In Vitro and In Vivo Metabolic Activation of Tolterodine Mediated by CYP3A.

Tolterodine (TOL) is an antimuscarinic drug used for the treatment of patients with overactive bladder presenting urinary frequency, urgency, and urge incontinence. During the clinical use of TOL, adverse events such as liver injury took place. The present study aimed at the investigation of the metabolic activation of TOL possibly associated with its hepatotoxicity. One GSH conjugate, two NAC conjugates, and two cysteine conjugates were found in both mouse and human liver microsomal incubations supplemented with TOL, GSH/NAC/cysteine, and NADPH. The detected conjugates suggest the production of a quinone methide intermediate. The same GSH conjugate was also observed in mouse primary hepatocytes and in the bile of rats receiving TOL. One of the urinary NAC conjugates was observed in rats administered TOL. One of the cysteine conjugates was found in a digestion mixture containing hepatic proteins from animals administered TOL. The observed protein modification was dose-dependent. CYP3A primarily catalyzes the metabolic activation of TOL. Ketoconazole (KTC) pretreatment reduced the generation of the GSH conjugate in mouse liver and cultured primary hepatocytes after TOL treatment. In addition, KTC reduced the susceptibility of primary hepatocytes to TOL cytotoxicity. The quinone methide metabolite may be involved in TOL-induced hepatotoxicity and cytotoxicity.

Association of circulating miR-125b and survival in patients with osteosarcoma-A single center experience.

BACKGROUND: It is known that miRNAs play various roles in malignant tumors. This study is designed to investigate whether miR-125b levels can be used to predict the clinical response of patients with osteosarcoma (OS) to cisplatin-based chemotherapy. METHODS: From January 2010 to July 2015, 82 patients with resectable OS and 56 patients with unresectable OS were enrolled. Blood samples were collected and quantitative real-time PCR was applied to determine miR-125b expression. Clinical data was collected through medical records, and patients were treated according to National Comprehensive Cancer Network guidelines on OS. RESULTS: Our study found that patients with low miR-125b expression had shorter disease-free survival (p<0.001) in the OS group, which was verified by Kaplan-Meier analysis and univariate and multivariate Cox analyses (p<0.001). For patients with unresectable OS, low miR-125b expression was found to be associated with advanced tumor stages (p=0.006). No complete remission was observed, and there were 13 patients with partial remission, 21 with stable disease, and 22 with disease progression. Negative correlation was found between miR-125b expression and response to chemotherapy (p<0.001, r=-0.606). Furthermore, ROC analysis indicated that miR-125b at the cut point of 0.61 yielded an area under the ROC curve of 0.793 (p<0.001, 95% CI: 0.664-0.890) in distinguishing chemotherapy-resistant OS from chemotherapy-sensitive OS, with sensitivity and specificity at 76.9% and 79.1%, respectively. Kaplan-Meier analysis and univariate and multivariate Cox analyses showed that patients with low miR-125b expression suffered shorter overall survival (p=0.014, p=0.024, and p=0.049, respectively). CONCLUSION: Down-regulation of circulating miR-125b might have the potential to predict cisplatin-based chemotherapy resistance and poor prognosis in OS.

[Clinical value of the comprehensive treatment in intermediate and advanced cervical cancer with uterine arterial interventional chemoembolization and radiotherapy].

OBJECTIVE: To investigate the long-term curative effect of the radiotherapy combined uterine arterial interventional chemoembolization for cervical cancer. METHODS: Records of 632 patients with cervical cancer stage II - IVa proved by pathology in Lanzhou Command General Hospital from January 1st, 1999 to August 31st, 2009 were retrospective analysed. One hundred and twenty-six cases of them were treated with radical radiotherapy combined uterine arterial interventional chemoembolization (arterial chemoembolization + radiotherapy group), 506 cases of them were treated with radical radiotherapy only (radiotherapy group); the evaluation of the late radiation injury was done, according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) advanced radiation injury criteria. Prognosis and complications were compared between two groups, relative risk factors of radiotherapy complications were identified by method of logistic regression. RESULTS: (1) Survival: the total survival rates of 1-year, 2-year, 5-year and 8-year were 94.4%, 82.3%, 48.8%, 29.1%, respectively. The survival rates of arterial chemoembolization + radiotherapy group were 96.0%, 82.1%, 37.2%, 25.7%, while the survival rates of radiotherapy group were 94.1%, 80.8%, 51.1%, 31.5%, in which there were significant differences between two groups (χ(2) = 0.009, P = 0.993; χ(2) = 0.158, P = 0.691; χ(2) = 11.197, P = 0.001;χ(2) = 9.649, P = 0.002). During the follow-up period, the rate of recurrence and metastasis in arterial chemoembolization + radiotherapy group were 77.0% (97/126), while 73.3% (371/506) in radiotherapy group (χ(2) = 0.705, P = 0.401). (2) Radiotherapy complications and relative risk factors: the total incidence of tardive bladder injury higher than RTOG/EORTC stage II was 5.5% (35/632), while it was 11.1% (14/126) in arterial chemoembolization + radiotherapy group, 4.2% (21/506) in the radiotherapy group (χ(2) = 9.344, P = 0.002). The results of logistic regression showed that the uterine arterial interventional chemoembolization was relative risk factors of the tardive bladder injury (χ(2) = 6.440, OR = 2.869, P = 0.011). CONCLUSIONS: Compared with the simple radiotherapy, there are a similar short-term survival rate and significant poor 5-year, 8-year survival rate in the patients treated with the uterine arterial interventional chemoembolization combined with radiotherapy, which also may be strong dangerous factor for the occurrence of tardive bladder injury. The results shown that the uterine arterial interventional chemoembolization do not recommend to be routine adjuvant therapy for the radical radiotherapy of cervical cancer.