Circulating biomarkers of cell death after treatment with the BH-3 mimetic ABT-737 in a preclinical model of small-cell lung cancer.

2.50
Hdl Handle:
http://hdl.handle.net/10541/56013
Title:
Circulating biomarkers of cell death after treatment with the BH-3 mimetic ABT-737 in a preclinical model of small-cell lung cancer.
Authors:
Micha, Dimitra; Cummings, Jeffrey; Shoemaker, Alex; Elmore, Steven; Foster, Kelly; Greaves, Martin J; Ward, Timothy H; Rosenberg, Saul; Dive, Caroline ( 0000-0002-1726-8850 ) ; Simpson, Kathryn L
Abstract:
PURPOSE: 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.
Affiliation:
Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.
Citation:
Circulating 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.
Journal:
Clinical Cancer Research
Issue Date:
15-Nov-2008
URI:
http://hdl.handle.net/10541/56013
DOI:
10.1158/1078-0432.CCR-08-0111
PubMed ID:
19010845
Type:
Article
Language:
en
ISSN:
1078-0432
Appears in Collections:
All Paterson Institute for Cancer Research; Clinical and Experimental Pharmacology Group

Full metadata record

DC FieldValue Language
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.en
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

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