Combination of irinotecan (CPT11) and 5-fluorouracil with an analysis of cellular determinants of drug activity

Biochem Pharmacol. 1998 Nov 15;56(10):1315-22. doi: 10.1016/s0006-2952(98)00205-6.

Abstract

We evaluated the combination SN38 (7-ethyl-10-hydroxycamptothecin) -5fluorouracil (5FU) +/- folinic acid (FA) on six human colon cancer cell lines expressing spontaneous sensitivity to both drugs. Tumoral parameters potentially related to drug sensitivity were investigated: topoisomerase I (topo I) cleavable complexes formed with SN38, thymidylate synthase (TS) activity, folylpolyglutamate synthetase activity and dihydropyrimidine dehydrogenase activity. Drugs (SN38 and/or 5FU +/- FA) were applied for 72 hr, either sequentially or together. The concentration ratio between SN38 and 5FU was 100. Cytotoxicity (MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] test), DNA flow cytometry and isobologram analysis (Chou and Talatay) were performed. Based on 5FU IC50 values and isobologram analyses, the most cytotoxic schedule was SN38 followed by 5FU - FA, with high synergistic effects. Flow cytometry indicated that SN38 induced a more or less marked S-G2 block in all cell lines. Sensitivity to SN38, 5FU +/- FA, or combinations were not linked to the potential above-cited tumoral parameters. Interestingly, an inverse correlation was demonstrated between TS activity and topo I cleavable complexes (r2 = 0.78, P = 0.019). These data emphasize the critical importance of the irinotecan-5FU schedule and strongly support this association for the treatment of potentially 5FU-sensitive tumors.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives
  • Colonic Neoplasms / pathology
  • Drug Screening Assays, Antitumor
  • Flow Cytometry
  • Fluorouracil / administration & dosage
  • Humans
  • Irinotecan
  • Tumor Cells, Cultured

Substances

  • Irinotecan
  • Fluorouracil
  • Camptothecin