Circulating Biomarkers of Cell Death After Treatment with the BH-3 Mimetic ABT-737 in a Preclinical Model of Small-Cell Lung Cancer

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 P P P P P 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 P P