title: 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.affiliation: Xenova Ltd, 957 Buckingham Avenue, Slough, Berkshire SL1 4NL, UK. sue.harris@slh.celltechgroup.com
authors.forename: S M
authors.initials: SM
authors.lastname: Harris
authors.forename: P
authors.initials: P
authors.lastname: Mistry
authors.forename: C
authors.initials: C
authors.lastname: Freathy
authors.forename: J L
authors.initials: JL
authors.lastname: Brown
authors.forename: P A
authors.initials: PA
authors.lastname: Charlton
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy*; D005472:Fluorouracil / Q000494:pharmacology; D045325:HCT116 Cells / Q000187:drug effects; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D010619:Phenazines / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D010619:Phenazines; C434883:XR5944; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin