Circulating biomarkers of cell death after treatment with the BH-3 mimetic ABT-737 in a preclinical model of small-cell lung cancer.
dc.contributor.author | Micha, Dimitra | |
dc.contributor.author | Cummings, Jeffrey | |
dc.contributor.author | Shoemaker, Alex | |
dc.contributor.author | Elmore, Steven | |
dc.contributor.author | Foster, Kelly | |
dc.contributor.author | Greaves, Martin J | |
dc.contributor.author | Ward, Timothy H | |
dc.contributor.author | Rosenberg, Saul | |
dc.contributor.author | Dive, Caroline | |
dc.contributor.author | Simpson, Kathryn L | |
dc.date.accessioned | 2009-03-17T16:46:51Z | |
dc.date.available | 2009-03-17T16:46:51Z | |
dc.date.issued | 2008-11-15 | |
dc.identifier.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. | en |
dc.identifier.issn | 1078-0432 | |
dc.identifier.pmid | 19010845 | |
dc.identifier.doi | 10.1158/1078-0432.CCR-08-0111 | |
dc.identifier.uri | http://hdl.handle.net/10541/56013 | |
dc.description.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. | |
dc.language.iso | en | en |
dc.subject | Small-Cell Lung Cancer | en |
dc.subject | Preclinical | en |
dc.subject | Cell Death | en |
dc.subject | BH-3 Mimetic ABT-737 | en |
dc.subject | Cell Line, Tumour | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Antineoplastic Agents | |
dc.subject.mesh | Apoptosis | |
dc.subject.mesh | Biomimetic Materials | |
dc.subject.mesh | Biphenyl Compounds | |
dc.subject.mesh | Butylated Hydroxytoluene | |
dc.subject.mesh | Caspase 3 | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Enzyme-Linked Immunosorbent Assay | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Immunohistochemistry | |
dc.subject.mesh | Keratin-18 | |
dc.subject.mesh | Lung Neoplasms | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Nitrophenols | |
dc.subject.mesh | Piperazines | |
dc.subject.mesh | Small Cell Lung Carcinoma | |
dc.subject.mesh | Sulfonamides | |
dc.subject.mesh | Tumor Markers, Biological | |
dc.subject.mesh | Xenograft Model Antitumor Assays | |
dc.title | Circulating biomarkers of cell death after treatment with the BH-3 mimetic ABT-737 in a preclinical model of small-cell lung cancer. | en |
dc.type | Article | en |
dc.contributor.department | Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom. | en |
dc.identifier.journal | Clinical Cancer Research | en |
refterms.dateFOA | 2020-04-20T14:57:16Z | |
html.description.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. |