抗肿瘤药物的不良反应与处理

概述常见的抗肿瘤药物的不良反应，为抗肿瘤药品的临床合理使用和不良反应处理提供参考。     

The Anti-Cancer Potency and Mechanism of a Novel Tumor-Activated Fused Toxin,DLM

Melittin, which acts as a membrane-disrupting lytic peptide, is not only cytotoxic to tumors, but also vital to normal cells. Melittin had low toxicity when coupled with target peptides. Despite significant research development with the fused toxin, a new fused toxin is needed which has a cleavable linker such that the fused toxin can release melittin after protease cleavage on the tumor cell surface. We describe a novel fused toxin, composed of disintegrin, uPA (urokinase-type plasminogen activator)-cleavable linker, and melittin. Disintegrin is a single strand peptide (73 aa) isolated from Gloydius Ussuriensis venom. The RGD (Arg-Gly-Asp) site of disintegrin dominates its interaction with integrins on the surface of the tumor cells. uPA is over-expressed and plays an important role in tumor cell invasiveness and metastatic progression. The DLM (disintegrin-linker-melittin) linker is uPA-cleavable, enabling DLM to release melittin. We compared binding activity of our synthesized disintegrin with native disintegrin and report that DLM had less binding activity than the native form. uPA-cleavage was evaluated in vitro and the uPA-cleavable linker released melittin. Treating tumors expressing uPA with DLM enhanced tumor cell killing as well as reduced toxicity to erythrocytes and other non-cancerous normal cells. The mechanism behind DLM tumor cell killing was tested using a DNA ladder assay, fluorescent microscopy, flow cytometry, and transmission electron microscopy. Data revealed tumor cell necrosis as the mechanism of cell death, and the fused DLM toxin with an uPA-cleavable linker enhanced tumor selectivity and killing ability.     

Polyphenolic Contents and Biological Activities of Rumex ecklonianus.

Abstract

Rumex ecklonianus. Meissner (Polygonaceae) is a wild South African herb whose leaves are edible when young. It is mildly purgative and is used in the treatment of chlorosis and anemia. The polyphenolic content and antioxidant and antibacterial activity of the acetone, methanol, and water extracts were determined in this study. The concentrations of the different classes of phenolic compounds were higher in the acetone and methanol extracts when compared with the water extracts; this also correlates highly with the total phenolic content. Antioxidant activities of acetone and methanol extracts as assessed by three established in vitro. methods, namely, 2,2-azinobis.-(3-ethyl benzothiazoline-6-sulfonic acid) (ABTS), 1,1-diphenyl-2-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) methods were comparable with that of butylated hydroxyl toluene. The extracts showed significant activity against both Gram-positive and Gram-negative bacteria. The strongest antibacterial activity was found in the acetone extract, whose activity was pronounced on 7 of the 10 bacterial strains used, with a MIC value of 2.0 mg/mL. None of the extracts, however, inhibited Staphylococcus epidermidis. or Salmonella pooni.. The data obtained in this study suggest that R. ecklonianus. may be a good candidate for functional foods as well as pharmaceutical plant-based products. This is the first report on the biological activity of R. ecklonianus..     

海洋天然抗肿瘤活性产物的临床研究现状

海洋特殊的生态系统是天然抗肿瘤活性物质的重要来源之一,许多源于海洋生物的抗肿瘤活性化合物已经进入临床研究阶段。简要介绍海洋天然抗肿瘤活性产物的作用机制,综述新近发现的海洋天然抗肿瘤活性化合物的最新临床研究进展。     

青蒿素类化合物抗肿瘤研究进展

青蒿素类化合物是一类有效的抗疟疾药物,近年来研究显示该类化合物也具有良好的抗肿瘤作用。其抗肿瘤机制主要包括铁参与的氧化应激反应、阻滞细胞周期、诱导细胞凋亡以及抗新生血管生成等。由于青蒿素类化合物对正常组织细胞毒性小,且对多药耐药的肿瘤细胞仍然有效,因此,开发该类化合物作为新型的抗肿瘤药物具有广阔前景。     

Acylation of Exenatide by Glycolic Acid and its Anti-Diabetic Activities in db/db Mice

Purpose

To prepare acylated exenatide analogues and investigate their biological properties for guiding the development of PLGA formulations of exenatide.

Methods

The acylated exenatide analogues were prepared by reaction with glycolic acid (GA), one constitutional unit of PLGA, and characterized by HPLC-MS/MS and Circular Dichroism (CD). The pharmacokinetic properties and anti-diabetic activities were studied in SD rats and db/db mice, respectively.

