title: Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia.
abstract: Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+)CD25(+) lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. This trial was registered at www.clinicaltrials.gov as #NCT00061048.
authors: Metabolism Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Jing
authors: J
authors: Chen
authors: Cynthia A
authors: CA
authors: Pise-Masison
authors: Joanna H
authors: JH
authors: Shih
authors: John C
authors: JC
authors: Morris
authors: John E
authors: JE
authors: Janik
authors: Kevin C
authors: KC
authors: Conlon
authors: Anne
authors: A
authors: Keating
authors: Thomas A
authors: TA
authors: Waldmann
mesh_terms: D000328:Adult; D000074323:Alemtuzumab; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000494:pharmacology; D013379:Substrate Specificity; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; D000074323:Alemtuzumab; C523798:sepantronium