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- W2156128049 endingPage "1944" @default.
- W2156128049 startingPage "1937" @default.
- W2156128049 abstract "Our recent findings in vitro in the human colon adenocar-cinoma cell line HCT-8 suggest that resistance to fluorouracil (5-FU) in patients with advanced colorectal cancer might be overcome by use of a different treatment schedule. We tested the hypothesis that HCT-8 cells resistant to short-term 5-FU exposure retain sensitivity to continuous exposure and studied interactions between the two schedules. Methods: HCT-8 cell lines resistant to short-term (pulse) treatment with 5-FU or to continuous exposure were obtained by six exposures to different concentrations of 5-FU for 4 hours or 7 days. We used a monolayer clonogenic assay to determine 5-FU-induced cell kill in resistant HCT-8 cells and sensitive parent cells. Parent cells were exposed to different concentrations of 5-FU for 1, 4, or 24 hours (short term), for 7 days (continuous exposure), or in a combination of both types of schedules. In astudy of the mechanism of interaction between short-term and continuous exposure in parent cells, we performed flow cytometric DNA analysis to determine the percentage of cells in S phase and assays of thymidylate synthase inhibition in intact cells and of incorporation of [6- 3 H]5-FU nucleotides into nucleic acids. Sensitive HCT-8 cells became fully resistant to 5-FU within five or six treatments, and low-dose continuous exposure almost immediately produced resistant clones. HCT-8 cells resistant to 5-FU given every 4 hours retained full sensitivity to continuous exposure, suggesting lack of cross-resistance between the two schedules, but cells resistant to continuous exposure were cross-resistant to short-term treatment Parent cells showed a statistically significant (synergistic) enhancement of the cytotoxic activity for 5-FU exposure for 1 hour (100,300, or 500 μ M ) followed by continuous exposure (0.5, 1, or 2 μ M ) or 4 hours (10, 30, or 60 μ M ) followed by continuous exposure (1 or 2 μ M ). Short-term plus continuous exposure produced a marked increase in percentage of S-phase cells, compared with the percentage for each schedule alone. The combination of 1-hour exposure and continuous exposure (1000 and 2 μ M , respectively) produced a marked accumulation of cells in S phase at 24 hours (59%), which lasted up to 96 hours (53%). The combination of the two schedules produced only additive enhancement of thymidylate synthase inhibition as well as incorporation of [6- 3 H]5-FU nucleotides into nucleic acids of HCT-8 cells. Our findings provide a rationale for the use of bolus 5-FU and continuous infusion 5-FU in sequence. Implications : We are conducting a clinical trial of bolus methotrexate followed by continuous-infusion 5-FU plus leu-covorin. [J Natl Cancer Inst 85:1937–1944, 1993]" @default.
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- W2156128049 date "1993-12-01" @default.
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- W2156128049 title "Synergism and Lack of Cross-resistance Between Short-term and Continuous Exposure to Fluorouracil in Human Colon Adenocarcinoma Cells" @default.
- W2156128049 doi "https://doi.org/10.1093/jnci/85.23.1937" @default.
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