Results

Structural characterizations of the acylated products showed that one to four glycolic acids (GAs) were connected to the primary amine groups of exenatide, and there was a conversion of α-helix to β-sheet to some extent. Pharmacokinetic studies in SD rats revealed that acylated exenatides had a similar Tmax with that of the prototype drug, whereas the Cmax and the AUC values of the adducts were significantly decreased. Biological activity tests demonstrated that exenatide and acylated exenatide analogues had similar in vivo antidiabetic activities in terms of controlling blood glucose concentration, HbA1c level, body weight and food intake.

Conclusions

These findings suggest that GA conjugated exenatide had no influence on the peptide efficacy, therefore it’s not necessary to inhibit exenatide acylation in PLGA formulations during the peptide release process.     

FRu（phen）2（3，8—2R—phen）-]^2＋（R=OH，H，F）电子结构与抗癌活性研究

用密度泛函(DFT)法，对配合物[Ru(phen)2(3，8-2R—phen)^2 (R=OH，H，F)进行了理论计算研究。探讨了配合物的电子结构与其抗癌活性的关系：主配体上3，8位上F原子的取代有利于配合物与DNA的作用，增加配合物的抗癌活性。计算结果能较好地预测配合物与DNA的作用强度、抗癌活性及指导具有较高抗癌活性配合物的合成。     

四氢吖啶类化合物的合成及其生物活性

以他克林为先导物,设计合成了１４个未见文献报道的新化合物,其中目的物８个。初步药理试验结果表明,所合成的目的物中（３ｂ）、（３ｆ）和（３ｈ）活性较好,显示９－位氨基、巯基和羧基取代物均有神经细胞保护作用,由于化合物（３ｆ）为他克林的苯并类似物,显著苯并他克林可提高他克林的神经细胞保护作用。     

Synthesis,characterization, and anti-cancer activity of new chalcone derivatives containing naphthalene and fluorine moieties

In recent years, chalcones and their derivatives have become the focus of global scientists due to increasing evidence reported towards their potency in antitumor and anti-cancer. Here, the chalcones designed and synthesized in our present study were derived from the derivatives of naphthaldehyde and acetophenone. Both these precursors have been reported in demonstrating a certain degree of anticancer property. Also, the substituents on these precursors such as hydroxyl, methoxy, prenyl, and chloro were shown able to enhance the anticancer efficiency. Hence, it is the interest of the current study to investigate the anticancer potential of the hybrid molecules (chalcones) consisting of these precursors with different alkoxy substituents and with or without the fluorine moiety. Two series of chalcone derivatives were designed, synthesized, and characterized using the elemental analysis, IR, ¹H and ¹³C NMR spectroscopy, subsequently evaluated for their anti-cancer activity. Interestingly, the results showed that the fluorinated chalcones 11–15 exhibited stronger cytotoxic activity towards the breast cancer cell lines (4T1) compared to non-fluorinated chalcone derivatives. Remarkably, the selectivity index obtained for these fluorinated chalcones derivatives against the breast cancer 4T1 cell line was higher than those exhibited by cisplatin, which is one of the most frequently deployed chemotherapy agents in current medical practice. These findings could provide an insight towards the potential of fluorinated chalcones being developed as an anti-cancer agent with moderate activity towards breast cancer cell and low inhibition of fibroblast cell at a concentration of 100 μM.     

dentification of DW532 as a novel anti-tumor agent targeting both kinases and tubulin

Aim： 7,8-Dihydroxy-4-（3-hydroxy-4-methoxyphenyl）-2H-chromen-2-one （DW532） is one of simplified analogues of hematoxylin that has shown broad-spectrum inhibition on tyrosine kinases and in vitro anti-cancer activities. The aim of this study was to identify DW532 as a agent targeting both kinases and tubulin, and to investigate its anti-cancer and anti-angiogenesis activities. Methods： In vitro tyrosine kinases activity was examined with ELISA, and tyrosine kinases activity in cells was evaluated with Western blot analysis. Tubulin turbidity assay, surface plasmon resonance and immunofluorescence technique were used to characterize the tubulin inhibitory activity. Cell proliferation was examined with SRB assay, and cell apoptosis and cell cycle distribution were analyzed with Annexin-V/PI staining and flow cytometry. Tube formation, aortic ring and chick chorioallantoic membrane assays were used to evaluate the anti-angiogenesis efficacy. Results： DW532 inhibited EGFR and VEGFR2 in vitro kinase activity （the ICso values were 4.9 and 5.5 pmol/L, respectively）, and suppressed their downstream signaling. DW532 dose-dependently inhibited tubulin polymerization via direct binding to tubulin, thus disrupting the mitotic spindle assembly and leading to abnormal cell division. In a panel of human cancer cells, DW532 （1 and 10 pmol/L） induced G2/M phase arrest and cell apoptosis, which subsequently resulted in cytotoxicity. Knockdown of BubR1 or Mpsl, the two core proteins of the spindle assembly checkpoint dramatically decreased DW532-induced cell cycle arrest in MDA-MB-468 cells. Moreover, treatment with DW532 potently and dose-dependently suppressed angiogenesis in vitro and in vivo. Conclusion： DW532 is a dual inhibitor against tubulin and tyrosine kinases, and deserves further development as a novel anti-cancer agent.     

