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Mechanism of action: The exact mechanism of antitumor-action of BCG is still unknown, but following hypothesis has been suggested: BCG is internalized within tumor cells through binding with fibronectin on the surface of tumor cells. These tumor cells; which internalize BCG, present antigens of BCG and/or tumor specific antigens to T-lymphocytes directly as antigen presenting cells (APC) or indirectly through macrophages after phagocytosed by macrophages, and thus T-lymphocytes are sensitized to BCG antigens as well as antigens of tumor cell. Cytotoxic T-lymphocytes directly kill target tumor cells. Various cytokines produced by helper T-lymphocytes also have an effect to damage tumor cells. Cytokines of Th1-type activates macrophages to enhance efficient phagocytosis and degradation of tumor cells.
Clinical studies: Efficacy in clinical studies: The summaries as follows show the results of clinical trials conducted at a total of 27 institutions including the University of Tokyo, Japan. (See Table 1.)
Click on icon to see table/diagram/imageAdverse reactions in the clinical trials: The incidence rate of subjective and/or objective symptoms out of evaluated 198 patients (superficial bladder cancer: 154 cases, carcinoma in situ: 44 cases) was 78.3% (155 cases), that of without any symptom was 21.7% (43 cases) in the clinical trials conducted before approval.
The most commonly observed adverse reactions were symptoms of bladder irritation, such as urodynia (57.6%), frequency of urination (56.6%), gross hematuria (29.3%), cloudy urine (21.2%), and dysuria (15.2%). Diminished bladder capacity (18.7%), fever (33.8%), proteinuria (29.8%), occult blood in urine (28.7%), urinary sediment (red blood cell) (38.1%), and urinary sediment (white blood cell) (59.1%) were also commonly observed.
Postmarketing Clinical Study: Clinical study of adjuvant therapy in patients with superficial bladder cancer after transurethral resection of bladder tumor (TURBT).
A randomized comparison study was performed to evaluate the efficacy of Immunobladder as adjuvant therapy after TURBT in patients with superficial bladder cancer (excluding a single primary lesion, or G3). In the study, Immunobladder was administered intravesically to 39 patients at a dose of 80 mg once a week (6 times in total), while doxorubicin hydrochloride was administered intravesically to 40 patients at a dose of 20 mg/40 mL once a week (2 times in total), then once every 2 weeks (7 times in total), and then once a month (8 times in total). In an unscheduled interim analysis, the recurrence-free survival rate was 71.8% (95% CI: 55.1%, 85.0%) for the Immunobladder group and 42.5% (95% CI: 27.0%, 59.1%) for the doxorubicin hydrochloride group (data cutoff date: 31 March 2003). However, since the basis for setting the significance level in the interim analysis is unknown, the analysis results cannot state the statistically significant efficacy of Immunobladder. (See figure.)
Click on icon to see table/diagram/imagePharmacokinetics: BCG seldom attaches to and penetrates through a normal urothelium of bladder wall after intravesical instillation. However, BCG will attach to damaged urotherium of a bladder due to bladder cancer, TUR or traumatic catheterization, be internalized into tumor cells and there grow to some extent, and then be carried to regional lymph-nodes. During these processes, antigenic information of BCG and tumor cell is transferred from phagocytic cells to T-lymphocytes. Thus T-lymphocytes, both CD4+ and CD8+ T-lymphocytes, are sensitized to antigens of tumor cells and those of BCG. Sensitized CD4+ T-lymphocytes secrete various kinds of lymphokines to activate macrophages and thus activated macrophages can kill BCG and also destroy tumor cells. Sensitized CD8+ T-lymphocytes have potentiated cytotoxic activity to kill tumor cells. NK cells are also activated by BCG stimulation and get enhanced activity to kill tumor cells.
