Anti-proliferative effects of tumor necrosis factor, gamma interferon and 5-fluorouracil on human colorectal carcinoma cell lines

J. H. Schiller, G. Bittner

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

We have previously utilized a bank of diverse human colorectal carcinoma cell lines to assess the synergistic anti-proliferative 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 1 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 1 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 1 hr on day 1. 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 1 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.

Original languageEnglish (US)
Pages (from-to)61-66
Number of pages6
JournalInternational Journal of Cancer
Volume46
Issue number1
DOIs
StatePublished - 1990

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Fluorouracil
Interferon-gamma
Colorectal Neoplasms
Tumor Necrosis Factor-alpha
Cell Line
HCT116 Cells
Growth
Appointments and Schedules
Drug Combinations
Clinical Trials

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Anti-proliferative effects of tumor necrosis factor, gamma interferon and 5-fluorouracil on human colorectal carcinoma cell lines. / Schiller, J. H.; Bittner, G.

In: International Journal of Cancer, Vol. 46, No. 1, 1990, p. 61-66.

Research output: Contribution to journalArticle

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abstract = "We have previously utilized a bank of diverse human colorectal carcinoma cell lines to assess the synergistic anti-proliferative 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 1 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 1 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 1 hr on day 1. 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 1 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.",
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