Biological Activities of Constituentsfrom Psychotria spectabilis

Abstract

In a biological and phytochemical study on the leaves of Psychotria spectabilis. Steyerm., seven compounds were isolated and identified from the CHCl₃/MeOH (2:1, v/v) and MeOH extracts. Among the isolates were two diterpenes, solidagenone and deoxysolidagenone; three coumarins, coumarin, umbelliferone, and psoralene; and two flavonols, quercetin and quercetrin. Biological evaluations showed that diterpenes and coumarins exhibited antifungal activity against the filamentous fungi Cladosporium cladosporioides. (Fresen) de Vries and C. sphaerospermum. Penzig. Solidagenone and psoralene also displayed selective cytotoxic activity against Rad 52Y mutant yeast strain of Saccharomyces cerevisiae.. In this paper, the isolation, structure elucidation, and bioactivity results of these compounds are reported.     

Recent progress in the development of ursolic acid derivatives as anti-diabetes and anti-cardiovascular agents

Ursolic acid (UA) is a pentacyclic triterpenoid, which exhibits many biological activities, particularly in anti-cardiovascular and anti-diabetes. The further application of UA is greatly limited due to its low bioavailability and poor water solubility. Up to date, various UA derivatives have been designed to overcome these shortcomings. In this paper, the authors reviewed the development of UA derivatives as the anti-diabetes anti-cardiovascular reagents.     

铜紫红素-18的合成及其保肝抗溃疡活性的初步研究

以蚕沙糊状叶绿素为原料，经脱镁、扩环制得紫红素－18，再与铜离子络合得到铜紫红素－18，收率32．7％，并以叶绿素铜钠为阳性对照，对其保肝及抗胃溃疡活性进行了初步研究。结果表明，给予本品后与空白对照相比，小鼠TAA急性肝损伤模型的SGPT活性和大鼠应激性胃溃疡模型溃疡指数显著降低。     

Synthesis and Biological Activities of Some Benzimidazolone Derivatives

The reaction of 5-nitrobenzimidazolone with phenoxyethyl bromide in presence of potassium carbonate in dimethyl formamide obtained 6-nitro-1,3-bis(2-phenoxyethyl)-1,3-dihydro-2H-benzimidazol-2-one. It was reduced using stannous chloride to get 6-amino -1,3-bis(2-phenoxyethyl)-1, 3-dihydro-2H-benzimidazol -2-one, which was further treated with aromatic sulphonyl chloride to obtain benzimidazolone derivatives, 6a-k. These compounds were tested for antibacterial, antituberculosis and antifungal activity. Most of them have shown very good activity against some gram positive and gram negative microorganisms and fungal strains. Some of them have shown moderate activity against Mycobacterium tuberculosis.     

Pyrularia Thionin: Physical Properties,Biological Responses and Comparison to Other Thionins and Cardiotoxin

Abstract

Pyrularia thionin (PT) is a unique thionin which occupies a position between the viscotoxins and Gramineae thionins. Like the viscotoxins, PT comes from a dicotyledonous plant, Pyrularia pubera, and PT has a higher degree of amino acid homology with the viscotoxins than it does with the cereal grain thionins (1). However, PT has 4 disulfide bonds, as do the cereal grain thionins, and the viscotoxins have only 3. PT is distinct from both in that it is monomorphic. All thionins interact with and increase the permeability of cell membranes and are cytotoxic to some degree. PT and cardiotoxins also depolarize cell membranes, and PT opens a Ca²⁺ channel. PT as well as the other thoinins are amphipathic. This is apparent in the reported three dimensional structure of α-1 purothionin, which clearly shows distinct hydrophilic and hydrophobic domains on the surface of the protein, which contains two helical and one anti-parallel β-pleated sheet region. Examination of the physical properties show that PT combines with acidic phospholipids in synthetic membranes, and shows some specificity for phosphatidylserine. Our thesis is that PT combines with a specific phospholipid domain on the cellular membrane, most likely contining phosphatidylserine, causing early changes in membrane properties, including an increase in order parameter of the phospholipids, an increase in membrane permeability, depolarization of the membrane and opening of a Ca²⁺ channel. Later membrane responses include blebbing of the membrane bilayer and activation of an endogenous phospholipase A₂. The activation of this enzyme results in membrane degradation and is the major cause of the long term cellular responses attributed to the basic peptide, including killing of cells in culture and neurotoxicity to animals. The cause of PT-induced hemolytic activity is not immediately apparent. In its binding properties, physical responses of the membrane and biological responses of cells, cardiotoxin from cobra venom behaves in a very similar manner to PT, indicating a similar mechanism of action for both toxic peptides.     

