ArticleBiochemical pharmacology2011
The synergistic cytotoxicity of clofarabine, fludarabine and busulfan in AML cells involves ATM pathway activation and chromatin remodeling.
Article in Biochemical pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 46 citations in OpenAlex.
- A randomized phase III study of pretransplant conditioning for AML/MDS with fludarabine and once daily IV busulfan ± clofarabine in allogeneic stem cell transplantation.Bone marrow transplantation · 2022Trial
- Population Pharmacokinetics of Clofarabine as Part of Pretransplantation Conditioning in Pediatric Subjects before Hematopoietic Cell Transplantation.Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation · 2019Trial
- Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results.Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation · 2017Trial
- Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2014Trial
- Results from a clofarabine-busulfan-containing, reduced-toxicity conditioning regimen prior to allogeneic stem cell transplantation: the phase 2 prospective CLORIC trial.Haematologica · 2014Trial
- Intravenous BU plus Mel: an effective, chemotherapy-only transplant conditioning regimen in patients with ALL.Bone marrow transplantation · 2013Trial
- Treosulfan or busulfan plus clofarabine as reduced intensity conditioning regimen before allotransplant for adults with myeloid malignancies.Bone marrow transplantation · 2026Article
- Cellular pharmacology of fludarabine: molecular determinants of transport and metabolism.Frontiers in pharmacology · 2026Review
- Effect of clofarabine and fludarabine exposure on outcome after pediatric allogeneic hematopoietic cell transplantation.Blood neoplasia · 2024Article
- Chemotherapy-induced intestinal epithelial damage directly promotes galectin-9-driven modulation of T cell behavior.iScience · 2024Article
- ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells.Oncotarget · 2024Article
- Synergistic cytotoxicity of fludarabine, clofarabine, busulfan, vorinostat and olaparib in AML cells.Frontiers in oncology · 2023Article
- Clofarabine-fludarabine-busulfan in HCT for pediatric leukemia: an effective, low toxicity, TBI-free conditioning regimen.Blood advances · 2022Article
- Recent progress in DNA methyltransferase inhibitors as anticancer agents.Frontiers in pharmacology · 2022Review
- ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells.Oncotarget · 2022Article
- Reduced intensity vs. myeloablative conditioning with fludarabine and PK-guided busulfan in allogeneic stem cell transplantation for patients with AML/MDS.Bone marrow transplantation · 2019Article
- Fludarabine exposure in the conditioning prior to allogeneic hematopoietic cell transplantation predicts outcomes.Blood advances · 2019Article
- Epigenetic modification enhances the cytotoxicity of busulfan and4-hydroperoxycyclophosphamide in AML cells.Experimental hematology · 2018Article
- Long-Term Outcomes after Treatment with Clofarabine ± Fludarabine with Once-Daily Intravenous Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and Myelodysplastic Syndrome.Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation · 2016Article
- Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
DNA alkylating agents alone or with ionizing radiation have been the preferred conditioning treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In search of less toxic alternatives, we hypothesized that combination of busulfan (Bu), fludarabine (Flu) and clofarabine (Clo) would provide superior efficacy. At low concentrations, these drugs show synergistic cytotoxicity in Bu-resistant AML KBM3/Bu250(6) cells. Similar molecular responses were observed in other AML cell lines and in primary explanted AML cells. The [Clo+Flu+Bu] combination activates an intense DNA damage response through the ATM pathway, leading to cell cycle checkpoint activation and apoptosis. Phosphorylations of SMC1 and SMC3, and methylations of histones 3 and 4, are much more pronounced in cells exposed to [Clo+Flu+Bu] than [Clo+Flu], suggesting their relevance in the efficacy of the triple-drug combination. A possible mechanism for these observed synergistic effects involves the capability of [Clo+Flu] to induce histone methylations and subsequent chromatin remodeling, which may render the genomic DNA more accessible to Bu alkylation. The Bu-mediated DNA cross-linking may provide a feedback loop which perpetuates the DNA damage response initiated by [Clo+Flu] and commits the cells to apoptosis. Our results provide a conceptual mechanistic basis for exploring this triple-drug combination in pretransplant conditioning therapy for allo-HSCT.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.