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

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.

• Authors: Dimitra Micha, Jeff Cummings, Alex Shoemaker, Steven Elmore, Kelly Foster, Martin Greaves, Tim Ward, Saul Rosenberg, Caroline Dive, Kathryn Simpson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 22 Pg. 7304-10 (Nov 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 19010845 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABT-737
• Antineoplastic Agents
• Biomarkers, Tumor
• Biphenyl Compounds
• Keratin-18
• Nitrophenols
• Piperazines
• Sulfonamides
• Butylated Hydroxytoluene
• BH 3
• Caspase 3

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects, physiology)
• Biomarkers, Tumor (blood)
• Biomimetic Materials (therapeutic use)
• Biphenyl Compounds (therapeutic use)
• Butylated Hydroxytoluene (analogs & derivatives, chemistry)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunohistochemistry
• Keratin-18 (blood, metabolism)
• Lung Neoplasms (blood, drug therapy)
• Mice
• Nitrophenols (therapeutic use)
• Piperazines (therapeutic use)
• Small Cell Lung Carcinoma (blood, drug therapy)
• Sulfonamides (therapeutic use)
• Xenograft Model Antitumor Assays