Hepatic activation of irinotecan predicts tumour response in patients with colorectal liver metastases treated with DEBIRI: exploratory findings from a ... View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2013-06-12

AUTHORS

R. P. Jones, P. Sutton, R. M. D. Greensmith, A. Santoyo-Castelazo, D. F. Carr, R. Jenkins, C. Rowe, J. Hamlett, B. K. Park, M. Terlizzo, E. O’Grady, P. Ghaneh, S. W. Fenwick, H. Z. Malik, G. J. Poston, N. R. Kitteringham

ABSTRACT

PurposeThe 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).MethodsTen 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.ResultsSerum 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 (r2 = 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 (r2 = 0.54, p = 0.01).ConclusionThis 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. More... »

PAGES

359-368

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00280-013-2199-5

DOI

http://dx.doi.org/10.1007/s00280-013-2199-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1005485939

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23756919


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30 schema:description PurposeThe 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).MethodsTen 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.ResultsSerum 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 (r2 = 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 (r2 = 0.54, p = 0.01).ConclusionThis 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.
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36 schema:keywords CES-2
37 ConclusionThis study
38 DEBIRI
39 II study
40 MethodsTen patients
41 PurposeThe response
42 ResultsSerum concentrations
43 SNPs
44 UGT1A1
45 activation
46 activation of irinotecan
47 approach
48 attempt
49 beads
50 colorectal liver metastases
51 concentration
52 correlation
53 delivery
54 differences
55 drug concentrations
56 drug metabolism
57 enzyme
58 evidence
59 exploratory findings
60 expression
61 fibrosis
62 findings
63 first evidence
64 hepatic activation
65 hepatic expression
66 hepatic metabolism
67 irinotecan
68 irinotecan metabolism
69 irinotecan metabolite
70 liver metastases
71 liver tissue
72 mass spectrometry-based proteomics
73 metabolising enzymes
74 metabolism
75 metabolites
76 metastasis
77 normal liver tissue
78 part
79 pathological response
80 patients
81 phase II study
82 potential predictors
83 predictors
84 proteomics
85 rational approach
86 replacement
87 response
88 serum drug concentrations
89 spectrometry-based proteomics
90 strong correlation
91 study
92 tissue
93 tumor metabolism
94 tumor replacement
95 tumor response
96 tumors
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