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?-H2AX foci formation as a pharmacodynamic marker of DNA damage produced by DNA cross-linking agents: results from 2 phase I clinical trials of SJG-136 (SG2000).

ABSTRACT: PURPOSE:To evaluate ?-H2AX foci as a pharmacodynamic marker for DNA damage induced by DNA interstrand cross-linking drugs. EXPERIMENTAL DESIGN:?-H2AX foci formation was validated preclinically in comparison with the Comet assay, and evaluated pharmacodynamically in two phase I studies of different dosing schedules of the novel cross-linking agent SJG-136 (SG2000). RESULTS:The measurement of ?-H2AX foci in human fibroblasts and lymphocytes in vitro was more than 10-fold more sensitive than Comet assay measurement of cross-linking, with peak ?-H2AX response 24 hours after the peak of cross-linking. In lymphocytes from a phase I study (every three week schedule), ?-H2AX foci were detectable 1 hour following the end of administration, and in all patients, maximum response was observed at 24 hours. Significant levels of foci were still evident at days 8 and 15 consistent with the known persistence of the DNA damage produced by this agent. In two tumor biopsy samples, foci were detected 4 hours postinfusion with levels higher than in lymphocytes. Extensive foci formation was also observed before the third dose in cycle 1 in lymphocytes from a second phase I study (daily × 3 schedule). These foci also persisted with a significant level evident before the second cycle (day 21). An increased ?-H2AX response was observed during the second cycle consistent with a cumulative pharmacodynamic effect. No clear relationship between foci formation and administered drug dose was observed. CONCLUSION:This is the first use of ?-H2AX as a pharmacodynamic response to a DNA cross-linking agent in a clinical trial setting.

SUBMITTER: Wu J

PROVIDER: S-EPMC6485439 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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γ-H2AX foci formation as a pharmacodynamic marker of DNA damage produced by DNA cross-linking agents: results from 2 phase I clinical trials of SJG-136 (SG2000).

Wu Jenny J Clingen Peter H PH Spanswick Victoria J VJ Mellinas-Gomez Maria M Meyer Tim T Puzanov Igor I Jodrell Duncan D Hochhauser Daniel D Hartley John A JA

Clinical cancer research : an official journal of the American Association for Cancer Research 20121218 3

<h4>Purpose</h4>To evaluate γ-H2AX foci as a pharmacodynamic marker for DNA damage induced by DNA interstrand cross-linking drugs.<h4>Experimental design</h4>γ-H2AX foci formation was validated preclinically in comparison with the Comet assay, and evaluated pharmacodynamically in two phase I studies of different dosing schedules of the novel cross-linking agent SJG-136 (SG2000).<h4>Results</h4>The measurement of γ-H2AX foci in human fibroblasts and lymphocytes in vitro was more than 10-fold more ...[more]

PMID: 23251007

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Project description:BackgroundIn response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as ?-H2AX. Formation of ?-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand breaks. ?-H2AX expression in peripheral blood mononuclear cells (PBMCs) was recently proposed as a diagnostic and disease activity marker for multiple sclerosis (MS).ObjectiveTo evaluate the significance of ?-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated ?-H2AX and 53BP1 foci detection.MethodsImmunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with ?-H2AX and 53BP1 specific antibodies. Nuclear ?-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of ?-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. ?-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls.ResultsThe median (range) number of ?-H2AX (0.04 [0-0.5]) and 53BP1 (0.005 [0-0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, ?-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. ?-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although ?-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, ?-H2AX values of both groups overlapped and ?-H2AX did not correlate with the number or volume of CEL.Conclusion?-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS.

Dataset Information

?-H2AX foci formation as a pharmacodynamic marker of DNA damage produced by DNA cross-linking agents: results from 2 phase I clinical trials of SJG-136 (SG2000).

Publications

γ-H2AX foci formation as a pharmacodynamic marker of DNA damage produced by DNA cross-linking agents: results from 2 phase I clinical trials of SJG-136 (SG2000).

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