An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model

An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model

Abstract In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma pa...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Hiromichi Oshiro, Yasunori Tome, Kentaro Miyake, Takashi Higuchi, Norihiko Sugisawa, Fuminori Kanaya, Kotaro Nishida, Robert M. Hoffman
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2021
Materias:
Medicine
R
Science
Q
Acceso en línea:https://doaj.org/article/0b91a6a245e14c3595b158c6ec10aae3
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:0b91a6a245e14c3595b158c6ec10aae3
record_format dspace
spelling oai:doaj.org-article:0b91a6a245e14c3595b158c6ec10aae32021-12-02T15:27:05ZAn mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model10.1038/s41598-021-87553-92045-2322https://doaj.org/article/0b91a6a245e14c3595b158c6ec10aae32021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87553-9https://doaj.org/toc/2045-2322Abstract In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p < 0.05). There was no significant body-weight loss in any group. Only the EVE-PAZ combination caused tumor necrosis. The present study demonstrates that a combination of an mTOR-VEGF inhibitor and a VEGFR inhibitor was effective for a DOX-resistant lung-metastatic osteosarcoma PDOX mouse model, at least in part due to strong anti-angiogenesis efficacy of the combination.Hiromichi OshiroYasunori TomeKentaro MiyakeTakashi HiguchiNorihiko SugisawaFuminori KanayaKotaro NishidaRobert M. HoffmanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Hiromichi Oshiro
Yasunori Tome
Kentaro Miyake
Takashi Higuchi
Norihiko Sugisawa
Fuminori Kanaya
Kotaro Nishida
Robert M. Hoffman
An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model
description Abstract In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p < 0.05). There was no significant body-weight loss in any group. Only the EVE-PAZ combination caused tumor necrosis. The present study demonstrates that a combination of an mTOR-VEGF inhibitor and a VEGFR inhibitor was effective for a DOX-resistant lung-metastatic osteosarcoma PDOX mouse model, at least in part due to strong anti-angiogenesis efficacy of the combination.
format article
author Hiromichi Oshiro
Yasunori Tome
Kentaro Miyake
Takashi Higuchi
Norihiko Sugisawa
Fuminori Kanaya
Kotaro Nishida
Robert M. Hoffman
author_facet Hiromichi Oshiro
Yasunori Tome
Kentaro Miyake
Takashi Higuchi
Norihiko Sugisawa
Fuminori Kanaya
Kotaro Nishida
Robert M. Hoffman
author_sort Hiromichi Oshiro
title An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model
title_short An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model
title_full An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model
title_fullStr An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model
title_full_unstemmed An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model
title_sort mtor and vegfr inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a pdox mouse model
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/0b91a6a245e14c3595b158c6ec10aae3
work_keys_str_mv AT hiromichioshiro anmtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT yasunoritome anmtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT kentaromiyake anmtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT takashihiguchi anmtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT norihikosugisawa anmtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT fuminorikanaya anmtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT kotaronishida anmtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT robertmhoffman anmtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT hiromichioshiro mtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT yasunoritome mtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT kentaromiyake mtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT takashihiguchi mtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT norihikosugisawa mtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT fuminorikanaya mtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT kotaronishida mtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
AT robertmhoffman mtorandvegfrinhibitorcombinationarrestsadoxorubicinresistantlungmetastaticosteosarcomainapdoxmousemodel
_version_ 1718387185376296960

Ejemplares similares