title: Hepatic activation of irinotecan predicts tumour response in patients with colorectal liver metastases treated with DEBIRI: exploratory findings from a phase II study.
abstract: OBJECTIVE
  The response of colorectal liver metastases to the cytotoxic agent irinotecan varies widely. Attempts to correlate tumour metabolism with response have been mixed. This study investigated the hepatic metabolism of irinotecan as a potential predictor of tumour response to irinotecan-eluting beads (DEBIRI).
  
  
  METHODS
  Ten patients with colorectal liver metastases were treated with 200 mg irinotecan (as DEBIRI) as part of the PARAGON II study. Hepatic expression of key metabolising enzymes was measured using mass spectrometry-based proteomics. Serum drug concentrations and hepatic irinotecan metabolism were characterised and correlated with tumour response.
  
  
  RESULTS
  Serum concentrations of irinotecan metabolites did not correlate with hepatic metabolism or pathological response. There was a strong correlation between hepatic CES-2 expression and activation of irinotecan (r (2) = 0.96, p < 0.001). Patients with a UGT1A1*28 6/7 SNP showed no difference in drug metabolism or pathological response. Hepatic CES-2 mediated activation of irinotecan clearly correlated with tumour replacement by fibrosis (r (2) = 0.54, p = 0.01).
  
  
  CONCLUSIONS
  This study provides the first evidence that hepatic activation of irinotecan predicts tumour response. Delivery of liver-targeted irinotecan to normal liver tissue rather than tumour may be a more rational approach to maximise response.
authors.affiliation: School of Cancer Studies, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. robjones@liv.ac.uk
authors.forename: R P
authors.initials: RP
authors.lastname: Jones
authors.forename: P
authors.initials: P
authors.lastname: Sutton
authors.forename: R M D
authors.initials: RM
authors.lastname: Greensmith
authors.forename: A
authors.initials: A
authors.lastname: Santoyo-Castelazo
authors.forename: D F
authors.initials: DF
authors.lastname: Carr
authors.forename: R
authors.initials: R
authors.lastname: Jenkins
authors.forename: C
authors.initials: C
authors.lastname: Rowe
authors.forename: J
authors.initials: J
authors.lastname: Hamlett
authors.forename: B K
authors.initials: BK
authors.lastname: Park
authors.forename: M
authors.initials: M
authors.lastname: Terlizzo
authors.forename: E
authors.initials: E
authors.lastname: O'Grady
authors.forename: P
authors.initials: P
authors.lastname: Ghaneh
authors.forename: S W
authors.initials: SW
authors.lastname: Fenwick
authors.forename: H Z
authors.initials: HZ
authors.lastname: Malik
authors.forename: G J
authors.initials: GJ
authors.lastname: Poston
authors.forename: N R
authors.initials: NR
authors.lastname: Kitteringham
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use*; D001711:Biotransformation; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000556:secondary* / Q000601:surgery; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D016503:Drug Delivery Systems; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology*; D013058:Mass Spectrometry; D008861:Microsomes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011446:Prospective Studies; D015203:Reproducibility of Results; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D004273:DNA, Neoplasm; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D009363:Neoplasm Proteins; D000099148:UGT1A1 Enzyme