Specific demonstration of drug-induced tumour cell apoptosis in human xenografts models using a plasma biomarker.

Abstract

Pharmacodynamic (PD) assays should be used before advancing new drugs to clinical trials. Most PD assays measure the response to drugs in tissue, a procedure which requires tissue biopsies. The M30-Apoptosense ELISA is a PD biomarker assay for the quantitative determination of caspase-cleaved cytokeratin 18 (CK18) released from apoptotic carcinoma cells into blood. We here demonstrate that whereas the M30-Apoptosense ELISA assay detects human caspase-cleaved CK18, the mouse and rat CK18 caspase cleavage products are detected with low affinity. The M30-Apoptosense ELISA therefore facilitates the determination of drug-induced apoptosis in human tumour xenografts in rodents using plasma samples, largely independently from host toxicity. Increases of caspase-cleaved CK18 were observed in plasma from different carcinoma xenograft models in response to anticancer drugs. The appearance caspase-cleaved CK18 in plasma was found to reflect formation of the caspase-cleaved epitope in FaDu head-neck carcinomas and in cultured cells. The M30-Apoptosense assay allows determination of tumour response in blood from xenograft models and from patients, providing a powerful tool for translational studies of anticancer drugs.

• Authors: M Hägg Olofsson, J Cummings, W Fayad, S Brnjic, R Herrmann, M Berndtsson, C Hodgkinson, E Dean, R Odedra, R W Wilkinson, K E Mundt, M Busk, C Dive, S Linder
• Journal: Cancer biomarkers : section A of Disease markers (Cancer Biomark) Vol. 5 Issue 3 Pg. 117-25 ( 2009) ISSN: 1574-0153 [Print] Netherlands
• PMID: 19407366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Keratin-18
• Peptide Fragments
• Doxorubicin
• Caspases

Topics

• Amino Acid Sequence
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Biomarkers, Tumor (analysis, blood, metabolism)
• Caspases (metabolism)
• Cell Line, Tumor
• Colonic Neoplasms (blood, drug therapy, pathology)
• Doxorubicin (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• HT29 Cells
• Head and Neck Neoplasms (blood, drug therapy, pathology)
• Humans
• Immunohistochemistry
• Keratin-18 (analysis, blood, metabolism)
• Male
• Mice
• Mice, SCID
• Neoplasms, Experimental (blood, drug therapy, pathology)
• Peptide Fragments (analysis, blood)
• Rats
• Rats, Nude
• Xenograft Model Antitumor Assays (methods)