ABSTRACT
Objective To investigate the efficacy and safety of hypofractionated thoracic radiotherapy combined with EP chemotherapy in the treatment of limited-stage small-cell lung cancer (LS-SCLC). Methods A total of 117 patients with LS-SCLC were enrolled and randomly divided into test group (n=59) and control group (n=58). Patients in the experiment group were given hypofractionated thoracic radiotherapy combined with EP chemotherapy, while patients in the control group were given hyperfractionation radiotherapy combined with EP chemotherapy. Objective response rate (ORR), 2-year overall survival (OS), 2-year progression free survival (PFS), and immune cell level were used to evaluate clinical efficacy. We compared the incidence of side effects between the two groups. Results After the treatment, the ORR of patients in the test group was higher than that in the control group (P > 0.05). The mean OS and PFS of patients in the test group were significantly longer than those in the control group (P < 0.05). The levels of CD3+, CD4+, CD4+/CD8+, and NK cells in the test group were significantly higher, whereas the levels of CD8+ were significantly lower than those in the control group (P < 0.05). The incidence of radiation pneumonitis, radiation esophagitis, and severe dermatitis in the test group was significantly lower than that in the control group (P < 0.05). Conclusion Hypofractionated radiotherapy combined with EP chemotherapy for treatment of LS-SCLC can effectively improve the anticancer efficacy and patient survival, reduce the damage to the body's immune function, and alleviate adverse reaction of radiotherapy.
ABSTRACT
Pyrrolizidine alkaloids (PAs) are the most common phytotoxins with documented human hepatotoxicity. PAs require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts, thereby causing cytotoxicity. This study investigated the role of the gut-liver axis in PA intoxication and the underlying mechanisms. We exposed mice to retrorsine (RTS), a representative PA, and for the first time found RTS-induced intestinal epithelium damage and disruption to intestinal barrier function. Using mice with tissue-selective ablation of P450 activity, we found that hepatic P450s, but not intestinal P450s, were essential for PA bioactivation. Besides, in RTS-exposed, bile duct-cannulated rats, we found the liver-derived reactive PA metabolites were transported by bile into the intestine to exert enterotoxicity. The impact of gut-derived pathogenic factors in RTS-induced hepatotoxicity was further studied in mice with dextran sulfate sodium (DSS)-induced chronic colitis. DSS treatment increased the hepatic endotoxin level and depleted hepatic reduced glutathione, thereby suppressing the PA detoxification pathway. Compared to RTS-exposed normal mice, the colitic mice displayed more severe RTS-induced hepatic vasculature damage, fibrosis, and steatosis. Overall, our findings provide the first mode-of-action evidence of PA-induced enterotoxicity and highlight the importance of gut barrier function in PA-induced liver injury.