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

Abstract

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.

• Authors: S M Harris, P Mistry, C Freathy, J L Brown, P A Charlton
• Journal: British journal of cancer (Br J Cancer) Vol. 92 Issue 4 Pg. 722-8 (Feb 28 2005) ISSN: 0007-0920 [Print] England
• PMID: 15700035 (Publication Type: Journal Article)

Chemical References

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

Topics

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