No abstract

No abstract

Cholangiocarcinoma is markedly resistant to chemotherapy and has a dismal prognosis, but its mechanism of drug resistance is unknown. This study examines whether glutathione S-transferase-(GSTP1-1) is involved in resistance to anticancer drugs in cholangiocarcinoma and whether GSTP1-1-specific inhibitors can overcome this resistance. First, immunohistochemical examination disclosed strong staining of all our 17 cholangiocarcinoma specimens for GSTP1-1, irrespective of histological type. Transfection of the GSTP1-1 antisense expression vector into a human cholangiocarcinoma cell line (HuCCT1) apparently decreased its intracellular GSTP1-1 concentration, and the sensitivity of transfectants to adriamycin (ADR), cisplatin, and alkylating agents such as melphalan and 4-hydroxyperoxycyclophosphamide (4-HC) was increased significantly, compared with that of mock transfectants. We next synthesized GSTP1-1-specific inhibitors by elongating the carbon chain of the ethylester at the N-terminal of ␥-glutamyl-Sbenzylcysteinyl-phenylglycyl diethylester and performed a pharmacokinetic study on them. Of six GSTP1-1 inhibitors tested, O 1 -hexadecyl-␥-glutamyl-S-benzylcysteinyl-D-phenylglycine ethylester (C16C2) showed the smallest volume of central compartment and smallest volume of distribution at steady state and the second smallest clearance, being the most effective inhibitor in vivo. The IC 50 value of ADR or 4-HC for HuCCT1 cells decreased greater by treatment with C16C2 in a dosedependent manner, paralleling the decrease in GSTP1-1 activity, than that of ADR or 4-HC alone. The antitumor activity of ADR or cyclophosphamide was clearly enhanced by combination therapy with C16C2 in a xenograft model. In conclusion, our results demonstrated that GSTP1-1 is a resistance factor for anticancer drugs in cholangiocarcinoma and that C16C2, a GSTP1-1-specific inhibitor, is a potent agent against the resistance.Cholangiocarcinoma is a cancer that is highly resistant to various anticancer drugs and thereby leads to poor prognosis (de Groen et al., 1999;Isa et al., 2001;Patel, 2001;Okuda et al., 2002). However, the mechanism of chemoresistance of this disease is totally unknown.It has been reported that there are gene abnormalities in K-ras, p53, and APC in cholangiocarcinoma (Tada et al., 1990;Kiba et al., 1993;Ohashi et al., 1995;Tannapfel et al., 2000;Isa et al., 2002). In particular, K-ras mutation has been detected in as many as 48 to 80% of these cases. We have recently reported the close relationship between K-ras mutation and the expression of glutathione-S-transferase-(GSTP1-1), a detoxification enzyme in precancerous lesions as well as in cancer tissue (Miyanishi et al., 2001). We also showed that GSTP1-1 is a multidrug-resistant factor for adriamycin (ADR), cisplatin (CDDP), and alkylating agents such as melphalan Kuga et al., 1997). Hayes et al. (1991) examined the expression of GSTP1-1 in cholangiocarcinoma by immunohistochemical staining and found that it was positive in eight of eight cases, indicating that GST...

Objective: The study objective was to investigate the progression of uncorrected mild aortic insufficiency and its impact on survival and functional status after left ventricular assist device implantation.Methods: We retrospectively reviewed 694 consecutive patients who underwent implantation of a continuous-flow left ventricular assist device between January 2006 and March 2018. Pre-left ventricular assist device transthoracic echocardiography identified 111 patients with mild aortic insufficiency and 493 patients with trace or no aortic insufficiency. To adjust for differences in preoperative factors, propensity score matching was used, resulting in 101 matched patients in each of the mild aortic insufficiency and no aortic insufficiency groups.Results: Although both groups showed similar survival (P ¼ .58), the mild aortic insufficiency group experienced higher incidence of readmission caused by heart failure (hazard ratio, 2.62; 95% confidence interval, 1.42-4.69; P < .01). By using the mixed effect model, pre-left ventricular assist device mild aortic insufficiency was a significant risk factor for both moderate or greater aortic insufficiency and worsening New York Heart Association functional status (P < .01).

No abstract