The Combination of the PARP Inhibitor Rucaparib and 5FU Is an Effective Strategy for Treating Acute Leukemias
| Autor: | Giovanni Martinelli, Andrea Ghelli Luserna di Rorà, Klaus-Michael Debatin, Francesco Bertolini, Chiara Ronchini, Lüder Hinrich Meyer, P G Pelicci, Mario Faretta, Ilaria Iacobucci, Stefania Orecchioni, Maria Vittoria Verga Falzacappa |
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| Přispěvatelé: | Falzacappa, Maria Vittoria Verga, Ronchini, Chiara, Faretta, Mario, Iacobucci, Ilaria, Ghelli Luserna Di Rorà, Andrea, Martinelli, Giovanni, Meyer, Lüder Hinrich, Debatin, Klaus-Michael, Orecchioni, Stefania, Bertolini, Francesco, Pelicci, Pier Giuseppe |
| Rok vydání: | 2015 |
| Předmět: |
DNA Replication
Male Antimetabolites Antineoplastic Cancer Research Xenograft Model Antitumor Assay Indoles DNA Repair Cell Survival DNA repair DNA damage Poly ADP ribose polymerase Apoptosis Poly(ADP-ribose) Polymerase Inhibitors Pharmacology Poly(ADP-ribose) Polymerase Inhibitor Mice chemistry.chemical_compound Cell Line Tumor Animals Humans Medicine Neoplasm Rucaparib Leukemia Animal business.industry Medicine (all) Apoptosi Myeloid leukemia Drug Synergism medicine.disease Xenograft Model Antitumor Assays Disease Models Animal Oncology chemistry Indole Drug Resistance Neoplasm PARP inhibitor Female Fluorouracil business Human DNA Damage |
| Zdroj: | Molecular Cancer Therapeutics. 14:889-898 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-14-0276 |
| Popis: | The existing treatments to cure acute leukemias seem to be nonspecific and suboptimal for most patients, drawing attention to the need of new therapeutic strategies. In the last decade the anticancer potential of poly ADP-ribose polymerase (PARP) inhibitors became apparent and now several PARP inhibitors are being developed to treat various malignancies. So far, the usage of PARP inhibitors has been mainly focused on the treatment of solid tumors and not too much about their efficacy on leukemias is known. In this study we test, for the first time on leukemic cells, a combined therapy that associates the conventional chemotherapeutic agent fluorouracil (5FU), used as a source of DNA damage, and a PARP inhibitor, rucaparib. We demonstrate the efficacy and the specificity of this combined therapy in killing both acute myeloid leukemia and acute lymphoid leukemia cells in vitro and in vivo. We clearly show that the inhibition of DNA repair induced by rucaparib is synthetic lethal with the DNA damage caused by 5FU in leukemic cells. Therefore, we propose a new therapeutic strategy able to enhance the cytotoxic effect of DNA-damaging agents in leukemia cells via inhibiting the repair of damaged DNA. Mol Cancer Ther; 14(4); 889–98. ©2015 AACR. |
| Databáze: | OpenAIRE |
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