L-乳酸脱氢酶抑制剂抑制成因的探讨

应用 HF/3 21G研究了抑制剂 H2N－ CO－ COO－对 L乳酸脱氢酶的抑制成因 .结果表明 ,酶被抑制的主要原因有 :(1)抑制剂与底物的稳定构象态在结构上极为相似 ,导致酶不能有效识别底物 ;(2)模型抑制剂各原子所带净电荷的优势使抑制剂更易与酶活性中心结合 ;(3)抑制剂通过对酶的诱导契合作用使酶活性中心的空间被缩小 ;(4)对活性中心有关结构的分析表明 ,底物的甲基分子片以及酶的氨基酸残基 Gln 102,对催化反应能否顺利进行 ,影响极大 .

Targeted systemic therapies for hepatocellular carcinoma:Clinical perspectives,challenges and implications

Hepatocellular carcinoma （HCC） is a lethal disease in most patients, due to its aggressive course and a lack of effective systemic therapies for advanced disease. Surgical resection and liver transplantation remain the only curative options for a small subset of patients. Few patients with HCC are diagnosed early enough to be eli- gible for curative treatment. Angiogenesis inhibition is a natural therapeutic target for all solid tumors, but par- ticularly for the highly vascularized HCC tumors. With the approval of the targeted agent sorafenib, there are now additional options for patients with HCC. Although sorafenib does produce some improvement in survival in HCC patients, the responses are not durable. In addi- tion, there are significant dermatologic, gastrointestinal, and metabolic toxicities, and, as importantly, there is still limited knowledge of its usefulness in special sub- populations with HCC. Other angiogenesis inhibitors are in development to treat HCC both in the first-line set- ting and for use following sorafenib failure; the furthest in development is brivanib, a dual fibroblast growth factor pathway and vascular endothelial growth factor receptor inhibitor. Additional agents with antiangiogenic properties also in phase IT and Ⅲ development for the treatment of patients with HCC include bevacizumab, ramucirumab, ABT-869, everolimus and ARQ 197.

Anti-angiogenesis in hepatocellular carcinoma treatment: Current evidence and future perspectives

Hepatocellular carcinoma(HCC) is among the most common cancer diseases worldwide.Arterial hypervascularisation is an essential step for HCC tumorigenesis and can be targeted by transarterial chemoembolization(TACE).This interventional method is the standard treatment for patients with intermediate stage HCC,but is also applied as "bridging" therapy for patients awaiting liver transplantation in many centers worldwide.Usually the devascularization effect induced by TACE is transient,consequently resulting in repeated cycles of TACE every 4-8 wk.Despite documented survival benefits,TACE can also induce the up-regulation of proangiogenic and growth factors,which might contribute to accelerated progression in patients with incomplete response.In 2007,sorafenib,a multi-tyrosine kinase and angiogenesis inhibitor,was approved as the first systemic treatment for advanced stage HCC.Other active targeted compounds,either inhibitors of angiogenesis and/or growth factors,are currently being investigated in numerous clinical trials.To overcome revascularisation or tumor progression under TACE treatment it seems therefore attractive to combine TACE with systemic targeted agents,which might theoretically block the effects of proangiogenic and growth factors.Over the last 12 mo,several retrospec-tive or prospective cohort studies combining TACE and sorafenib have been published.Nevertheless,robust results of the efficacy and tolerability of such combination strategies as proven by randomized,controlled trials are awaited in the next two years.

Controlled and reversible induction of differentiation and activation of adult human hepatocytes by a biphasic culture technique

AIM:Clinical application of human hepatocytes (HC) is hampered by the progressive loss of growth and differentiation in vitro. The object of the study was to evaluate the effect of a biphasic culture technique on expression and activation of growth factor receptors and differentiation of human adult HC. METHODS: Isolated HC were sequentially cultured in a hormone enriched differentiation medium (DM) containing nicotinamide, insulin, transferrin, selenium, and dexame-thasone or activation medium (AM) containing hepatocyte growth factor (HGF), epidermal growth factor (EGF), and granulocyte-macrophage colony-stimulating factor (GMCSF). Expression, distribution and activation of the HC receptors (MET and EGFR) and the pattern of characteristic cytokeratin (CK) filaments were measured by fluorometry, confocal microscopy and Western blotting. RESULTS: In the biphasic culture system, HC underwent repeated cycles of activation (characterized by expression and activation of growth factor receptors) and re-differentiation (illustrated by distribution of typical filaments CK-18 but low or absent expression of CK-19). In AM increased expression of MET and EGFR was associated with receptor translocation into the cytoplasm and induction of atypical CK-19. In DM low expression of MET and EGFR was localized on the cell membrane and CK-19 was reduced. Receptor phosphorylation required embedding of HC in collagen type I gel. CONCLUSION: Control and reversible modulation of growth factor receptor activation of mature human HC can be accomplished in vitro, when defined signals from the extracellular matrix and sequential growth stimuli are provided. The biphasic technique helps overcome dedifferentiation, which occurs during continuous stimulation by means of growth factors.

