Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors

Y Pi&ntilde;a1, C Decatur1, TG Murray1, SK Houston1, D Gologorsky1, M Cavalcante1, L Cavalcante1, E Hernandez1, M Celdran1, W Feuer1, T Lampidis21Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; 2Department of Cell Biology and Anatomy, University of...

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Autores principales:	Y Pi&ntilde;a, C Decatur, TG Murray, et al
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2011
Materias:	Ophthalmology RE1-994
Acceso en línea:	https://doaj.org/article/cf117072b98044bdb024218daeab150b
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spelling	oai:doaj.org-article:cf117072b98044bdb024218daeab150b2021-12-02T01:46:34ZAdvanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors1177-54671177-5483https://doaj.org/article/cf117072b98044bdb024218daeab150b2011-03-01T00:00:00Zhttp://www.dovepress.com/advanced-retinoblastoma-treatment-targeting-hypoxia-by-inhibition-of-t-a6583https://doaj.org/toc/1177-5467https://doaj.org/toc/1177-5483Y Pi&ntilde;a1, C Decatur1, TG Murray1, SK Houston1, D Gologorsky1, M Cavalcante1, L Cavalcante1, E Hernandez1, M Celdran1, W Feuer1, T Lampidis21Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; 2Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL, USAPurpose: The purpose of this study is to analyze the dose response of the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, on tumor burden and hypoxia, and study the treatment effect on vasculature in LHBETATAG retinal tumors.Methods: This study was approved by the Institutional Animal Care and Use Committee and follows Association for Research in Vision and Ophthalmology guidelines. Eighteen-week-old LHBETATAG retinal tumor eyes (n = 30) were evaluated. Mice were divided into five groups and received periocular injections once weekly for two consecutive weeks of: a) 80% DMSO (dimethyl sulfoxide, vehicle control), b) 0.00333 mg/kg, c) 0.167 mg/kg, d) 3.33 mg/kg, and e) 6.67 mg/kg of rapamycin. Tumor sections were analyzed for hypoxia, tumor burden, and vasculature with immunohistochemistry techniques.Results: Reduction in tumor burden and hypoxia was significantly different between rapamycin doses and control (P &lt; 0.002). Eyes treated with rapamycin at 0.167, 3.33, and 6.67 mg/kg showed a significant decrease in tumor burden in comparison with the vehicle control group (P = 0.019, P = 0.001, P = 0.009, respectively) and the 0.00333 mg/kg dose response (P = 0.023, P = 0.001, P = 0.010, respectively). Eyes treated with rapamycin at 3.33 mg/kg showed a significant reduction in the amount of hypoxia in comparison with the lower concentration groups (0.00333 and 0.167 mg/kg) of rapamycin (P = 0.024 and P = 0.052, respectively). The number of mature vessels was significantly lower in the 3.33 mg/kg treated versus vehicle control (P = 0.015; equal variances assumed, t-test for equality of means). The number of neovessels was not significantly different between both groups (P = 0.092).Conclusion: Inhibition of mTOR was shown to reduce tumor burden, hypoxia, and vasculature in the LHBETATAG retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control.Keywords: rapamycin, mTOR, hypoxia, retinoblastoma, anaerobic glycolysis Y Pi&ntilde;aC DecaturTG Murrayet alDove Medical PressarticleOphthalmologyRE1-994ENClinical Ophthalmology, Vol 2011, Iss default, Pp 337-343 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Ophthalmology RE1-994
spellingShingle	Ophthalmology RE1-994 Y Pi&ntilde;a C Decatur TG Murray et al Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors
description	Y Pi&ntilde;a1, C Decatur1, TG Murray1, SK Houston1, D Gologorsky1, M Cavalcante1, L Cavalcante1, E Hernandez1, M Celdran1, W Feuer1, T Lampidis21Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; 2Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL, USAPurpose: The purpose of this study is to analyze the dose response of the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, on tumor burden and hypoxia, and study the treatment effect on vasculature in LHBETATAG retinal tumors.Methods: This study was approved by the Institutional Animal Care and Use Committee and follows Association for Research in Vision and Ophthalmology guidelines. Eighteen-week-old LHBETATAG retinal tumor eyes (n = 30) were evaluated. Mice were divided into five groups and received periocular injections once weekly for two consecutive weeks of: a) 80% DMSO (dimethyl sulfoxide, vehicle control), b) 0.00333 mg/kg, c) 0.167 mg/kg, d) 3.33 mg/kg, and e) 6.67 mg/kg of rapamycin. Tumor sections were analyzed for hypoxia, tumor burden, and vasculature with immunohistochemistry techniques.Results: Reduction in tumor burden and hypoxia was significantly different between rapamycin doses and control (P &lt; 0.002). Eyes treated with rapamycin at 0.167, 3.33, and 6.67 mg/kg showed a significant decrease in tumor burden in comparison with the vehicle control group (P = 0.019, P = 0.001, P = 0.009, respectively) and the 0.00333 mg/kg dose response (P = 0.023, P = 0.001, P = 0.010, respectively). Eyes treated with rapamycin at 3.33 mg/kg showed a significant reduction in the amount of hypoxia in comparison with the lower concentration groups (0.00333 and 0.167 mg/kg) of rapamycin (P = 0.024 and P = 0.052, respectively). The number of mature vessels was significantly lower in the 3.33 mg/kg treated versus vehicle control (P = 0.015; equal variances assumed, t-test for equality of means). The number of neovessels was not significantly different between both groups (P = 0.092).Conclusion: Inhibition of mTOR was shown to reduce tumor burden, hypoxia, and vasculature in the LHBETATAG retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control.Keywords: rapamycin, mTOR, hypoxia, retinoblastoma, anaerobic glycolysis
format	article
author	Y Pi&ntilde;a C Decatur TG Murray et al
author_facet	Y Pi&ntilde;a C Decatur TG Murray et al
author_sort	Y Pi&ntilde;a
title	Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors
title_short	Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors
title_full	Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors
title_fullStr	Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors
title_full_unstemmed	Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors
title_sort	advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mtor) in lhbetatag retinal tumors
publisher	Dove Medical Press
publishDate	2011
url	https://doaj.org/article/cf117072b98044bdb024218daeab150b
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Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors

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