摘要:

Non-resectable biliary tract cancer is associated with poor prognosis due to widespread resistance to chemotherapeutic agents and radiotherapy. It is therefore essential to explore new therapeutic approaches like the inhibition of tyrosine kinases. The aim of this study was to determine the expression of c-kitand platelet-derived growth factor (PDGF) receptors (PDGFRs) and the effects of the tyrosine kinase inhibitor imatinib±5-fluorouracil (5-FU) on proliferation and apoptosis in biliary tract cancer cell lines. The expression of c-kitand PDGFR mRNA was examined in 12 biliary tract cancer cell lines using RT-PCR. Cells were treated with imatinib (1, 10, 20 and 50 μmol/l)±5-FU (0.1 μg/ml) for 6 days and inhibition of cell growth was assessed by manual cell counting. Cell proliferation and apoptosis were analyzed by flow cytometry of BrdU and Annexin-V/propidium iodide-stained cells. c-kitand PDGF mRNA expression was detected in 50 and 75%, respectively. Imatinib (10 and 20 μmol/l) alone inhibited cell growth significantly higher in c-kit+cell lines (p<0.02) and inhibition was independent of PDGFR status. The combination with 5-FU increased the effect of imatinib mesylate in all cell lines. Treatment of cells with imatinib±5-FU was associated with a significant induction of apoptosis, but no inhibition of proliferation. We conclude that imatinib alone exerts marked effects on c-kit+biliary tract cancer cell lines only at intermediate and high concentrations, but there is a potential role of low-dose imatinib in combination with 5-FU for the treatment of biliary tract cancers.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

UCN-01, a selective inhibitor of protein kinase C, is known to inhibit the growth of cancer cells. Although it is currently undergoing clinical evaluation, information about its effect on human colon cancer is limited and the mechanism responsible is lacking. The objective of this study was to examine the cytotoxicity of UCN-01 to human colon cancer cellsin vitroand its effect on the apoptotic molecules. HT-29, a radiation- and chemotherapy-resistant human colon cancer cell, was used in the study. Cell death/apoptosis was determined by the MTT assay and DNA fragmentation measurement. NF-κB activity was measured by an enzyme immunoassay method. Western blot was employed to examine the expression of relevant apoptotic molecules. The result showed that UCN-01 could induce apoptosis of human colon cancer cells in a time- and dose-dependent manner. It markedly reduced the expression of Bcl-xL, but enhanced the level of p38 MAPK. In addition to Bcl-xLand p38 MAPK, UCN-01 also increased both caspase-3 and peroxisome proliferator activated receptor &ggr; protein levels. HT-29 cells transfected with exogenous Bcl-xLshowed a significant increase in NF-κB activity and prevented apoptosis induced by UCN-01. The overexpression of Bcl-xLalso reversed other relevant molecular changes observed in UCN-01-treated cells. In conclusion, UCN-01 exerted an antitumor effect in human colon cancer cells by inducing apoptosis. The mechanism responsible appeared to be related to reduction of Bcl-xLand increased p38 MAPK. The overexpression of Bcl-xLcan significantly prevent apoptosis induced by UCN-01.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The MTT assay was used to measure the effects of pamidronate, clodronate and mevastatin on the cell viability of Ewing's sarcoma cell lines 6647, CADO-ES-1, ES-2, ES-3, RD-ES, SK-ES-1, STA-ET-2.1 and VH-64. Treatment of these cells with pamidronate inhibited cell viability in a time- and dose-dependent manner. After a 72-h incubation period with 50 μM pamidronate, cell numbers were reduced by up to 80%, whereas the monophosphonate analog 3-aminopropyl phosphonate had no effect at concentrations up to 2 mM. Clodronate reduced cell viability by maximally 40% at 1 mM. These data provide the first evidence for a direct growth-inhibitory effect of pamidronate on Ewing's sarcoma cells. Hence, pamidronate definitely merits a more thorough exploration into its potential use in the therapy of patients with Ewing's sarcoma.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID