Enhanced Antitumor Effect of Bacillus Calmette-Guérin in Combination with Fibrinogen on Urinary Bladder Tumor

Abstract

Although intravesical instillation of Bacillus Calmette-Guérin (BCG) is an established and effective therapy for superficial urinary bladder tumor (UBT), the current major problems are BCG-resistant UBT and recurrence after BCG therapy. The injection of BCG and fibrinogen could be expected to induce the formation of a fibrin mesh, which would trap BCG and prolong its antitumor action. The present study has been designed to investigate whether fibrinogen has the ability to augment antitumor activity of BCG against UBT. A single injection of BCG/fibrinogen solution into the subcutaneous tissue of C3H/He mice was performed. Histopathological examination revealed prolonged accumulation of BCG and marked infiltration of inflammatory cells at the injected site, as compared with the injection of BCG or fibrinogen alone. When BCG was used in combination with gelatin sponge, prolonged BCG accumulation was also observed, but not many inflammatory cells were induced, as compared with injection of BCG/fibrinogen combination. When BCG/fibrinogen solution was injected into MBT-2 murine UBT transplanted into C3H/He mice, the formation of fibrin fibers, which trap BCG, was induced, and many inflammatory cells around the tumor were seen. A pronounced inhibitory effect on tumor growth and prolonged survival of tumorbearing mice were achieved, as compared with the injection of BCG alone. Dead BCG/fibrinogen solution had a modest inhibitory effect on the tumor growth. This study suggests that combination treatment with BCG and exogenous fibrinogen may prolong accumulation of BCG by trapping BCG in fibrin meshwork, and may induce marked infiltration of inflammatory cells into tumor stroma, causing marked regression of the tumor. The possible clinical implications of the combined use of BCG and fibrinogen are discussed.