Effect of clinically modeled regimens on the growth response and development of resistance in human colon carcinoma cell lines

Biochem Pharmacol. 1995 Feb 14;49(4):559-65. doi: 10.1016/0006-2952(94)00445-r.

Abstract

Two human colon cell lines, HCT-8 and HT-29, were exposed to 5-fluorouracil (FUra) under conditions similar to the human plasma pharmacokinetic profile achieved by a single bolus dose or a sustained i.v. infusion. The bolus treatment for 5 days caused a substantial cell kill; however, only a moderate inhibition in cell growth was obtained with sustained exposure to the clinically relevant level of 2 microM. To achieve a cell kill equivalent to the bolus method, a sustained concentration of 10 microM was required. This would constitute a 60% increase in the total area under the curve (AUC) compared with the bolus treatment. After three courses of therapy with each of the schedules, emerging cell lines displayed a similar degree of resistance. HT-29 resistant cell lines returned to the original sensitivity within a few weeks, and most of the enzymes involved in the metabolic activation of FUra returned to their pretreatment activities. However, resistance and enzymatic modifications remained in the HCT-8 line for at least 3 months. In the HCT-8 cell line derived from bolus treatment, resistance was associated with a 50-60% reduction in uridine kinase activity. In the line derived from continuous exposure, there was a 35-40% reduction in uridine kinase in addition to a greater reduction in the activity of orotate phosphoribosyltransferase. These changes in both resistant cell lines resulted in a decreased incorporation of [3H]FUra into nucleic acids and a reduced formation of di- and triphosphate nucleotides of FUra.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Division / drug effects
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / pathology
  • Drug Resistance
  • Fluorouracil / administration & dosage
  • Fluorouracil / pharmacology*
  • Humans
  • Orotate Phosphoribosyltransferase / metabolism
  • Time Factors
  • Tumor Cells, Cultured / drug effects
  • Uridine Kinase / metabolism

Substances

  • Orotate Phosphoribosyltransferase
  • Uridine Kinase
  • Fluorouracil