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Table S3 from Radiosensitization In Vivo by Histone Deacetylase Inhibition with No Increase in Early Normal Tissue Radiation Toxicity

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posted on 2023-04-03, 15:07 authored by Blaz Groselj, Jia-Ling Ruan, Helen Scott, Jessica Gorrill, Judith Nicholson, Jacqueline Kelly, Selvakumar Anbalagan, James Thompson, Michael R.L. Stratford, Sarah J. Jevons, Ester M. Hammond, Cheryl L. Scudamore, Martin Kerr, Anne E. Kiltie

A) Assessment of acute large bowel damage. CD1-nude mice treated with mock treatment or PAN (10 mg/kg) +/-IR. Lesions were scored semi-quantitatively using a 0-5 scale where 0 is no lesion present to 5 where the entire organ was affected by the pathology. B) Assessment of damage to intestine and bladder at 12 weeks. P=lesion present; scoring is semi-quantitative. Cage 2 mouse 1 was culled 2 days after being irradiated in error without the collimator present and cage 2 mouse 5 became unwell 7.5 weeks post-treatment and was culled, but no histopathological effects of the treatment were observed in the bowel. Cage 4 mouse 4 developed moderate diffuse ulcerative colitis. Amyloid was present in the small intestine of animals from all groups including the control group and is considered a pre-existing spontaneous lesion not related to the experimental protocol. Lesions were scored semi-quantitatively using a 0-5 scale where 0 is no lesion present to 5 where the entire organ was affected by the pathology.

Funding

Cancer Research UK

Rosetrees Trust

Slovene Human Resources Development and Scholarship Fund

History

ARTICLE ABSTRACT

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. Mol Cancer Ther; 17(2); 381–92. ©2017 AACR.See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”