alpha-Fluoro beta alanine in urine of workers occupationally exposed to 5 fluorouracil in a 5 fluorouracil producing factory

Because of possible harmful health effects increased attention is being paid to the occupational exposure to cytostatic drugs of workers in hospitals and industry. In this study a biomarker for exposure to 5-fluorouracil (5FU) based on GC-MSMS was applied to study the occupational exposure of four workers in a pharmaceutical factory producing 5FU. The four workers all excreted-fluoro--alanine (FBAL), a metabolite of 5FU, via the urine (range excretion rates: 0-88 9 g per 8h). This is in accordance with the presence of 5FU and/or its precursor ethoxyfluorouracil (EFU) in stationary and personal air wipe samples taken from the the workplace.     

A flavone from the ethyl acetate extract of Leea rubra leaves with DNA damage protection and antineoplastic activity

Among the major constituents of Leea rubra (Family Vitaceae) leaves, phenolic and flavonoind compounds are most important for therapeutic purposes and the plant parts have been used in traditional medicine to treat several diseases for long. Thus, in order to scientifically confirm the traditional uses of the L. rubra leaves, the present study was designed to investigate the efficacy of the isolated flavones against AAPH induced oxidative damage to pUC19 DNA by gel electrophoresis and antineoplastic activity was evaluated on Ehrlich ascites carcinoma (EAC) bearing Swiss albino mice by evaluating percentage inhibition of cell growth, morphological changes of EAC cells and hematological parameters of the mice. The isolation was carried out by column chromatography and structure was revealed by ¹H-NMR and ¹³C NMR. The result shows that, the isolated compound was identified as myricetin 4'-methoxy-3-O-α-l-rhamnopyranoside based on previously reported data. The isolated flavone effectively inhibited AAPH-induced oxidative damage to DNA; because it could inhibit the formation of circular and linear forms of the DNA. In anti-proliferative assay, 76% growth inhibition of EAC cells was observed as compare to the control mice (p<0.05) at a dose 100 mg/kg body weight. Thus the isolated flavone showed great importance as a possible therapeutic agent in preventing oxidative damage to DNA and the chronic diseases caused by such DNA damage, and can also become important in cancer chemotherapy.     

sTRAIL蛋白原核表达载体的构建、表达及抗肿瘤活性研究

目的:从HL-60细胞中获得了sTrail基因片段,优化蛋白表达条件,并研究其抗肿瘤活性。方法:培养HL-60细胞,提取总RNA,通过RT-PCR扩增sTRAIL蛋白基因片段,并将目的基因克隆至原核表达载体p ET28a上,并电击转化E.coli BL21(DE3),IPTG诱导表达,优化蛋白表达条件,Ni-IDA柱纯化重组蛋白,SDS-PAGE蛋白电泳,胶内酶解质谱鉴定。纯化后的重组蛋白作用HUVEC,He La,Hep-3B,HCT-116,MDA-MB-231,H460细胞检测蛋白生物学作用。结果:DNA测序结果证实成功构建了重组质粒p ET28a-sTrail,SDS-PAGE蛋白电泳,胶内酶解质谱检测显示成功表达sTRAIL蛋白,MTT法和流式细胞术结果显示,sTRAIL蛋白对肿瘤细胞包括He La,HCT-116,MDA-MB-231,H460,Hep-3B细胞有良好的生物活性,对正常的HUVEC细胞无毒性。结论:成功构建可以高效表达sTRAIL蛋白的原核表达载体,优化蛋白的表达和纯化后所得sTRAIL蛋白具有良好的抗肿瘤生物活性,为研究和发展利用sTRAIL蛋白作为临床治疗抗肿瘤药物提供了重要基础。     

In vitro apoptotic activity of 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones in L5178Y cells

Compounds containing B-N bonds have shown interesting biological activity. One class of such molecules is the 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones (3a-j), which contain a B-N bond, have an alpha-amino acid moiety in the heterocycle, and have an exocyclic moiety related to an amino acid. The purpose of this work was to determine the inhibitory effects of 3a-j on the proliferation of murine L5178Y lymphoma cells. A new five-membered heterocyclic nucleus with apoptotic activity was found. The target products showed potent cytotoxicity in the L5178Y cell line. Among them, 3a exhibited the highest antineoplastic activity in L5178Y cells with an IC(50) value of 22.5+/-0.2 microM.     

Metal complexes as inhibitors of the 26S proteasome in tumor cells

The ubiquitin/proteasome pathway is the main mechanism available for eukaryotic cells to eliminate defective proteins and enzymes. Tumor cells -particularly those in solid tumors such as prostate cancer- seem to display increased proteasomal activity associated to cell growth. When such activity is inhibited apoptotic cell death takes place. Thus, the understanding of the chemical mechanisms by which this inhibition occurs is relevant to the development of new therapeutic antineoplastic agents. Here a short review is presented on the synthesis, characterization, and activity of metal-containing species with asymmetric ligands containing the methylpyridin-amino-methylphenol moiety. These complexes were scrupulously investigated structurally and spectroscopically, and have been shown to inhibit the chymotrypsin-like activity of the 20S and 26S proteasome in vitro and in vivo. Recent developments in the understanding of such inhibition are discussed and point out to the influence exerted by ligand substituents, the electronic configurations and charges of the metal ion, and the role of counterions.     

