title: Synergistic effects of combination with fludarabine and carboplatin depend on fludarabine-mediated inhibition of enhanced nucleotide excision repair in leukemia.
abstract: Overcoming drug resistance remains a major obstacle to curing relapsed or refractory lymphoma and obtaining a beneficial long-term prognosis for patients, despite the introduction of several salvage regimens to date. Our ultimate purpose is to establish a standard second-line salvage chemotherapy regimen for curing relapsed/refractory lymphoma. In this basic pre-clinical study, we evaluated a combination regimen consisting of 9-β-D: -arabinofuranosyl-2-fluoroadenine (F-araA) and carboplatin that targeted nucleotide excision repair (NER) of DNA in five representative leukemia lineages in vitro. Isobologram analysis demonstrated that simultaneous exposure to these two drugs produced synergistic interactions in U937 and K562 cells, in which lines showed enhanced NER activity by the measurement of UV or drug-induced DNA strand break (comet assay), or quantitation of ERCC1 mRNA (RT-PCR), a key enzyme for NER. Histone γH2AX formation was synergistically induced, but no such formation was observed after exposure to either agent alone in K562 cells. In summary, we synergistically inhibited the NER activity of leukemia cells by treating them with a combination of F-araA and carboplatin, suggesting that this combinatory regimen could be used as a novel salvage therapy for refractory or drug-resistant lymphoma.
authors.affiliation: Hematology and Oncology Division, School of Medical Science, University of Fukui, Matsuoka Shimoaizuki 23, Eiheiji, Fukui, 910-1193, Japan. ktakagi@u-fukui.ac.jp.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Takagi
authors.affiliation: Hematology and Oncology Division, School of Medical Science, University of Fukui, Matsuoka Shimoaizuki 23, Eiheiji, Fukui, 910-1193, Japan.
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Kawai
authors.affiliation: Hematology and Oncology Division, School of Medical Science, University of Fukui, Matsuoka Shimoaizuki 23, Eiheiji, Fukui, 910-1193, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Hematology and Oncology Division, School of Medical Science, University of Fukui, Matsuoka Shimoaizuki 23, Eiheiji, Fukui, 910-1193, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Hematology and Oncology Division, School of Medical Science, University of Fukui, Matsuoka Shimoaizuki 23, Eiheiji, Fukui, 910-1193, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Ueda
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy; D016879:Salvage Therapy; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016190:Carboplatin; D014740:Vidarabine; C024352:fludarabine