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    Optimization of circulating biomarkers of obatoclax-induced cell death in patients with small cell lung cancer.

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    Authors
    Dean, Emma J
    Cummings, Jeffrey
    Roulston, Anne
    Berger, Mark
    Ranson, Malcolm R
    Blackhall, Fiona H
    Dive, Caroline
    Affiliation
    Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
    Issue Date
    2011-04
    
    Metadata
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    Abstract
    Small cell lung cancer (SCLC) is an aggressive disease in which, after initial sensitivity to platinum/etoposide chemotherapy, patients frequently relapse with drug-resistant disease. Deregulation of the Bcl-2 pathway is implicated in the pathogenesis of SCLC, and early phase studies of Bcl-2 inhibitors have been initiated in SCLC. Obatoclax is a small-molecule drug designed to target the antiapoptotic Bcl-2 family members to a proapoptotic effect. Preclinical studies were conducted to clarify the kinetics of obatoclax-induced apoptosis in a panel of SCLC cell lines to assist with the interpretation of biomarker data generated during early phase clinical trials. In vitro, obatoclax was synergistic with cisplatin and etoposide, and "priming" cells with obatoclax before the cytotoxics maximized tumor cell death. Peak levels of apoptosis, reflected by cleaved cytokeratin 18 (CK18) levels (M30 ELISA) and caspase activity (SR-DEVD-FMK), occurred 24 hours after obatoclax treatment. A phase 1b-2 trial of obatoclax administered using two infusion regimens in combination with carboplatin and etoposide has been completed in previously untreated patients with extensive-stage SCLC. Circulating pharmacodynamic biomarkers of cell death, full-length and/or cleaved CK18, and oligonucleosomal DNA were studied in the phase 1b trial. All SCLC patients classified as "responders" after two cycles of treatment showed significantly increased levels of full-length and cleaved CK18 (M65 ELISA) on day 3 of study. However, the preclinical data and the absence of a peak in circulating caspase-cleaved CK18 in trial patients suggest suboptimal timing of blood sampling, which will need refinement in future trials incorporating obatoclax.
    Citation
    Optimization of circulating biomarkers of obatoclax-induced cell death in patients with small cell lung cancer. 2011, 13 (4):339-47 Neoplasia
    Journal
    Neoplasia
    URI
    http://hdl.handle.net/10541/135881
    DOI
    10.1593/neo.101524
    PubMed ID
    21472138
    Type
    Article
    Language
    en
    ISSN
    1476-5586
    ae974a485f413a2113503eed53cd6c53
    10.1593/neo.101524
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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