Synthesis of cholesteryl doxorubicin and its anti-cancer activity

Doxorubicin (dox) has been used as anti-cancer agent, but there are disadvantages such as rapid excretion, short retention time and cardiotoxicity. For giving lipophilic properties to dox, it was modified with cholesterol derivatives that were validated as a component of liposomal gene delivery. This article describes the synthesis of dox derivatives (lipo-dox A-D), their cytotoxicity and cellular uptake. In A549, HeLa, MCF7 and MDA MB 231 cell lines, lipo-dox A and lipo-dox B substituted at alcohol group showed similar anti-cancer effect as dox, but lipo-dox C and lipo-dox D substituted at amino group did not. As a result, the amino group of dox seems an important site for its cancer cell inhibition. Lipophilic property of lipo-dox A and lipo-dox B induced more accumulation in cells compared to parent drug. Therefore, the newly synthesized lipo-dox A and lipo-dox B would be a good candidate for anti-cancer agent.     

Cytotoxicity of boron containing dipeptide analogs

Summary This work is an extension of our previous work (Hall et al., 1993) on the synthesis and cytotoxic activity of boronated peptides. The aim of this work was to carry out structural modifications of the amine terminal in compounds1 and2, to increase water solubility, and its effect on the cytotoxicity to tumor cell lines. Surprisingly, only compounds4,7 and8 were more water soluble than the parent compounds. With the exception of compound4, the new derivatives were generally less effective than the parent compounds (1 and2). There was no apparent correlation between structure and activity. Cytotoxic effect was more pronounced in single cell suspended cells. The growth of solid tumor cell lines was not significantly reduced. The most active derivative, (methanamine)dihydro[[[1-(phenylmethyl)-2-methylamino-2-oxoethyl]amino]carboxy]boron (4), inhibited DNA, RNA, and protein synthesis in Tmolt₃ cells. Enzymatic activities, e.g., DNA polymerase, m-RNA polymerase, PRPP amidotransferase, carbamyl phosphate synthetase, TMP-kinase, TDP-kinase, dihydrofolate reductase, and ribonucleoside reductase were reduced after 60 min incubation with4. d(TTP) and d(CTP) pool levels were also reduced by 60 min incubation with4.     

Risk of developing hypothyroidism with the use of tyrosine kinase inhibitors and immune checkpoint inhibitors

BackgroundThe survival rate of patients with cancer has been increasing because of the sustained anticancer effect of new drugs, such as immune checkpoints inhibitors (ICI). Unlike the existing cytotoxic chemotherapies, immunotherapy causes immune system disturbance, such as hypothyroidism. Comparative studies on hypothyroidism following administration of ICI alone and in combination with other drugs are scarce. Therefore, we investigated the incidence of hypothyroidism after ICI in patients with cancer using a national population-based database.MethodsUsing the claims data from the Health Insurance Review and Assessment service in Korea, we retrospectively investigated patients with cancer who received chemotherapy between January 1, 2014 and February 28, 2021.ResultsOf all patients with cancer (n = 665,445) who received all kinds of chemotherapy, those who have received ICI accounted for 1.91 %. Compare with cytotoxic chemotherapy and angiogenesis inhibitors (AIs), ICI was associated with earlier (236.1 ± 248.4 vs. 811.1 ± 661.7, P < 0.01) and more frequent (7.7 % vs. 4.4 %, P < 0.01) occurrence of hypothyroidism, as well as an increased risk of developing hypothyroidism (odds ratio [OR] 1.69, 95 % confidence interval [CI] 1.58–1.80). However, the incidence of grade 2 or higher hypothyroidism was similar in both groups of patients who received ICI (3.3 %) and AI (3.1 %). The incidence of hypothyroidism was 4.4 times higher in patients who received both AI and ICI than in those who were treated with ICI alone (OR 4.41, 95 % CI 3.40–5.71).ConclusionsThis study showed a synergistic effect in patients who received multiple administrations of a drug that might be associated with thyroid dysfunction. Therefore, special attention should be paid to the treatment-related side effects when using drugs, such as AIs, concomitant with ICI treatment.     

纤维蛋白胶-抗肿瘤药物缓释系统的临床应用进展

纤维蛋白胶作为药物缓释载体的研究已经引起各国研究人员的注意,其中纤维蛋白胶—抗肿瘤药物缓释系统的研究取得了较好的效果,倍受瞩目。本文对纤维蛋白胶—抗肿瘤药物缓释系统的临床应用进展进行了总结。