title: 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.affiliation: Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute and Hospital, Stockholm, Sweden.
authors.forename: M Hägg
authors.initials: MH
authors.lastname: Olofsson
authors.forename: J
authors.initials: J
authors.lastname: Cummings
authors.forename: W
authors.initials: W
authors.lastname: Fayad
authors.forename: S
authors.initials: S
authors.lastname: Brnjic
authors.forename: R
authors.initials: R
authors.lastname: Herrmann
authors.forename: M
authors.initials: M
authors.lastname: Berndtsson
authors.forename: C
authors.initials: C
authors.lastname: Hodgkinson
authors.forename: E
authors.initials: E
authors.lastname: Dean
authors.forename: R
authors.initials: R
authors.lastname: Odedra
authors.forename: R W
authors.initials: RW
authors.lastname: Wilkinson
authors.forename: K E
authors.initials: KE
authors.lastname: Mundt
authors.forename: M
authors.initials: M
authors.lastname: Busk
authors.forename: C
authors.initials: C
authors.lastname: Dive
authors.forename: S
authors.initials: S
authors.lastname: Linder
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000097:blood / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D019073:HT29 Cells; D006258:Head and Neck Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053538:Keratin-18 / Q000032:analysis / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D010446:Peptide Fragments / Q000032:analysis / Q000097:blood; D051381:Rats; D011923:Rats, Nude; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D053538:Keratin-18; D010446:Peptide Fragments; D004317:Doxorubicin; D020169:Caspases