Radiosensitization In Vivo by Histone Deacetylase Inhibition with No Increase in Early Normal Tissue Radiation Toxicity
As the population ages, more elderly patients are receiving radiotherapy for pelvic malignancies, such as muscle-invasive bladder cancer, due to their unfitness for major surgery. This highlights the urgent need for radiosensitizing agents that are minimally toxic to normal tissues, including the bowel and bladder. We developed methods to assess normal tissue toxicity in the intestine and bladder in vivo, using advanced radiotherapy techniques on a small animal radiation research platform (SARRP).
To evaluate the effects of panobinostat, we studied its impact on tumor growth delay using subcutaneous xenografts in athymic nude mice. We measured panobinostat concentrations in xenografts, plasma, and normal tissues in CD1-nude mice. These mice were treated with drug/irradiation combinations to evaluate acute normal tissue effects in the small intestine through the intestinal crypt assay, and later assessed for effects in the small and large intestine at 11 weeks by stool examination and at 12 weeks by histological analysis.
In vitro, we assessed the effects of panobinostat via qPCR and compared it with TMP195 and mocetinostat using clonogenic assays and Western blot analysis. Panobinostat caused growth delay in RT112 bladder cancer xenografts but did not significantly increase acute (3.75 days) or 12-week normal tissue radiation toxicity. Radiosensitization by panobinostat was effective in hypoxic bladder cancer cells, linked to class I HDAC inhibition and reduced levels of HDAC2 and MRE11.
While pan-HDAC inhibition shows promise as a radiosensitization strategy, more selective agents may be more clinically useful, potentially resulting in fewer systemic side effects.