title: The Combination of the PARP Inhibitor Rucaparib and 5FU Is an Effective Strategy for Treating Acute Leukemias.
abstract: 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.
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. vittoria.falzacappa@ieo.eu piergiuseppe.pelicci@ieo.eu.
authors: Maria Vittoria Verga
authors: MV
authors: Falzacappa
authors: Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
authors: Chiara
authors: C
authors: Ronchini
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors: Mario
authors: M
authors: Faretta
authors: Institute of Hematology "L. e A. Seràgnoli," Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors: Ilaria
authors: I
authors: Iacobucci
authors: Institute of Hematology "L. e A. Seràgnoli," Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors: Andrea Ghelli Luserna
authors: AG
authors: Di Rorà
authors: Institute of Hematology "L. e A. Seràgnoli," Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors: Giovanni
authors: G
authors: Martinelli
authors: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors: Lüder Hinrich
authors: LH
authors: Meyer
authors: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors: Klaus-Michael
authors: KM
authors: Debatin
authors: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors: Stefania
authors: S
authors: Orecchioni
authors: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors: Francesco
authors: F
authors: Bertolini
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy. vittoria.falzacappa@ieo.eu piergiuseppe.pelicci@ieo.eu.
authors: Pier Giuseppe
authors: PG
authors: Pelicci
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531549:rucaparib; D005472:Fluorouracil