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dc.contributor.authorMicha, Dimitra
dc.contributor.authorCummings, Jeffrey
dc.contributor.authorShoemaker, Alex
dc.contributor.authorElmore, Steven
dc.contributor.authorFoster, Kelly
dc.contributor.authorGreaves, Martin J
dc.contributor.authorWard, Timothy H
dc.contributor.authorRosenberg, Saul
dc.contributor.authorDive, Caroline
dc.contributor.authorSimpson, Kathryn L
dc.date.accessioned2009-03-17T16:46:51Z
dc.date.available2009-03-17T16:46:51Z
dc.date.issued2008-11-15
dc.identifier.citationCirculating biomarkers of cell death after treatment with the BH-3 mimetic ABT-737 in a preclinical model of small-cell lung cancer. 2008, 14 (22):7304-10 Clin. Cancer Res.en
dc.identifier.issn1078-0432
dc.identifier.pmid19010845
dc.identifier.doi10.1158/1078-0432.CCR-08-0111
dc.identifier.urihttp://hdl.handle.net/10541/56013
dc.description.abstractPURPOSE: This study evaluated epithelial cell death ELISAs that measure circulating cytokeratin 18 in mice bearing small-cell lung cancer xenografts treated with a proapoptotic dose of the BH-3 mimetic ABT-737. EXPERIMENTAL DESIGN: H146 tumor-bearing and non-H146 tumor-bearing severe combined immunodeficient (SCID)/bg mice were treated with ABT-737 or vehicle control. Plasma collected before and 2 to 360 hours after treatment was analyzed by M30 (caspase-cleaved cytokeratin 18) and M65 (intact and cleaved cytokeratin 18) ELISA. In parallel, tumors were interrogated for cleaved caspase-3 and cleaved cytokeratin 18 as biomarkers of apoptosis. RESULTS: ABT-737-treated tumors regressed by 48 hours (P < 0.01) compared with controls, correlating with increased cleaved cytokeratin 18 (P < 0.01; 6 and 24 hours) and increased intact cytokeratin 18 (P < 0.01; 24 hours). Cleaved cytokeratin 18 levels decreased below baseline between 72 and 360 hours for ABT-737-treated and control mice whereas intact cytokeratin 18 decreased below the level of detection at 8 and 15 days in ABT-737-treated mice only. Apoptosis in tumors reflected changes in circulating cytokeratin 18 (cleaved caspase-3, P < 0.05 at 2 hours and P < 0.001 at 6, 12, and 24 hours; caspase-cleaved cytokeratin 18, P < 0.05 at 15 days, for drug treated versus controls). CONCLUSIONS: ABT-737 caused tumor regression by apoptosis in H146 xenografts that mapped to a drug-specific, early increase in circulating cleaved cytokeratin 18 that subsequently declined. Circulating, intact cytokeratin 18 levels correlated with tumor burden. Cleaved caspase-3 and caspase-cleaved cytokeratin 18 in tumor correlated with treatment (P < 0.05, 2 hours; P < 0.001, 6, 12, and 24 hours; cleaved caspase-3, P < 0.05, 15 days; caspase-cleaved cytokeratin 18), indicating that events in plasma were tumor derived. These circulating biomarker data will be translated to clinical trials wherein serial tumor biopsies are rarely obtained.
dc.language.isoenen
dc.subjectSmall-Cell Lung Canceren
dc.subjectPreclinicalen
dc.subjectCell Deathen
dc.subjectBH-3 Mimetic ABT-737en
dc.subjectCell Line, Tumour
dc.subject.meshAnimals
dc.subject.meshAntineoplastic Agents
dc.subject.meshApoptosis
dc.subject.meshBiomimetic Materials
dc.subject.meshBiphenyl Compounds
dc.subject.meshButylated Hydroxytoluene
dc.subject.meshCaspase 3
dc.subject.meshCell Line, Tumor
dc.subject.meshEnzyme-Linked Immunosorbent Assay
dc.subject.meshHumans
dc.subject.meshImmunohistochemistry
dc.subject.meshKeratin-18
dc.subject.meshLung Neoplasms
dc.subject.meshMice
dc.subject.meshNitrophenols
dc.subject.meshPiperazines
dc.subject.meshSmall Cell Lung Carcinoma
dc.subject.meshSulfonamides
dc.subject.meshTumor Markers, Biological
dc.subject.meshXenograft Model Antitumor Assays
dc.titleCirculating biomarkers of cell death after treatment with the BH-3 mimetic ABT-737 in a preclinical model of small-cell lung cancer.en
dc.typeArticleen
dc.contributor.departmentClinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.en
dc.identifier.journalClinical Cancer Researchen
refterms.dateFOA2020-04-20T14:57:16Z
html.description.abstractPURPOSE: This study evaluated epithelial cell death ELISAs that measure circulating cytokeratin 18 in mice bearing small-cell lung cancer xenografts treated with a proapoptotic dose of the BH-3 mimetic ABT-737. EXPERIMENTAL DESIGN: H146 tumor-bearing and non-H146 tumor-bearing severe combined immunodeficient (SCID)/bg mice were treated with ABT-737 or vehicle control. Plasma collected before and 2 to 360 hours after treatment was analyzed by M30 (caspase-cleaved cytokeratin 18) and M65 (intact and cleaved cytokeratin 18) ELISA. In parallel, tumors were interrogated for cleaved caspase-3 and cleaved cytokeratin 18 as biomarkers of apoptosis. RESULTS: ABT-737-treated tumors regressed by 48 hours (P < 0.01) compared with controls, correlating with increased cleaved cytokeratin 18 (P < 0.01; 6 and 24 hours) and increased intact cytokeratin 18 (P < 0.01; 24 hours). Cleaved cytokeratin 18 levels decreased below baseline between 72 and 360 hours for ABT-737-treated and control mice whereas intact cytokeratin 18 decreased below the level of detection at 8 and 15 days in ABT-737-treated mice only. Apoptosis in tumors reflected changes in circulating cytokeratin 18 (cleaved caspase-3, P < 0.05 at 2 hours and P < 0.001 at 6, 12, and 24 hours; caspase-cleaved cytokeratin 18, P < 0.05 at 15 days, for drug treated versus controls). CONCLUSIONS: ABT-737 caused tumor regression by apoptosis in H146 xenografts that mapped to a drug-specific, early increase in circulating cleaved cytokeratin 18 that subsequently declined. Circulating, intact cytokeratin 18 levels correlated with tumor burden. Cleaved caspase-3 and caspase-cleaved cytokeratin 18 in tumor correlated with treatment (P < 0.05, 2 hours; P < 0.001, 6, 12, and 24 hours; cleaved caspase-3, P < 0.05, 15 days; caspase-cleaved cytokeratin 18), indicating that events in plasma were tumor derived. These circulating biomarker data will be translated to clinical trials wherein serial tumor biopsies are rarely obtained.


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