CYTOKINE-MEDIATED ANTITUMOR EFFECT OF BACILLUS-CALMETTE-GUERIN ON TUMOR-CELLS IN-VITRO

Intravesical instillation therapy of bacillus Calmette-Guerin (BCG) is a useful modality for recurrent superficial transitional-cell carcino ma (TCC) of the urinary bladder. The mechanism of BCG effect has not y et been well characterized. BCG was tested in vitro for cytokine-media ted antiproliferative activity against T24 and KK47 cells (cell lines established from human TCC of the urinary bladder), and ACHN cells (ce ll line established from human renal cell carcinoma) using a modified human tumor clonogenic assay. Continuous exposure of cells to BCG at c oncentrations of more than 5 mu g/ml in the presence of peripheral blo od mononuclear cells (PBMC) consisting of a mixture of 5 x 10(4) monoc ytes/dish and 5 x 10(5) lymphocytes/dish, obtained from healthy donors , significantly inhibited colony formation of T24 and ACHN cells in co mparison with growth inhibition in the absence of PBMC (P <0.05). Slig htly inhibited colony formation was observed with KK47 cells under the same conditions. At the same time various cytokines were measured in supernatants when BCG and the same conditioned PBMC were co-cultured. Tumor necrosis factor alpha (TNF alpha) and interleukin-1 beta (IL-1 b eta) were detected at markedly high levels at 24 h, and interferon gam ma (IFN gamma) was detected at 120 h. IL-2 and macrophage-colony-stimu lating factor were not detected. Neutralizing anti-TNF alpha monoclona l antibody significantly reduced the anti-proliferative activity of AC HN cells, and anti-IFN gamma antibody reduced that of T24 cells. The r esults obtained suggest that cytokines mediated by BCG play an importa nt role in the antitumor activity of BCG and that the sensitivity of b ladder cancer cells to the cytokines induced by BCG may differ conside rably.