Development of a Preclinical Therapeutic Model of Human Brain Metastasis with Chemoradiotherapy

Currently, survival of breast cancer patients with brain metastasis ranges from 2 to 16 months. In experimental brain metastasis studies, only 10% of lesions with the highest permeability exhibited cytotoxic responses to paclitaxel or doxorubicin. Therefore, radiation is the most frequently used tre...

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Main Authors: Ignasi Modolell, Angels Sierra, Cristina Picón, Vanessa Hernández, Antonio Martínez-Aranda
Format: Article
Language:English
Published: MDPI AG 2013-04-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:http://www.mdpi.com/1422-0067/14/4/8306
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spelling doaj-7e5d0440819448308577eebb4ecbac572020-11-24T21:53:28ZengMDPI AGInternational Journal of Molecular Sciences1422-00672013-04-011448306832710.3390/ijms14048306Development of a Preclinical Therapeutic Model of Human Brain Metastasis with ChemoradiotherapyIgnasi ModolellAngels SierraCristina PicónVanessa HernándezAntonio Martínez-ArandaCurrently, survival of breast cancer patients with brain metastasis ranges from 2 to 16 months. In experimental brain metastasis studies, only 10% of lesions with the highest permeability exhibited cytotoxic responses to paclitaxel or doxorubicin. Therefore, radiation is the most frequently used treatment, and sensitizing agents, which synergize with radiation, can improve the efficacy of the therapy. In this study we used 435-Br1 cells containing the fluorescent protein (eGFP) gene and the photinus luciferase (PLuc) gene to develop a new brain metastatic cell model in mice through five in vivo/in vitro rounds. BR-eGFP-CMV/Luc-V5 brain metastatic cells induce parenchymal brain metastasis within 60.8 ± 13.8 days of intracarotid injection in all mice. We used this model to standardize a preclinical chemoradiotherapy protocol comprising three 5.5 Gy fractions delivered on consecutive days (overall dose of 16.5 Gy) which improved survival with regard to controls (60.29 ± 8.65 vs. 47.20 ± 11.14). Moreover, the combination of radiotherapy with temozolomide, 60 mg/Kg/day orally for five consecutive days doubled survival time of the mice 121.56 ± 52.53 days (Kaplan-Meier Curve, p < 0.001). This new preclinical chemoradiotherapy protocol proved useful for the study of radiation response/resistance in brain metastasis, either alone or in combination with new sensitizing agents.http://www.mdpi.com/1422-0067/14/4/8306brain metastasisbreast cancerexperimental modelsradiationtemozolomidetherapy
collection DOAJ
language English
format Article
sources DOAJ
author Ignasi Modolell
Angels Sierra
Cristina Picón
Vanessa Hernández
Antonio Martínez-Aranda
spellingShingle Ignasi Modolell
Angels Sierra
Cristina Picón
Vanessa Hernández
Antonio Martínez-Aranda
Development of a Preclinical Therapeutic Model of Human Brain Metastasis with Chemoradiotherapy
International Journal of Molecular Sciences
brain metastasis
breast cancer
experimental models
radiation
temozolomide
therapy
author_facet Ignasi Modolell
Angels Sierra
Cristina Picón
Vanessa Hernández
Antonio Martínez-Aranda
author_sort Ignasi Modolell
title Development of a Preclinical Therapeutic Model of Human Brain Metastasis with Chemoradiotherapy
title_short Development of a Preclinical Therapeutic Model of Human Brain Metastasis with Chemoradiotherapy
title_full Development of a Preclinical Therapeutic Model of Human Brain Metastasis with Chemoradiotherapy
title_fullStr Development of a Preclinical Therapeutic Model of Human Brain Metastasis with Chemoradiotherapy
title_full_unstemmed Development of a Preclinical Therapeutic Model of Human Brain Metastasis with Chemoradiotherapy
title_sort development of a preclinical therapeutic model of human brain metastasis with chemoradiotherapy
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1422-0067
publishDate 2013-04-01
description Currently, survival of breast cancer patients with brain metastasis ranges from 2 to 16 months. In experimental brain metastasis studies, only 10% of lesions with the highest permeability exhibited cytotoxic responses to paclitaxel or doxorubicin. Therefore, radiation is the most frequently used treatment, and sensitizing agents, which synergize with radiation, can improve the efficacy of the therapy. In this study we used 435-Br1 cells containing the fluorescent protein (eGFP) gene and the photinus luciferase (PLuc) gene to develop a new brain metastatic cell model in mice through five in vivo/in vitro rounds. BR-eGFP-CMV/Luc-V5 brain metastatic cells induce parenchymal brain metastasis within 60.8 ± 13.8 days of intracarotid injection in all mice. We used this model to standardize a preclinical chemoradiotherapy protocol comprising three 5.5 Gy fractions delivered on consecutive days (overall dose of 16.5 Gy) which improved survival with regard to controls (60.29 ± 8.65 vs. 47.20 ± 11.14). Moreover, the combination of radiotherapy with temozolomide, 60 mg/Kg/day orally for five consecutive days doubled survival time of the mice 121.56 ± 52.53 days (Kaplan-Meier Curve, p < 0.001). This new preclinical chemoradiotherapy protocol proved useful for the study of radiation response/resistance in brain metastasis, either alone or in combination with new sensitizing agents.
topic brain metastasis
breast cancer
experimental models
radiation
temozolomide
therapy
url http://www.mdpi.com/1422-0067/14/4/8306
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