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Cancer Biomark ; 5(3): 117-25, 2009.
Article in English | MEDLINE | ID: mdl-19407366

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.


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