Cargando…

Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer

BACKGROUND: Many prostate cancers demonstrate an increased expression of growth factor receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) which have been correlated with increased resistance to radiotherapy and poor prognosis in...

Descripción completa

Detalles Bibliográficos
Autores principales: Brooks, Colin, Sheu, Tommy, Bridges, Kathleen, Mason, Kathy, Kuban, Deborah, Mathew, Paul, Meyn, Raymond
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494537/
https://www.ncbi.nlm.nih.gov/pubmed/22967802
http://dx.doi.org/10.1186/1748-717X-7-154
_version_ 1782249403782791168
author Brooks, Colin
Sheu, Tommy
Bridges, Kathleen
Mason, Kathy
Kuban, Deborah
Mathew, Paul
Meyn, Raymond
author_facet Brooks, Colin
Sheu, Tommy
Bridges, Kathleen
Mason, Kathy
Kuban, Deborah
Mathew, Paul
Meyn, Raymond
author_sort Brooks, Colin
collection PubMed
description BACKGROUND: Many prostate cancers demonstrate an increased expression of growth factor receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) which have been correlated with increased resistance to radiotherapy and poor prognosis in other tumors. Therefore, response to radiation could potentially be improved by using inhibitors of these abnormally activated pathways. We have investigated the radiosensitizing effects of sunitinib, a potent, multi-tyrosine kinase inhibitor of the VEGFR and PDGFR receptors, on human prostate cancer cells. METHODS: The radiosensitizing effects of sunitinib were assessed on human prostate cancer cell lines DU145, PC3 and LNCaP by clonogenic assay. Sunitinib’s ability to inhibit the activities of its key targets was determined by immunoblot analysis. The radiosensitizing effects of sunitinib in vivo were tested on human tumor xenografts growing in nude mice where response was assessed by tumor growth delay. RESULTS: Clonogenic survival curve assays for both DU145 and PC3 cells showed that the surviving fraction at 2 Gy was reduced from 0.70 and 0.52 in controls to 0.44 and 0.38, respectively, by a 24 hr pretreatment with 100 nM sunitinib. LNCaP cells were not radiosensitized by sunitinib. Dose dependent decreases in VEGFR and PDGFR activation were also observed following sunitinib in both DU145 and PC3 cells. We assessed the ability of sunitinib to radiosensitize PC3 xenograft tumors growing in the hind limb of nude mice. Sunitinib given concurrently with radiation did not prolong tumor growth delay. However, when animals were treated with sunitinib commencing the day after fractionated radiation was complete, tumor growth delay was enhanced compared to radiation alone. CONCLUSIONS: We conclude, based on the in vivo results, that sunitinib and radiation do not interact directly to radiosensitize the PC3 tumor cells in vivo as they did in vitro. The fact that tumor growth delay was enhanced when sunitinib was given after radiotherapy was completed suggests that sunitinib may be acting on the irradiated tumor stroma and suppressing its ability to sustain regrowth of the irradiated tumor. Based on these preclinical findings, we suggest that the combination of sunitinib and radiation for the treatment of prostate cancer deserves further development.
format Online
Article
Text
id pubmed-3494537
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-34945372012-11-10 Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer Brooks, Colin Sheu, Tommy Bridges, Kathleen Mason, Kathy Kuban, Deborah Mathew, Paul Meyn, Raymond Radiat Oncol Research BACKGROUND: Many prostate cancers demonstrate an increased expression of growth factor receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) which have been correlated with increased resistance to radiotherapy and poor prognosis in other tumors. Therefore, response to radiation could potentially be improved by using inhibitors of these abnormally activated pathways. We have investigated the radiosensitizing effects of sunitinib, a potent, multi-tyrosine kinase inhibitor of the VEGFR and PDGFR receptors, on human prostate cancer cells. METHODS: The radiosensitizing effects of sunitinib were assessed on human prostate cancer cell lines DU145, PC3 and LNCaP by clonogenic assay. Sunitinib’s ability to inhibit the activities of its key targets was determined by immunoblot analysis. The radiosensitizing effects of sunitinib in vivo were tested on human tumor xenografts growing in nude mice where response was assessed by tumor growth delay. RESULTS: Clonogenic survival curve assays for both DU145 and PC3 cells showed that the surviving fraction at 2 Gy was reduced from 0.70 and 0.52 in controls to 0.44 and 0.38, respectively, by a 24 hr pretreatment with 100 nM sunitinib. LNCaP cells were not radiosensitized by sunitinib. Dose dependent decreases in VEGFR and PDGFR activation were also observed following sunitinib in both DU145 and PC3 cells. We assessed the ability of sunitinib to radiosensitize PC3 xenograft tumors growing in the hind limb of nude mice. Sunitinib given concurrently with radiation did not prolong tumor growth delay. However, when animals were treated with sunitinib commencing the day after fractionated radiation was complete, tumor growth delay was enhanced compared to radiation alone. CONCLUSIONS: We conclude, based on the in vivo results, that sunitinib and radiation do not interact directly to radiosensitize the PC3 tumor cells in vivo as they did in vitro. The fact that tumor growth delay was enhanced when sunitinib was given after radiotherapy was completed suggests that sunitinib may be acting on the irradiated tumor stroma and suppressing its ability to sustain regrowth of the irradiated tumor. Based on these preclinical findings, we suggest that the combination of sunitinib and radiation for the treatment of prostate cancer deserves further development. BioMed Central 2012-09-11 /pmc/articles/PMC3494537/ /pubmed/22967802 http://dx.doi.org/10.1186/1748-717X-7-154 Text en Copyright ©2012 Brooks et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Brooks, Colin
Sheu, Tommy
Bridges, Kathleen
Mason, Kathy
Kuban, Deborah
Mathew, Paul
Meyn, Raymond
Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer
title Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer
title_full Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer
title_fullStr Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer
title_full_unstemmed Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer
title_short Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer
title_sort preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494537/
https://www.ncbi.nlm.nih.gov/pubmed/22967802
http://dx.doi.org/10.1186/1748-717X-7-154
work_keys_str_mv AT brookscolin preclinicalevaluationofsunitinibamultityrosinekinaseinhibitorasaradiosensitizerforhumanprostatecancer
AT sheutommy preclinicalevaluationofsunitinibamultityrosinekinaseinhibitorasaradiosensitizerforhumanprostatecancer
AT bridgeskathleen preclinicalevaluationofsunitinibamultityrosinekinaseinhibitorasaradiosensitizerforhumanprostatecancer
AT masonkathy preclinicalevaluationofsunitinibamultityrosinekinaseinhibitorasaradiosensitizerforhumanprostatecancer
AT kubandeborah preclinicalevaluationofsunitinibamultityrosinekinaseinhibitorasaradiosensitizerforhumanprostatecancer
AT mathewpaul preclinicalevaluationofsunitinibamultityrosinekinaseinhibitorasaradiosensitizerforhumanprostatecancer
AT meynraymond preclinicalevaluationofsunitinibamultityrosinekinaseinhibitorasaradiosensitizerforhumanprostatecancer