质子泵抑制剂提高肿瘤化学治疗敏感性的研究进展

恶性肿瘤对化学治疗药物产生耐药是肿瘤患者化学治疗失败的主要原因。肿瘤细胞外微环境高度酸化是肿瘤细胞对化学治疗药物产生耐药的机制之一。改变肿瘤细胞内外pH梯度是逆转耐药的一种有效方法。用于治疗酸相关疾病的质子泵抑制剂能通过抑制质子泵功能,改变胞内外pH梯度而阻断肿瘤微环境酸化,达到提高肿瘤对化学治疗药物敏感性的目的。此文就其在化学治疗增敏方面的研究进展作一综述。

Bile acids as endogenous etiologic agents in gastrointestinal cancer

Bile acids are implicated as etiologic agents in cancer of the gastrointestinal (GI) tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious effects of bile acid exposure, likely related to carcinogenesis, include: induction of reactive oxygen and reactive nitrogen species; induction of DNA damage; stimulation of mutation; induction of apoptosis in the short term, and selection for apoptosis resistance in the long term. These deleterious effects have, so far, been reported most consistently in relation to esophageal and colorectal cancer, but also to some extent in relation to cancer of other organs. In addition, evidence is reviewed for an association of increased bile acid exposure with cancer risk in human populations, in specific human genetic conditions, and in animal experiments. A model for the role of bile acids in GI carcinogenesis is presented from a Darwinian perspective that offers an explanation for how the observed effects of bile acids on cells contribute to cancer development.

Twenty-four hour intra-arterial infusion of 5-fluorouracil,cisplatin,and leucovorin is more effective than 6-hour infusion for advanced hepatocellular carcinoma

AIM. To evaluate the time dependence of intra-arterial 5-fluorouracil （5-FU） therapy for advanced hepatocellular carcinoma （aHCC）. METHODS： Thirty-seven adult Japanese patients who had aHCC and liver cirrhosis were treated with combined intra-arterial 5-FU, cisplatin （CDDP）, and leucovorin （LV）. The Japan Integrated Staging score （JIS score） of each patient was 3 or more. The patients were divided into two groups, alter which the 15 patients in group S were treated with 6-h infusion chemotherapy （LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m^2 per 4 h） and the 22 patients in group L were treated with 24-h infusion chemotherapy （LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m^2 per 22 h）. Continuous infusion chemotherapy was performed v/a the proper hepatic artery every 5 d for 4 wk using an implanted drug reservoir. RESULTS： The percentages of patients with a partial response after 4 wk of chemotherapy were 6.7% in group S and 31.8% in group L. The survival of group L was significantly better than that of group S, with the median survival time being 496 d in group L and 226 d in group S （P 〈 0.05）. CONCLUSION： Continuous 24-h intra-arterial infusion is more effective for aHCC and can markedly prolong survival time as compared to 6-h infusion.

Carbonic anhydrases in normal gastrointestinal tract and gastrointestinal tumours

Carbonic anhydrases (CAs) catalyse the hydration of C02 to bicarbonate at physiological pH. This chemical interconversion is crucial since HCO3- is the substrate for several biosynthetic reactions. This review is focused on the distribution and role of CA isoenzymes in both normal and pathological gastrointestinal (GI) tract tissues. It has been known for many years that CAs are widely present in the GI tract and play important roles in several physiological functions such as production of saliva, gastric acid, bile, and pancreatic juice as well as in absorption of salt and water in intestine. New information suggests that these enzymes participate in several processes that were not envisioned earlier. Especially, the recent reports on plasma membrane-bound isoenzymes IX and XII have raised considerable interest since they were reported to participate in cancer invasion and spread. They are induced by tumour hypoxia and may also play a role in von Hippel-Lindau (VHL)-mediated carcinogenesis.

Phosphorylated KDR can be located in the nucleus of neoplastic cells

KDR （kinase insert domain receptor） phosphorylation induces several effects which lead eventually to cell proliferation and survival. The precise mechanisms by which KDR, once it is activated, communicates with the nucleus are starting to be understood but have not yet been completely unravelled. Two in vitro studies on animal cell lines reported in the literature have demonstrated that, following stimulation with VEGF, KDR is actually translocated within the nucleus. Our aim was to investigate whether this translocation occurs in human cells both in vitro and in vivo. Using laser scanning confocal microscopy, a variable nuclear localization of phosphorylated and total KDR in cell lines and tumour samples was found. In human neoplastic cell lines, hypoxic stimulation greatly increased the nuclear amount of total KDR but less so that of the phosphorylated form. Only after hypoxia and VEGF stimulation there was a comparably increased expression of phosphorylated and total KDR observed in the nuclei of these cells. We conclude that neoplastic cells show a variable expression of total and phosphorylated KDR in the nucleus. The precise functional meaning of nuclear location remains to be established.

TNF-α induces apoptosis of Molt-4 cells and cell cycle specificity of Bcl-2 phosphorylation

Objective： The aim of the study was to observe the expression of Bcl-2 and its phosphorylation in Molt-4 cells induced by tumor necrosis factor-α （TNF-α）, and to investigate the possible mechanism of cell cycle specificity of apoptosis. Methods： Exponentially growing Molt-4 cells were treated with TNF-α. Apoptosis was detected by DNA fragmentation assay. API method was applied to illustrate the cell cycle specificity of apoptotic cells. Cells of sub-phases were sorted by FACSvan- tage flow cytometer and then submitted to immunoblot. Results： Molt-4 cells which were treated with TNF-α went to apoptosis and showed a DNA ladder pattern. Most apoptosis happened in Gl-phase of cell cycle. Bcl-2 expression increased for the Molt-4 cells treated with TNF-α. The phosphorylation state of Bcl-2 was only presented in Gl-phase cells, in accordance with the specified time and cell cycle phase of apoptosis. Conclusion： The phosphorylation of Bcl-2 in the Molt-4 cells treated with TNF-α happened with the same cell cycle specificity as cell apoptosis. The cell cycle specificity of Bcl-2 phosphorylation was one of the mechanisms of receptor-mediated apoptosis. The cell cycle machine can trigger the apoptosis program.

IDENTIFICATION OF SPECIFIC PEPTIDE LIGANDS FOR B-LYMPHOMA CELL AND ITS EFFECT ON TYROSINE PHOSPHORYLATION AND CELL APOPTOSIS

Objective To search novel method for diagnosis and therapy of B-lymphoma, specific small mo-lecular peptide ligands against binding site of tumor cells were screened and its effects on signal transduction and cell apoptosis were tested. Methods Specific peptide ligands were screened by binding with site of human B lymphoma cell(OC1LY8)using peptide-bead libraries. The identified peptides were characterized with responsible cellsby rebinding test. The role of tyrosine phosphorylation of peptide ligand was tested by Western blot; and its apoptosispromoting role was observed by confocal fluorescent microscope. Results Specific peptide ligand was able to bind specifically to site on cell surface and enter into cytoplasm. Tetrameric peptide ligand was able to strongly trigger signal transduction resulting in tyrosine phosphorylation and cellular apoptosis in OC1LY8 cell line. Conclusion Screened peptide ligand can effectively bind with OC1LY8 cell, stimulate cellular tyro-sine phosphorylation and induce cellular apoptosis.