ArticleClinical cancer research : an official journal of the American Association for Cancer Research2013
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).
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma.Leukemia · 2022Trial
- Deficiencies in the Fanconi anemia or homologous recombination pathway enhance the antitumor effects of the hypoxia-activated prodrug CP-506.Molecular therapy. Oncology · 2026Article
- Tumor-intrinsic and immune-related features associated with treatment failure in human papillomavirus-related oropharyngeal cancer.Journal of the National Cancer Institute · 2025Article
- Association of oropharyngeal cancer recurrence with tumor-intrinsic and immune-mediated sequelae of reduced genomic instability.bioRxiv : the preprint server for biology · 2024Article
- TRIM17-mediated ubiquitination and degradation of RBM38 promotes cisplatin resistance in non-small cell lung cancer.Cellular oncology (Dordrecht, Netherlands) · 2023Article
- Investigating the Functional Roles of Aldehyde Dehydrogenase 3A1 in Human Corneal Epithelial Cells.International journal of molecular sciences · 2023Article
- Celastrol-induced degradation of FANCD2 sensitizes pediatric high-grade gliomas to the DNA-crosslinking agent carboplatin.EBioMedicine · 2019Article
- DNA damage in human whole blood caused by radiopharmaceuticals evaluated by the comet assay.Mutagenesis · 2019Article
- Novel pathway of 3-hydroxyanthranilic acid formation in limazepine biosynthesis reveals evolutionary relation between phenazines and pyrrolobenzodiazepines.Scientific reports · 2018Article
- A statistical framework for radiation dose estimation with uncertainty quantification from the γ-H2AX assay.PloS one · 2018Article
- Advances in the drug therapies of acute myeloid leukemia (except acute wpromyelocytic leukemia).Drug design, development and therapy · 2018Review
- Enabling the controlled assembly of antibody conjugates with a loading of two modules without antibody engineering.Chemical science · 2017Article
- From Anthramycin to Pyrrolobenzodiazepine (PBD)-Containing Antibody-Drug Conjugates (ADCs).Angewandte Chemie (International ed. in English) · 2017Review
- Carcinogenicity of chromium and chemoprevention: a brief update.OncoTargets and therapy · 2017Review
- BO-1055, a novel DNA cross-linking agent with remarkable low myelotoxicity shows potent activity in sarcoma models.Oncotarget · 2016Article
- A potential role for protein palmitoylation and zDHHC16 in DNA damage response.BMC molecular biology · 2016Article
- Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients.EMBO molecular medicine · 2016Article
- The dynamic behavior of Ect2 in response to DNA damage.Scientific reports · 2016Article
- Characterization of Interstrand DNA-DNA Cross-Links Using the α-Hemolysin Protein Nanopore.ACS nano · 2015Article
- Absolute quantification of acetylation and phosphorylation of the histone variant H2AX upon ionizing radiation reveals distinct cellular responses in two cancer cell lines.Radiation and environmental biophysics · 2015Article
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
purposeTo evaluate γ-H2AX foci as a pharmacodynamic marker for DNA damage induced by DNA interstrand cross-linking drugs. EXPERIMENTAL
designγ-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).
resultsThe 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.
conclusionThis is the first use of γ-H2AX as a pharmacodynamic response to a DNA cross-linking agent in a clinical trial setting.
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