Effects of isoniazid on the proliferation and cytokine production of bladder cancer cells in vitro induced by bacille Calmette-Guerin

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Abstract
To determine the effects of isoniazid (isonicotinic acid hydrazide), used to reduce the serious side-effects of immunotherapy of superficial bladder cancer with bacille Calmette-Guérin (BCG), on the proliferation and constitutive BCG-induced synthesis of interleukins 6 (IL6) and 8 (IL8) in human bladder cancer cells cultured in vitro. Three poorly differentiated human cell lines, T24, TCC-SUP and BT-B, were used to study the effect of isoniazid on cell proliferation. Cells were inoculated in tissue culture plates and various concentrations of isoniazid added to the medium. Cell density was then monitored for up to 6 days using a colorimetric assay. To determine the effects of isoniazid on constitutive and BCG-induced cytokine synthesis, cells were cultured in medium containing no additions, BCG, isoniazid or BCG with isoniazid, at various concentrations. Samples of medium were collected regularly for 6 h and the cytokine content (IL6 and IL8) determined using enzyme-linked immunosorbent assays. Continuous incubation of proliferating T24, TCC-SUP and BT-B cells with isoniazid at concentrations of 0-100 micrograms/mL did not affect the rate of proliferation. Unlike TCC-SUP and BT-B cells, T24 cells released more IL6 and IL8 during incubation with BCG. At 6 h after the addition of BCG, the cumulative mean (SD) IL6 and IL8 production of T24 cells was 2.6 (0.1) and 2.3 (0.4) ng per 3 x 10(5) cells, compared with a constitutive level of 0.1 (0.0) and 1.3 (0.2) ng, respectively. There was no significant effect of isoniazid (1-100 micrograms/mL) on either the constitutive or BCG-induced synthesis of IL6 and IL8 in T24 cells. Assuming an essential role of (tumour) epithelial cells in the local immune response induced by BCG, these in vitro results suggest that the administration of isoniazid does not interfere with this part of the mechanisms by which BCG operates.

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