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dc.contributor.authorBaricevic, Ivona
dc.contributor.authorJones, David R
dc.contributor.authorRoberts, Darren L
dc.contributor.authorLutzen, A
dc.contributor.authorLundby, A
dc.contributor.authorWorm, J
dc.contributor.authorHansen, B
dc.contributor.authorRenehan, Andrew G
dc.date.accessioned2015-07-01T07:50:20Zen
dc.date.available2015-07-01T07:50:20Zen
dc.date.issued2015-05-30en
dc.identifier.citationA framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues. 2015: Carcinogenesisen
dc.identifier.issn1460-2180en
dc.identifier.pmid26026165en
dc.identifier.doi10.1093/carcin/bgv071en
dc.identifier.urihttp://hdl.handle.net/10541/558712en
dc.description.abstractEpidemiological and laboratory studies raised the possibility of a link between clinically prescribed insulin analogues and increased cancer risk. Accordingly, there is a regulatory mandate for cancer-related pre-clinical safety evaluation during insulin analogue development, but currently, there is no standardised framework for such in vitro evaluation. We tested human insulin; the super-mitogenic insulin, X10; and IGF-I, in four cancer cell lines with a range of IGF-IR/IR ratios (HCT 116, HT-29, COLO 205, MCF7), and related these to IGF-IR and IR expression in 17 human adenocarcinomas. All cell types were IRA isoform dominant. We determined IGF-IR/IR signalling pathway endpoints in dose- and time-varying experiments, and performed mitogenic dose-response equivalent assays to derive EC50 values, and correlated these with IGF-IR/IR ratios. We superimposed relative EC50 values onto data from the literature in a meta-analysis. The IGF-IR/IR ratios varied from < 1 to 12 in the selected cell lines; similar pattern ranges were observed in human adenocarcinomas. The three ligands demonstrated differential IR/IGF-IR and Akt phosphorylation, which correlated with cell-specific IGF-IR/IR ratios. Mitogenic profiles of X10 mimicked those for IGF-I, and correlated with IGF-IR/IR ratios. The meta-analysis, adding data from 5 additional studies, supported the hypothesis that ligand mitogenic potency, relative to human insulin, increases with increasing cell-specific IGF-IR/IR ratio. This study established a framework for the in vitro evaluation of cancer-relevant bio-assays for comparisons of insulin analogues, and specifically consolidated earlier studies that determination of the cell-specific IGF-IR/IR ratio is crucial for the interpretation of ranking relative biological activities.
dc.languageENGen
dc.language.isoenen
dc.rightsArchived with thanks to Carcinogenesisen
dc.titleA framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues.en
dc.typeArticleen
dc.contributor.departmentInstitute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UKen
dc.identifier.journalCarcinogenesisen
html.description.abstractEpidemiological and laboratory studies raised the possibility of a link between clinically prescribed insulin analogues and increased cancer risk. Accordingly, there is a regulatory mandate for cancer-related pre-clinical safety evaluation during insulin analogue development, but currently, there is no standardised framework for such in vitro evaluation. We tested human insulin; the super-mitogenic insulin, X10; and IGF-I, in four cancer cell lines with a range of IGF-IR/IR ratios (HCT 116, HT-29, COLO 205, MCF7), and related these to IGF-IR and IR expression in 17 human adenocarcinomas. All cell types were IRA isoform dominant. We determined IGF-IR/IR signalling pathway endpoints in dose- and time-varying experiments, and performed mitogenic dose-response equivalent assays to derive EC50 values, and correlated these with IGF-IR/IR ratios. We superimposed relative EC50 values onto data from the literature in a meta-analysis. The IGF-IR/IR ratios varied from < 1 to 12 in the selected cell lines; similar pattern ranges were observed in human adenocarcinomas. The three ligands demonstrated differential IR/IGF-IR and Akt phosphorylation, which correlated with cell-specific IGF-IR/IR ratios. Mitogenic profiles of X10 mimicked those for IGF-I, and correlated with IGF-IR/IR ratios. The meta-analysis, adding data from 5 additional studies, supported the hypothesis that ligand mitogenic potency, relative to human insulin, increases with increasing cell-specific IGF-IR/IR ratio. This study established a framework for the in vitro evaluation of cancer-relevant bio-assays for comparisons of insulin analogues, and specifically consolidated earlier studies that determination of the cell-specific IGF-IR/IR ratio is crucial for the interpretation of ranking relative biological activities.


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