| Background and ObjectivesHepatocellular carcinoma (HCC) has become one of the major diseases for human being. Hepatic surgery and multimodality therapy are currently the treatment choices for HCC, however, chemotherapy is still needed, especially in the treatment of HCC with extrahepatic metastasis. 5-Fluorouracil (5-FU) has been used in the treatment of a variety of tumor types, unfortunately its response rate was only around 15%, and serious sides were also observed. Capecitabine (XelodaTM) is a novel pr-drug of 5-FU that rapidly absorbed from the gastrointestinal tract after oral administration. In 1998, capecitabine was approved by FDA for treating paclitaxel-refractory breast cancer. Zhou et al in own institution recently demonstrated that capecitabine might inhibit the recurrence and metastasis after resection of a highly metastatic liver cancer. Capecitabine is preferentially converted to the cytotoxic 5-FU in target tumor tissue through a series of 3 metabolic steps, in which thymidine phsophorylase (TP) is a rate-limiting enzyme. TP shows higher concentrations in tumor tissue than normal tissue in numerous tumors, and resulted in higher 5-FU concentrations selectively in tumor tissue. TP has been reported to be identical to the angiogenic factor platelet-derived endothelial cell growth factor (PD-ECGF). Zhou et al demonstrated that the expression of PD-ECGF/TP mRNA in portal vein tumor thrombosis (PVTT), hepatocellular carcinoma (HCC) and tumor-free liver tissue were 77.8%, 67.9% and 35.7%. Another report said that PD-ECGF expression was noted in 51.9% of HCC, particularly in those with high Edmondson grades (III-IV) or PVTT. Unfortunately the level of TP activity in HCC was comparable to that in normal liver tissue, being 159.2±91.7 versus 143.5±72.1μg 5-FU/mg protein/hr. Therefore, it is important to find a way to enhance the expression of TP in HCC for making it more sensible to pr-drugs of 5-FU.The literature revealed that the sensitivity to capecitabine was enhanced in human renal carcinoma cells transfected with TP cDNA. The efficacy of 5(-deoxy-5-fluorouridine(5(-dFUrd) had been reported to be enhanced through the up-regulation of TP activity by various factors, such as IL-1α, TNFα, IFNγ, bFGF, PD-GF. In addition, IL-12 enhanced the efficacy of 5(-dFUrd and capecitabine in the tumormodels via up-regulation of IFNγ. Taxol, taxotere, and mitomycin also greatly enhanced the levels of TP in the tumors. Previous studies indicated that the catalytic activity of TP was indispensable for its angiogenic effects. When transfected into breast carcinoma cells, TP was found to enhance both angiogenesis and tumor growth in nude mice after inoculation of the cells. The high level of TP was positively related to tumor metastasis and poor prognosis.It is therefore needed to resolve the contradiction between enhancement of sensitivity to pr-drugs and increase metastasis potential via angiogenesis after up-regulation of TP.IFNs have pleiotropic effects on cellular function, including influences on cell growth, differetiation, and immunologic function. Treatment of human colon carcinoma cells with IFNα caused a 5-10-fold increase in the levels of TP mRNA in vitro, and enhanced TP expression was in patients treated with IFNα. Wang et al in our institution demonstrated that high-dose and long-term therapy with IFNα dose-dependendently inhibited tumor growth and recurrence after resection of HCC, mediated by antiangiogenesis. In the literature phase Ⅱ study with cisplatin, doxorubicin, 5-fluorouracil, and IFNαin advanced unresectable HCC demonstrates that complete pathological remission is possible.The purpose of present study is to evaluate the possibility of modulating TP by transfected with TP cDNA or by use of IFNα, furthermore to detect the changes of cell apoptosis, endothelial cell chemotactic activities and sensitivity to the fluoropyrimidine drugs, and to explore the dose of IFN not only inducing TP to increase sensitivity to fluoropyrimidine drugs, but also preventin...
|
PDF Full Text Request