PURPOSE: To evaluate γ-H2AX foci as a pharmacodynamic marker for DNA damage induced by DNA interstrand cross-linking drugs. EXPERIMENTAL DESIGN: 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). RESULTS: The measurement of γ-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 γ-H2AX response 24 hours after the peak of cross-linking. In lymphocytes from a phase I study (every three week schedule), γ-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 γ-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 γ-H2AX as a pharmacodynamic response to a DNA cross-linking agent in a clinical trial setting.
PURPOSE: To evaluate γ-H2AX foci as a pharmacodynamic marker for DNA damage induced by DNA interstrand cross-linking drugs. EXPERIMENTAL DESIGN: 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). RESULTS: The measurement of γ-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 γ-H2AX response 24 hours after the peak of cross-linking. In lymphocytes from a phase I study (every three week schedule), γ-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 γ-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 γ-H2AX as a pharmacodynamic response to a DNA cross-linking agent in a clinical trial setting.
Authors: Tanveer Ahmad; Isaac K Sundar; Chad A Lerner; Janice Gerloff; Ana M Tormos; Hongwei Yao; Irfan Rahman Journal: FASEB J Date: 2015-03-19 Impact factor: 5.191
Authors: Franziska Graf; Jörg Fahrer; Stephan Maus; Alfred Morgenstern; Frank Bruchertseifer; Senthil Venkatachalam; Christian Fottner; Matthias M Weber; Johannes Huelsenbeck; Mathias Schreckenberger; Bernd Kaina; Matthias Miederer Journal: PLoS One Date: 2014-02-07 Impact factor: 3.240
Authors: Maria Mellinas-Gomez; Victoria J Spanswick; Solange R Paredes-Moscosso; Matthew Robson; R Barbara Pedley; David E Thurston; Stephen J Baines; Anneliese Stell; John A Hartley Journal: BMC Vet Res Date: 2015-08-19 Impact factor: 2.741