA42487001, and CA44426-01 from the National Cancer Institute. M. A. H. was a recipient of an American Foundation for Urological Disease Scholarship, July 1988–June 1990.

² To whom requests for reprints should be addressed, at the Scott Department of Urology, Baylor College of Medicine, 6624 Fannin, Suite 1280, Houston, TX 77030.

Received 1/ 9/91. Accepted 5/ 7/91.