Inhibited proliferation of cyclooxygenase-2 expressing human hepatoma cells by NS-398, a selective COX-2 inhibitor.

Hepatocellular carcinoma (HCC) is a growing human health problem worldwide. Limited treatment and poor prognosis of this disease emphasize the importance in developing an effective chemoprevention. Overexpression of cyclooxygenase-2 (COX-2) has been associated with hepatocarcinogenesis. Although COX-2 inhibitors have been tested for chemoprevention of colon cancer, it remains unknown whether these agents possess anti-HCC effects as well. The present study assessed the effects of a selective COX-2 inhibitor, NS-398, on proliferation of human hepatoma cells in association with COX-2 expression, and the possible mechanisms. In four tested human hepatoma cell lines, overexpression of COX-2 was confirmed in HepG2, HuH7, and Chang liver cells, but not in PLC/PRF/5 cells. Addition of 50 micro M NS-398 resulted in both dose-dependent and time-course inhibition of HepG2 proliferation. In contrast, addition of 50 micro M NS-398 to COX-2 non-expressing PLC/PRF/5 cells resulted in only a mild reduction of cell proliferation. Consistent with this, a 48-h culture of HepG2 cells with 50 micro M NS-398 caused a significant decrease of prostaglandin E2 (PGE2) production. While, the same NS-398 treatment showed only a mild suppression of PGE2 production in COX-2 non-expressing PLC/PRF/5 cells. These findings indicate that NS-398-induced suppression of HepG2 proliferation appears mediated by decreased COX-2/prostaglandin (PG) production. We also found that NS-398-induced inhibition of HepG2 proliferation was associated with decreased 5-bromo-2'-deoxyuridine (BrdU) uptake, suggesting a reduced cell cycle progression in G1-S transition. NS-398 treatment also enhanced the apoptotic rate in COX-2 expressing HepG2 cells, but not in COX-2 non-expressing PLC/PRF/5 cells. Our findings confirmed an effective inhibitory effect of NS-398 on proliferation of COX-2 expressing human hepatoma cells through a decreased COX-2/PG activity that is associated with altered cell cycle progression and apoptotic rate.

Superior long-term results of renal transplantation in children under 5 years of age.

Despite improving overall results of pediatric renal transplantation children under 5 years of age remain a high-risk group with poorer outcomes often because of a higher rate of surgical complications. This retrospective report details a 12-year experience at a single center and examines the outcome in this high-risk group of patients. We reviewed the medical records of 21 children under 5 years of age who received renal transplantation at Loma Linda University Medical Center between July 1988 and August 2000. The patients were evaluated regularly by the same pediatric nephrologist throughout the study period at our outpatient clinic. Mean recipient age was 3 +/- 1.2 (range 2-5) years; weight at transplantation was 13.3 +/- 5.4 kg. Ten (48%) patients received living related donor (LRD) kidneys and 11 (52%) received cadaver (CAD) kidneys. Mean donor ages for CAD and LRD were 14.4 +/- 10 years and 26.6 +/- 4.9 years, respectively. The mean cold ischemia time (CAD only) was 23.3 +/- 10.6 hours. Renal dysplasia (n = 8) and obstructive uropathy (n = 5) were the most common primary diagnoses. Maintenance immunosuppression consisted of Azathioprine or mycophenolate mofetil (MMF), cyclosporine or tacrolimus and prednisone. Mean follow-up was 80.1 +/- 51.4 months. Twelve (57%) grafts have a follow-up >5 years. Patient survival was 100 per cent. Overall graft survival at one, 3, 5, and 10 years were 95, 95, 88, and 88 per cent respectively. Graft survival for LRD recipients was 100 per cent. No graft was lost as a result of a technical problem or vascular thrombosis. One graft each was lost because of delayed graft function complicated by severe cytomegalovirus infection and chronic rejection. At one year the mean serum creatinine was 0.6 +/- 0.2 mg/dL with a mean calculated glomerular filtration rate of 93 +/- 32 mL/min. All 17 children who are now of school age are attending school. We conclude that excellent rehabilitation and superior long-term patient and graft survival can be achieved with renal transplantation in children of this age group with the use of good surgical techniques and close follow-up.