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Monitoring Drug-Induced gamma H2AX as a Pharmacodynamic Biomarker in Individual Circulating Tumor Cells

  1. Author:
    Wang, L. H.
    Pfister, T. D.
    Parchment, R. E.
    Kummar, S.
    Rubinstein, L.
    Evrard, Y. A.
    Gutierrez, M. E.
    Murgo, A. J.
    Tomaszewski, J. E.
    Doroshow, J. H.
    Kinders, R. J.

  2. Author Address

    [Wang, Lihua H.; Pfister, Thomas D.; Parchment, Ralph E.; Kinders, Robert J.] NCI, Lab Human Toxicol & Pharmacol, Frederick, MD 21702 USA. [Evrard, Yvonne A.] NCI, Appl & Dev Res Support Directorate, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Kummar, Shivaani; Gutierrez, Martin E.; Doroshow, James H.] NCI, Med Oncol Branch, Bethesda, MD USA. [Doroshow, James H.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD USA. [Rubinstein, Larry] NCI, Biometr Res Branch, Bethesda, MD USA. [Murgo, Anthony J.; Tomaszewski, Joseph E.; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD USA.;Kinders, RJ, NCI, Lab Human Toxicol & Pharmacol, Bldg 315,Room 6, Frederick, MD 21702 USA.;kindersr@mail.nih.gov
    1. Year: 2010
    2. Date: Feb
  2. Journal: Clinical Cancer Research
    1. 16
    2. 3
    3. Pages: 1073-1084
  4. Type of Article: Article
  5. ISSN: 1078-0432
  1. Abstract:

    Purpose: Circulating tumor cells (CTC) in peripheral blood of patients potentially represent a fraction of solid tumor cells available for more frequent pharmacodynamic assessment of drug action than is possible using tumor biopsy. However, currently available CTC assays are limited to cell membrane antigens. Here, we describe an assay that directly examines changes in levels of the nuclear DNA damage marker gamma H2AX in individual CTCs of patients treated with chemotherapeutic agents. Experimental Design: An Alexa Fluor 488-conjugated monoclonal gamma H2AX antibody and epithelial cancer cell lines treated with topotecan and spiked into whole blood were used to measure DNA damage-dependent nuclear gamma H2AX signals in individual CTCs. Time-course changes in both CTC number and gamma H2AX levels in CTCs were also evaluated in blood samples from patients undergoing treatment. Results: The percentage of gamma H2AX-positive CTCs increased in a concentration-dependent manner in cells treated with therapeutically relevant concentrations of topotecan ex vivo. In samples from five patients, percent gamma H2AX-positive cells increased post-treatment from a mean of 2% at baseline (range, 0-6%) to a mean of 38% (range, 22-64%) after a single day of drug administration; this increase was irrespective of increases or decreases in the total CTC count. Conclusions: These data show promise for monitoring dynamic changes in nuclear biomarkers in CTCs (in addition to CTC count) for rapidly assessing drug activity in clinical trials of molecularly targeted anticancer therapeutics as well as for translational research. Clin Cancer Res; 16(3); 1073-84. (C) 2010 AACR.

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  2. DOI: 10.1158/1078-0432.ccr-09-2799
  3. View record in Web of Science®
  4. WOS: 000278545100032

Library Notes

  1. Fiscal Year: FY2009-2010
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