Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug

Abstract Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with γδ T cells expressing Vγ2 Vδ2 TCRs. Although treatment with γδ T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate γδ T cells but we...

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Autores principales:	Yoshimasa Tanaka, Masashi Iwasaki, Kaoru Murata-Hirai, Kenji Matsumoto, Kosuke Hayashi, Haruki Okamura, Tomoharu Sugie, Nagahiro Minato, Craig T. Morita, Masakazu Toi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9f0bf342bae840ad95d227a5c3a671ad
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spelling	oai:doaj.org-article:9f0bf342bae840ad95d227a5c3a671ad2021-12-02T12:32:25ZAnti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug10.1038/s41598-017-05553-02045-2322https://doaj.org/article/9f0bf342bae840ad95d227a5c3a671ad2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05553-0https://doaj.org/toc/2045-2322Abstract Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with γδ T cells expressing Vγ2 Vδ2 TCRs. Although treatment with γδ T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate γδ T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodrugs has led to important drugs for hepatitis C and HIV. Using a similar approach, we synthesized bisphosphonate prodrugs and found that they efficiently limit tumor cell growth. Pivoxil bisphosphonate esters enter cells where esterases convert them to their active acids. The bisphosphonate esters stimulated γδ T cells to secrete TNF-α in response to a variety of tumor cells more efficiently than their corresponding acids. The most active compound, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1- bisphosphonate (7), specifically expanded γδ T cells and stimulated them to secrete interferon-γ and kill tumor cells. In preclinical studies, combination therapy with compound 7 and γδ T cells prolonged survival of mice inoculated with either human bladder cancer or fibrosarcoma cells. Therefore, bisphosphonate prodrugs could enhance the effectiveness of adoptive cancer immunotherapy with γδ T cells.Yoshimasa TanakaMasashi IwasakiKaoru Murata-HiraiKenji MatsumotoKosuke HayashiHaruki OkamuraTomoharu SugieNagahiro MinatoCraig T. MoritaMasakazu ToiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yoshimasa Tanaka Masashi Iwasaki Kaoru Murata-Hirai Kenji Matsumoto Kosuke Hayashi Haruki Okamura Tomoharu Sugie Nagahiro Minato Craig T. Morita Masakazu Toi Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug
description	Abstract Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with γδ T cells expressing Vγ2 Vδ2 TCRs. Although treatment with γδ T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate γδ T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodrugs has led to important drugs for hepatitis C and HIV. Using a similar approach, we synthesized bisphosphonate prodrugs and found that they efficiently limit tumor cell growth. Pivoxil bisphosphonate esters enter cells where esterases convert them to their active acids. The bisphosphonate esters stimulated γδ T cells to secrete TNF-α in response to a variety of tumor cells more efficiently than their corresponding acids. The most active compound, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1- bisphosphonate (7), specifically expanded γδ T cells and stimulated them to secrete interferon-γ and kill tumor cells. In preclinical studies, combination therapy with compound 7 and γδ T cells prolonged survival of mice inoculated with either human bladder cancer or fibrosarcoma cells. Therefore, bisphosphonate prodrugs could enhance the effectiveness of adoptive cancer immunotherapy with γδ T cells.
format	article
author	Yoshimasa Tanaka Masashi Iwasaki Kaoru Murata-Hirai Kenji Matsumoto Kosuke Hayashi Haruki Okamura Tomoharu Sugie Nagahiro Minato Craig T. Morita Masakazu Toi
author_facet	Yoshimasa Tanaka Masashi Iwasaki Kaoru Murata-Hirai Kenji Matsumoto Kosuke Hayashi Haruki Okamura Tomoharu Sugie Nagahiro Minato Craig T. Morita Masakazu Toi
author_sort	Yoshimasa Tanaka
title	Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug
title_short	Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug
title_full	Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug
title_fullStr	Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug
title_full_unstemmed	Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug
title_sort	anti-tumor activity and immunotherapeutic potential of a bisphosphonate prodrug
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/9f0bf342bae840ad95d227a5c3a671ad
work_keys_str_mv	AT yoshimasatanaka antitumoractivityandimmunotherapeuticpotentialofabisphosphonateprodrug AT masashiiwasaki antitumoractivityandimmunotherapeuticpotentialofabisphosphonateprodrug AT kaorumuratahirai antitumoractivityandimmunotherapeuticpotentialofabisphosphonateprodrug AT kenjimatsumoto antitumoractivityandimmunotherapeuticpotentialofabisphosphonateprodrug AT kosukehayashi antitumoractivityandimmunotherapeuticpotentialofabisphosphonateprodrug AT harukiokamura antitumoractivityandimmunotherapeuticpotentialofabisphosphonateprodrug AT tomoharusugie antitumoractivityandimmunotherapeuticpotentialofabisphosphonateprodrug AT nagahirominato antitumoractivityandimmunotherapeuticpotentialofabisphosphonateprodrug AT craigtmorita antitumoractivityandimmunotherapeuticpotentialofabisphosphonateprodrug AT masakazutoi antitumoractivityandimmunotherapeuticpotentialofabisphosphonateprodrug
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Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug

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