Acquired irinotecan resistance is accompanied by stable modifications of cell cycle dynamics independent of MSI status

Int J Oncol. 2013 May;42(5):1644-53. doi: 10.3892/ijo.2013.1868. Epub 2013 Mar 27.


Irinotecan is a major anticancer agent specifically targeting DNA topoisomerase I. Its cytotoxicity is mediated via a two-step process involving accumulation of reversible DNA‑topoisomerase I complexes associated with transient DNA single-strand breaks which subsequently are converted into permanent DNA double-strand breaks by the replication fork during S phase. Irinotecan may be selectively active for treatment of colorectal cancers that show microsatellite instability (MSI) due to deficiencies in mismatch repair enzymes, compared to tumors that are microsatellite stable but show chromosome instability (CIN). Although the clinical activity of irinotecan is principally limited by acquired drug resistance, surprisingly little is known about the influence of prolonged irinotecan exposure on the cell cycle dynamics. We have developed two colon cancer cell lines resistant to SN-38, the active metabolite of irinotecan, one derived from HT-29 (CIN), the other from HCT-116 (MSI). We here show that besides classical resistance mechanisms, SN-38 resistance is accompanied by an increased generation doubling time, a decreased S phase fraction and an increased G2 fraction in vitro as in tumor xenografts for both CIN and MSI models. As a consequence, SN-38-resistant cells and tumors show cross-resistance to the S-phase selective agent 5-fluorouracil. The resistance is accompanied by increased basal levels of γ-H2AX and phospho-Chk2 without notable changes in the levels of phospho-Chk1. Taken together, our results show that prolonged irinotecan exposure is accompanied by stable modifications of cell cycle dynamics which could have profound impact on tumor sensitivity to a wide range of antitumor agents and may influence tumor progression in patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Breaks, Single-Stranded / drug effects
  • DNA Topoisomerases, Type I / drug effects
  • DNA Topoisomerases, Type I / genetics
  • Drug Resistance, Neoplasm / genetics*
  • HCT116 Cells
  • Humans
  • Irinotecan
  • Microsatellite Instability / drug effects
  • S Phase / drug effects
  • S Phase / genetics


  • Antineoplastic Agents
  • Irinotecan
  • DNA Topoisomerases, Type I
  • Camptothecin