顺铂药效和毒性作用的依时特征

目的:探索顺铂药效和毒性依时特征.方法:通过监测S180实体瘤小鼠的瘤重、外周血尿素氮和LD50评价昼夜不同时间顺铂给药的反应.结果:顺铂凌晨2:00给药作用强、毒性大,晚上18:00给药毒性小,作用弱.结论:顺铂的药效和毒性反应同步运行,对于小鼠晚上给药不良反应小,提示顺铂临床用药应避开毒性反应最大的时间.     

YL529, a novel,orally available multikinase inhibitor,potently inhibits angiogenesis and tumour growth in preclinical models

Background and Purpose

Targeted chemotherapy using small-molecule inhibitors of angiogenesis and proliferation is a promising strategy for cancer therapy.

Experimental Approach

YL529 was developed via computer-aided drug design, de novo synthesis and high-throughput screening. The biochemical, pharmacodynamic and toxicological profiles of YL529 were investigated using kinase and cell viability assays, a mouse tumour cell-containing alginate bead model, a zebrafish angiogenesis model and several human tumour xenograft models in athymic mice.

Key Results

In vitro, YL529 selectively inhibited the activities of VEGFR2/VEGFR3 and serine/threonine kinase RAF kinase. YL529 inhibited VEGF₁₆₅-induced phosphorylation of VEGFR2, as well as the proliferation, migration, invasion and tube formation of human umbilical vascular endothelial cells. It also significantly blocked vascular formation and angiogenesis in the zebrafish model. Moreover, YL529 strongly attenuated the proliferation of A549 cells by disrupting the RAF/mitogen-activated protein (MAP) or extracellular signal-regulated kinase (Erk) kinase (MEK) kinase kinase/MAPK pathway. Oral administration of YL529 (37.5–150 mg⁻¹·kg⁻¹·day⁻¹) to nude mice bearing established tumour xenografts significantly prevented the growth (60–80%) of A549, SPC-A1, A375, OS-RC-2 and HCT116 tumours without detectable toxicity. YL529 markedly reduced microvessel density and increased tumour cell apoptosis in the tumours formed in mice inoculated with the lung cancer cells, SPC-A1 and A549, and the colon carcinoma cells, HCT116.

Conclusions and Implications

YL529, an orally active multikinase inhibitor, shows therapeutic potential for solid tumours, and warrants further investigation as a possible anticancer agent.     

New NO-Donors with Antithrombotic and Vasodilating Activities,IV: Chemical Reactivity of Nitrosimines and its Implications for their Pharmacologic Properties

Nitrososydnone-5-imines and Thiazole-2-nitrosimines are susceptible to photolytic cleavage of the ?N? NO bond. This can be achieved with a tungsten lamp. In water the corresponding syndnone imine salts are formed in 90% yield at 37°C. Only at higher temp. (70°C) ring opening is observed. In methanol about 25% of sydnones are obtained. On the other hand NO? and N₂O were detected in the head space of the reaction vials when oxygen was excluded. The formation of N₂O from nitrososydnone imine was increased up to elevenfold by glutathione while the amount of NO? was decreased. In the presence of light and thiols soluble guanylate cyclase (s-GC) was stimulated. The results suggest that the nitroxylate anion NO^? plays an important role in the stimulation of s-GC.     

Synthesis of Palmitoyl Derivatives of Insulin and Their Biological Activities

In order to improve the lipophilicity of peptides, bovine insulin was chosen for the chemical modification using palmitic acid. The N-hydroxysuccinimide ester of palmitic acid was used for attachment to terminal amino groups, and p-methoxybenzoxycarbonyl azide was used for protection of the glycine-Al amino terminus. We obtained two purified derivatives of insulin, Bl-monopalmitoyl- and Bl,B29-dipalmitoyl-insulin, which were confirmed to be more lipophilic than the parent insulin on high-performance liquid chromatography (HPLC). The hypoglycemic effects of both products were measured in rats after intravenous and intramuscular injections. The mono derivative was more active than the di derivative and produced a longer effect duration than the native insulin after intravenous injection. The derivatives were also shown to be less immunoreactive as judged by an enzyme immunoassay.