Antitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines

Br J Cancer. 2005 Feb 28;92(4):722-8. doi: 10.1038/sj.bjc.6602403.


XR5944 (MLN944), a novel bis-phenazine, has demonstrated potent cytotoxic activity against a variety of murine and human tumour models. In the present study, the antitumour activity of XR5944 was investigated in combination with 5-fluorouracil (5-FU) or irinotecan in human colon carcinoma cell lines and xenografts. In vitro cytotoxicity of the combinations following exposure to the drugs sequentially or simultaneously was evaluated by the sulphorhodamine-B assay and interactions were determined using median-effect analysis. Antagonism was observed (CI >1) following exposure of HT29 cells simultaneously to XR5944 and 5-FU or SN38 (active metabolite of irinotecan). In contrast, sequential exposure of either combination in either order demonstrated at least an additive response (CI< or =1). At least an additive response was also observed with these combinations in HCT116 cells regardless of schedule. Antitumour activity in HT29 xenografts in nude mice was enhanced by sequential administration of 5-FU (65 mg kg(-1)) or irinotecan (CPT-11) (35 mg kg(-1)) 48 h before XR5944 (5, 10, or 15 mg kg(-1)) compared to single agent treatment at the same or higher doses. Administration of irinotecan (35 mg kg(-1)) and XR5944 (15 mg kg(-1)) just 30 min apart yielded similar efficacy to sequential administration 48 h apart. All combinations were well tolerated. These data suggest that combinations of XR5944 with irinotecan or 5-FU are of significant interest in the treatment of colon cancer.

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Colonic Neoplasms / drug therapy*
  • Fluorouracil / pharmacology
  • HCT116 Cells / drug effects
  • HT29 Cells / drug effects
  • Humans
  • Irinotecan
  • Mice
  • Mice, Nude
  • Phenazines / pharmacology*
  • Transplantation, Heterologous


  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents, Phytogenic
  • Phenazines
  • XR5944
  • Irinotecan
  • Fluorouracil
  • Camptothecin