The effect of rh-endostatin on micrangium and angiogenic factors in tumor and myocardium tissue

Objective： The aim of this study was to compare effect of rh-endostatin on microvasculature in tumor and myocardium tissue. Methods： Nude mice were randomized into 4 groups, blank control group [did not burden tumor, normalsaline （NS） 100 μL/d], drug control group （did not burden tumor, rh-endostatin 400 μg/d）, model group （mice burdened tumor, NS 100 μL/d） and treatment group （mice burdened tumor, rh-endostatin 400 μg/d）, administration was given during d1-d28. The volume of tumor and the weight of mouse were measured before and after administration. The expression of CD34, MMP-2, MMP-9, HIF-la and VEGF in myocardium and tumor were detected by immunohistochemistry. The structure of vasculature was observed by immunoenzymatic double staining with CD34 and Masson. Results： The tumor volume increase of treatment group （48.18 mm3） was less than the model group （113.80 mm3）, the change of weight was not significant among the four groups. After treated with endotar, the expression of MMP-9 and VEGF in tumor were obviously down-regulated, but the same results was not found in MMP-2, HIF-la of tumor. MVD in tumor of treatment group decreased significantly compared with model group. Proportion of tumor vessels covered by collagen in treatment group increased compared with model group. However, MVD and microvasculature in myocardium did not change significantly. Conclusion： Rh-endostatin can decrease the expression of MMP-9, VEGF and MVD to inhibit growth of tumor and normalize micrangium in tumor but cannot weaken MMPs and MVD of mature micrangium in myocardium.

Toxicarioside A inhibits SGC-7901 proliferation,migration and invasion via NF-κB/bFGF signaling

AIM:To investigate the inhibitory role of toxicarioside A on the gastric cancer cell line human gastric cancer cell line(SGC-7901) and determine the underlying molecular mechanism.METHODS:After SGC-7901 cells were treated with toxicarioside A at various concentrations(0.5,1.5,4.5,9.0 μg/mL) for 24 h or 48 h,cell viability was determined by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl2H-tetrazolium bromide assay,and the motility and invasion of tumor cells were assessed by the Transwell chamber assay.Immunofluorescence staining,reverse transcription polymerase chain reaction and Western blotting were performed to detect the expression of basic fibroblast growth factor(bFGF) and fibroblast growth factor receptor-1(FGFR1),and nuclear factorkappa B(NF-κB) activation was examined by electrophoretic mobility shift assay.RESULTS:The results showed that toxicarioside A was capable of reducing cell viability,inhibiting cell growth,and suppressing cell migration and invasion activities in a time-and dose-dependent manner in SGC-7901 cells.Further analysis revealed that not only the expression of bFGF and its high-affinity receptor FGFR1 but also the NF-κB-DNA binding activity were effectively blocked by toxicarioside A in a dose-dependent manner compared with the control group(P < 0.05 or P < 0.01).Interestingly,application of the NF-κB specific inhibitor,pyrrolidinedithiocarbamate(PDTC),to SGC-7901 cells significantly potentized the toxicarioside A-induced down-regulation of bFGF compared with the control group(P < 0.05).CONCLUSION:These findings suggest that toxicarioside A has an anti-gastric cancer activity and this effect may be achieved partly through down-regulation of NF-κB and bFGF/FGFR1 signaling.

Molecular targeted therapy in gastrointestinal cancer

Gastrointestinal cancer is one of the highly prevalent malignant diseases worldwide which is a major cause of morbidity and mortality. Gastric cancer is the second leading cause of cancer mortality in the world and its management, especially in advanced stages, has evolved relatively little [1]. Colorectal cancer (CRC) remains the third most common ma-lignancy and the third leading cause of cancer death worldwide [2]. The surgical treatment is still the most effective therapy for the gastrointestinal cancer. However, the majority of the patients had lost the opporunity of surgical therapy when it was detected at advanced stage, so to seek means other than surgical treatment of gastrointestinal cancer metastasis and recur-rence also has an important significance. With the deeping research of the molecular biology, molecular targeted therapy has become the hotspot and focus of comprehensive treatment of gastrointestinal cancer which is proposed against the molecular biological targets such as tumor cell growth, apoptosis, cell cycle, invasion and angiogenesis. Molecular targeted therapy can be grouped into six main areas: the epidermal growth factor receptor (EGFR) inhibitors, anti-angiogenic factors, cell cycle inhibitors, apoptosis promoters and matrix metalloproteinase inhibitors, cyclooxygenase inhibitors. The review of the progress are as follows.