We have previously utilized a bank of diverse human colorectal carcinoma cell lines to assess the synergistic antiproliferative effect of tumor necrosis factor (TNF) and IFN‐gamma (IFN‐γ) in combination. In this study, we used 3 of these cell lines (HCT 116, SKCOI and VACO 9P) to study the growth‐inhibitory effects of TNF and IFN‐γ (TNF/IFN‐γ) on these cells when administered in conjunction with 5‐fluorouracil (5‐FU). All 3 cell lines were sensitive to suprapharmacologic concentrations of 5‐FU. However, the 3 lines varied in their sensitivities to clinically achievable concentrations of 5‐FU. Concentrations of 0.1 μg/ml of 5‐FU administered for 96 hr, and 50 μg/ml administered for I hr, inhibited the growth of HCT 116 cells by 20% and 77%, that of SKCOI cells by 25% and 66%, and that of VACO 9P cells by 25% and 55%, respectively. All 3 cell lines were sensitive to the anti‐proliferative effects of TNF/IFN‐γ in a dose‐dependent and duration‐dependent fashion. TNF/IFN‐γ was administered for I hr every other day on days 1, 3 and 5 to the 3 cell lines. Cells were also exposed to 5‐FU, administered either concomitantly for 96 hr, or for I hr on day I. The addition of TNF/IFN‐γ to clinically achievable concentrations of 5‐FU in both schedules resulted in additive cytotoxicity. For example, the addition of 10 ng/ml of both TNF and IFN‐γ to 96 hr of 0.1 μg/ml 5‐FU resulted in 10%, 5%, and 20% of control growth for the HCT 116 cell line, SKCOI cell line, and VACO 9P cell line, respectively. The addition of 10 ng/ml of both TNF and IFN‐γ to I hr of 50 μg/ml of 5‐FU inhibited all cell growth in all 3 cell lines. We conclude that TNF/IFN‐γ and 5‐FU can be combined to achieve higher anti‐tumor activity than either 5‐FU or TNF/IFN‐γ alone in this in vitro model, that the 3‐drug combination has potent growth‐inhibitory effects at pharmacologic concentrations which are not schedule‐dependent, and that this combination warrants further study in clinical trials.
ASJC Scopus subject areas
- Cancer Research