Anti-proliferative effects of tumor necrosis factor, gamma interferon and 5-fluorouracil on human colorectal carcinoma cell lines.
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-gamma) in combination. In this study, we used 3 of these cell lines (HCT 116, SKO1 and VACO 9P) to study the growth-inhibitory effects of TNF and IFN-gamma (TNF/IFN-gamma) 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 microgram/ml of 5-FU administered for 96 hr, and 50 micrograms/ml administered for 1 hr, inhibited the growth of HCT 116 cells by 20% and 77%, that of SKCO1 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-gamma in a dose-dependent and duration-dependent fashion. TNF/IFN-gamma 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-gamma 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-gamma to 96 hr of 0.1 microgram/ml 5-FU resulted in 10%, 5%, and 20% of control growth for the HCT 116 cell line, SKCO1 cell line, and VACO 9P cell line, respectively. The addition of 10 ng/ml of both TNF and IFN-gamma to 1 hr of 50 micrograms/ml of 5-FU inhibited all cell growth in all 3 cell lines. We conclude that TNF/IFN-gamma and 5-FU can be combined to achieve higher anti-tumor activity than either 5-FU or TNF/IFN-gamma 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.
Schiller
J H
JH
William S. Middleton Memorial Veterans Administration Hospital, Madison, WI 53792.
Bittner
G
G
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D005472:Fluorouracil