Radiation cystitis (RC) and enteritis (RE) are debilitating conditions that can develop following radiotherapy for pelvic and abdominal malignancies, including those of the prostate, cervix and rectum. RC presents with urothelial damage, inflammation and bladder overactivity while RE, inflammation of small intestine, presents with diarrhea, nausea, vomiting, and stomach cramps. Moreover, because of cross-innervation, inflammation in one organ may be transmitted to the other. In many cases, these symptoms subside within several weeks after cessation of radiotherapy. However, 5-10% of patients experience late-onset symptoms including life threatening hemorrhagic cystitis/enteritis and fibrosis developing months to years after radiation treatment ends. These conditions are however likely underreported due to the long dormancy period before emergence. Presently, there are no preventative treatments or cures, so these conditions represent a significant unmet medical need worldwide. Palliative therapies include fulguration, hyperbaric oxygen, and oral/instilled drug treatments, focusing on lessening hemorrhaging but not the extensive fibrosis that causes bladder dysfunction and intestinal dysmotility which may require a cystectomy or resection, respectively.

Irradiation kills tumor cells by inducing DNA breaks preventing cell division or damaging mitochondria forcing cells into senescence and subsistence on glycolysis in lieu of higher energy oxidative phosphorylation. These cells can acquire a senescence-associated secretory phenotype (SASP) with different paracrine messengers orchestrating functional decline which may later emerge as RC/RE. The soluble guanylate cyclase activator, cinaciguat, is a senotherapeutic agent that selectively kills senescent cells (i.e., senolytic) as well as inhibits all or part of their SASP characteristics (i.e., senomorphic). Alternatively, bladder instillation of the mitochondrial-targeted free radical scavenger, XJB-5-131, prior to irradiation, has been shown to prevent the development of RC in animals—work that won the ASPET-Astellas award in translational pharmacology and resulted in two United States Patents. Thus, targeting bladder or colonic mitochondria with a free-radical scavengers prior to irradiation of pelvic/abdominal tumors, or targeting cellular senescence with cinaciguat post irradiation may be two promising strategies to prevent these debilitating conditions.

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