学術雑誌論文 Combined treatment of pancreatic cancer xenograft with 90Y-ITGA6B4-mediated radioimmunotherapy and PI3K/ mTOR inhibitor

Winn, Aung  ,  Tsuji, Atsushi  ,  Sudo, Hitomi  ,  Sugyo, Aya  ,  Ukai, Yoshinori  ,  Kouda, Katsushi  ,  Kurosawa, Yoshikazu  ,  Furukawa, Takako  ,  Saga, Tsuneo  ,  Higashi, Tatsuya

23 ( 42 )  , pp.7551 - 7562 , 2017-11 , Baishideng Publishing Group Inc
ISSN:1007-9327
内容記述
AIMTo investigate the therapeutic effect of combinedintegrin α6β4-targeted radioimmunotherapy (RIT) andPI3K/mTOR inhibitor BEZ235 in a pancreatic cancermodel.METHODSPhosphorylation of Akt, mTOR, the downstreameffectors eukaryotic initiation factor 4E bindingprotein 1 (4EBP1) and S6 ribosomal protein (S6) wereevaluated in BxPC-3 human pancreatic cancer cellstreated with Yttrium-90 (90Y) labeled anti-integrin α6β4antibody (ITGA6B4) and BEZ235 by western blotting.The cytotoxic effect of BEZ235 was investigatedusing a colony formation assay. Therapeutic efficacyenhancement by oral BEZ235 administration wasassessed using mice bearing BxPC-3 xenograft tumors.Tumor volume measurements and immunohistochemicalanalyses (cell proliferation marker Ki-67, DNA damagemarker p-H2AX and p-4EBP1 staining) of tumors wereperformed for evaluation of combined treatment with90Y-ITGA6B4 plus BEZ235, or each arm alone.RESULTSWe found that phosphorylation of Akt (p-Akt), 4EBP1(p-4EBP1) and S6 (p-S6) was inhibited by BEZ235.Colony formation in BxPC-3 cells was additivelysuppressed by the combination of 90Y-ITGA6B4 andBEZ235. Pretreatment with BEZ235 before 90Y-ITGA6B4exposure resulted in significant reduction of cells platingefficiency (PE) (0.54 ± 0.11 vs 2.81 ± 0.14 with 185kBq/mL 90Y-ITGA6B4 exposure, P < 0.01; 0.39 ± 0.08vs 1.88 ± 0.09 with 370 kBq/mL 90Y-ITGA6B4 exposure,P < 0.01) when 5 × 103 cells per dish were plated. Invivo , the combined treatment with 90Y-ITGA6B4 plusBEZ235 enhanced the inhibition of tumor growth andstatistically significant differences of relative tumorvolume were observed for 27 d after the treatmentstart date when compared with the 90Y-ITGA6B4 singleinjection treatment (1.03 ± 0.38 vs 1.5 ± 0.15 at Day27, P < 0.05), and for 41 d when compared with theBEZ235 treatment alone (1.8 ± 0.7 vs 3.14 ± 1.19at Day 41, P < 0.05). Tumors from treatment groupsshowed reduction in volumes, decreased Ki-67-positivecells, increased p-H2AX-positive cells and decreasedp-4EBP1 expression.CONCLUSIONThe therapeutic efficacy of 90Y-ITGA6B4-RIT can beimproved by combining with dual PI3K and mTORinhibitor, BEZ235, in a pancreatic cancer modelsuggesting potential clinical application.Key words: Radioimmunotherapy; Pancreatic cancer;anti-integrin α6β4 antibody; Yttrium-90; NVP-BEZ235

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