Document Detail

Comparison of γδ T cell responses and farnesyl diphosphate synthase inhibition in tumor cells pretreated with zoledronic acid.
MedLine Citation:
PMID:  23387443     Owner:  NLM     Status:  MEDLINE    
Exposing human tumor cells to nitrogen-containing bisphosphonates, such as zoledronic acid (Zol), greatly increases their susceptibility to killing by γδ T cells. Based on this finding and other studies, cancer immunotherapy using γδ T cells and nitrogen-containing bisphosphonates has been studied in pilot clinical trials and has shown benefits. Although Zol treatment can render a wide variety of human tumor cells susceptible to γδ T cell killing, there has not been a systematic investigation to determine which types of tumor cells are the most susceptible to γδ T cell-mediated cytotoxicity. In this study, we determined the Zol concentrations required to stimulate half maximal tumor necrosis factor-α production by γδ T cells cultured with various tumor cell lines pretreated with Zol and compared these concentrations with those required for half maximal inhibition of farnesyl diphosphate synthase (FPPS) in the same tumor cell lines. The inhibition of tumor cell growth by Zol was also assessed. We found that FPPS inhibition strongly correlated with γδ T cell activation, confirming that the mechanism underlying γδ T cell activation by Zol is isopentenyl diphosphate (IPP) accumulation due to FPPS blockade. In addition, we showed that γδ T-cell receptor-mediated signaling correlated with γδ T cell tumor necrosis factor-α production and cytotoxicity. Some lymphoma, myeloid leukemia, and mammary carcinoma cell lines were relatively resistant to Zol treatment, suggesting that assessing tumor sensitivity to Zol may help select those patients most likely to benefit from immunotherapy with γδ T cells.
Atif S M Idrees; Tomoharu Sugie; Chiyomi Inoue; Kaoru Murata-Hirai; Haruki Okamura; Craig T Morita; Nagahiro Minato; Masakazu Toi; Yoshimasa Tanaka
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-03-19
Journal Detail:
Title:  Cancer science     Volume:  104     ISSN:  1349-7006     ISO Abbreviation:  Cancer Sci.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-16     Completed Date:  2013-09-13     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  101168776     Medline TA:  Cancer Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  536-42     Citation Subset:  IM    
Copyright Information:
© 2013 Japanese Cancer Association.
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MeSH Terms
Cell Line, Tumor
Cytotoxicity, Immunologic / drug effects,  immunology
Diphosphonates / immunology,  pharmacology*
Geranyltranstransferase / antagonists & inhibitors*,  immunology,  metabolism
HL-60 Cells
Hemiterpenes / immunology,  metabolism
Imidazoles / immunology,  pharmacology*
K562 Cells
Leukemia, Myeloid / drug therapy*,  immunology,  metabolism
Lymphoma / drug therapy*,  immunology,  metabolism
MCF-7 Cells
Organophosphorus Compounds / immunology,  metabolism
Receptors, Antigen, T-Cell, gamma-delta / immunology*,  metabolism
T-Lymphocytes / drug effects*,  immunology
Tumor Necrosis Factor-alpha / immunology,  metabolism
U937 Cells
Grant Support
Reg. No./Substance:
0/Diphosphonates; 0/Hemiterpenes; 0/Imidazoles; 0/Organophosphorus Compounds; 0/Receptors, Antigen, T-Cell, gamma-delta; 0/Tumor Necrosis Factor-alpha; 118072-93-8/zoledronic acid; 358-71-4/isopentenyl pyrophosphate; EC

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