TY - JOUR
T1 - Radiosensitization in vivo by histone deacetylase inhibition with no increase in early normal tissue radiation toxicity
AU - Groselj, Blaz
AU - Ruan, Jia Ling
AU - Scott, Helen
AU - Gorrill, Jessica
AU - Nicholson, Judith
AU - Kelly, Jacqueline
AU - Anbalagan, Selvakumar
AU - Thompson, James
AU - Stratford, Michael R.L.
AU - Jevons, Sarah J.
AU - Hammond, Ester M.
AU - Scudamore, Cheryl L.
AU - Kerr, Martin
AU - Kiltie, Anne E.
N1 - Funding Information:
This work was supported by Cancer Research UK (grant C5255/ A15935), Nuffield Department of Surgical Sciences, University of Oxford, Rosetrees Trust (grant M331), OCRC Development Grants 0213 and 0713, and The Slovene Human Resources Development and Scholarship Fund.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/2
Y1 - 2018/2
N2 - As the population ages, more elderly patients require radiotherapy-based treatment for their pelvic malignancies, including muscle-invasive bladder cancer, as they are unfit for major surgery. Therefore, there is an urgent need to find radiosensitizing agents minimally toxic to normal tissues, including bowel and bladder, for such patients. We developed methods to determine normal tissue toxicity severity in intestine and bladder in vivo, using novel radiotherapy techniques on a small animal radiation research platform (SARRP). The effects of panobinostat on in vivo tumor growth delay were evaluated using subcutaneous xenografts in athymic nude mice. Panobinostat concentration levels in xenografts, plasma, and normal tissues were measured in CD1-nude mice. CD1-nude mice were treated with drug/irradiation combinations to assess acute normal tissue effects in small intestine using the intestinal crypt assay, and later effects in small and large intestine at 11 weeks by stool assessment and at 12 weeks by histologic examination. In vitro effects of panobinostat were assessed by qPCR and of panobinostat, TMP195, and mocetinostat by clonogenic assay, and Western blot analysis. Panobinostat resulted in growth delay in RT112 bladder cancer xenografts but did not significantly increase acute (3.75 days) or 12 weeks' normal tissue radiation toxicity. Radiosensitization by panobinostat was effective in hypoxic bladder cancer cells and associated with class I HDAC inhibition, and protein downregulation of HDAC2 and MRE11. Pan-HDAC inhibition is a promising strategy for radiosensitization, but more selective agents may be more useful radiosensitizers clinically, resulting in fewer systemic side effects.
AB - As the population ages, more elderly patients require radiotherapy-based treatment for their pelvic malignancies, including muscle-invasive bladder cancer, as they are unfit for major surgery. Therefore, there is an urgent need to find radiosensitizing agents minimally toxic to normal tissues, including bowel and bladder, for such patients. We developed methods to determine normal tissue toxicity severity in intestine and bladder in vivo, using novel radiotherapy techniques on a small animal radiation research platform (SARRP). The effects of panobinostat on in vivo tumor growth delay were evaluated using subcutaneous xenografts in athymic nude mice. Panobinostat concentration levels in xenografts, plasma, and normal tissues were measured in CD1-nude mice. CD1-nude mice were treated with drug/irradiation combinations to assess acute normal tissue effects in small intestine using the intestinal crypt assay, and later effects in small and large intestine at 11 weeks by stool assessment and at 12 weeks by histologic examination. In vitro effects of panobinostat were assessed by qPCR and of panobinostat, TMP195, and mocetinostat by clonogenic assay, and Western blot analysis. Panobinostat resulted in growth delay in RT112 bladder cancer xenografts but did not significantly increase acute (3.75 days) or 12 weeks' normal tissue radiation toxicity. Radiosensitization by panobinostat was effective in hypoxic bladder cancer cells and associated with class I HDAC inhibition, and protein downregulation of HDAC2 and MRE11. Pan-HDAC inhibition is a promising strategy for radiosensitization, but more selective agents may be more useful radiosensitizers clinically, resulting in fewer systemic side effects.
UR - http://www.scopus.com/inward/record.url?scp=85041468545&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-17-0011
DO - 10.1158/1535-7163.MCT-17-0011
M3 - Article
C2 - 28839000
AN - SCOPUS:85041468545
VL - 17
SP - 381
EP - 392
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 2
ER -