海洋微生物抗肿瘤活性物质的研究进展

海洋微生物因其特殊的生存环境而具有产生新型生物活性物质的巨大潜力,从海洋微生物中寻找和开发抗肿瘤药物是一个前途广阔的新领域。近年来,从海洋微生物（海洋放线菌、真菌和细菌）分离鉴定了许多结构新颖的抗肿瘤活性物质,这些化合物显示了良好的抗肿瘤生物活性。本文就近几年从海洋微生物中分离得到的抗肿瘤活性物质的研究进展作了综述。     

Characterization and immunostimulatory activity of a polysaccharide from the spores of Ganoderma lucidum

Spores of Ganoderma lucidum contain a large amount of bioactive substances and have a higher bioactivity than the fruit bodies of G. lucidum. However, ingredients from spores are less studied due to the difficulties in collecting the spores and breaking the rigid shell. In this study, a water-soluble polysaccharide named GSG was extracted from the spores of G. lucidum. GSG is characterized to be a branched glucan that contains several different kinds of linkages. It was an effective inducer of MAPKs- and Syk-dependent TNF-α and IL-6 secretion in murine resident peritoneal macrophages. Dectin-1 could recognize GSG and partially mediate its biological activities. Additionally, in vivo administration of GSG potentiated the Con A-induced proliferative response of splenocytes and induced anti-tumor activity against Lewis lung cancer in mice. Therefore, these results suggest that GSG is an effective immunomodulator and may be a promising adjuvant remedy for anti-tumor therapies.     

Crystal structure of an anti-ganglioside antibody, and modelling of the functional mimicry of its NeuGc-GM3 antigen by an anti-idiotypic antibody

N-Glycolylated (NeuGc) gangliosides are tumor-specific antigens and as such represent attractive targets for cancer immunotherapy. The chimeric antibody chP3 selectively recognizes a broad variety of NeuGc gangliosides, showing no cross-reactivity to the highly similar N-acetylated (NeuAc) gangliosides that are common cellular antigens in humans. Here, we report the crystal structure of the chP3 Fab and its computer-docking model with the trisaccharide NeuGcα3Galβ4Glcβ, which represents the carbohydrate moiety of the tumor-antigen NeuGc-GM3. The interaction involves only the heavy chain of the chP3 antibody. The modelled complex is consistent with all available experimental data and shows good surface complementarity. The negatively charged sialic acid residue NeuGc is buried in a pocket flanked by two arginine residues, VH Arg31 and VH Arg100A. We have further investigated the interaction of chP3 with its anti-idiotypic antibody, 1E10 (also known as Racotumomab), currently in clinical trials as a cancer vaccine. While many of the chP3 residues predicted to interact with the NeuGc ganglioside also feature prominently in the modelled complex of chP3 and 1E10, we do not observe structural mimicry. Rather, we suspect that the anti-idiotype 1E10 may serve as an imprint of the structural characteristics of the chP3 idiotype and, consequently, give rise to antibodies with P3-like properties upon immunization.     

Combined yeast-derived β-glucan with anti-tumor monoclonal antibody for cancer immunotherapy

β-glucan is an immuno-stimulating agent that has been used to treat cancer and infectious disease for many years with varying and unpredictable efficacy. Recent studies have unraveled the action mode of yeast-derived β-glucan in combination with anti-tumor monoclonal antibodies (mAbs) in cancer therapy. It has demonstrated that particulate or large molecular weight soluble β-glucans are ingested and processed by macrophages. These macrophages secrete the active moiety that primes neutrophil complement receptor 3 (CR3) to kill iC3b-opsonized tumor cells. In vitro and in vivo data demonstrate that successful combination therapy requires complement activation and deposition on tumors and CR3 expression on granulocytes. Pre-clinical animal studies have demonstrated the efficacy of combined β-glucan with anti-tumor mAb therapy in terms of tumor regression and long-term survival. Clinical trials are underway using anti-epidermal growth factor receptor mAb (cetuximab) in combination with β-glucan for metastatic colorectal cancer. This review provides a brief overview of this combination therapy in cancer and describes in detail the β-glucan composition and structure, mechanism of action, and preclinical studies in human carcinoma xenograft models. It is proposed that the addition of β-glucan will further improve the therapeutic efficacy of anti-tumor mAbs in cancer patients.     

Targeting anti-tumor DNA vaccines to dendritic cells via a short CD11c promoter sequence

We describe for the first time a short sequence of the CD11c promoter (700 bp, named as CD11cS) which induces selective antigen expression in dendritic cells (DCs). It showed a stronger promoter activity than the hitherto used long CD11c promoter (5.5 kb, named as CD11cL), which had been reported inefficient to induce immune responses. After application to the ear pinna and electroporation (EP), CD11cS based DNA vaccines induced specific B- and T-cell responses, including IFN-γ secretion. Such vaccines achieved induction of anti-tumor immunity comparable in strength to vaccines having the strong tissue non-specific CMV promoter, in both prophylactic and therapeutic settings of mouse tumor models. This short CD11c promoter appears to be a safe and a practical tool for DC-specific gene targeting and for vaccination.     

白花蛇舌草水溶性提取物的抗肿瘤作用和对化疗损伤的保护作用的研究

白花蛇舌草Hedyotisdiffusa是一种传统的抗肿瘤中药 ,可广泛应用于治疗各种肿瘤 ,从白花蛇舌草中提取出水溶性提取物 (H1 和H2 ) ,采用接种S 180的荷瘤小鼠灌服其 10天 ,观察H1 和H2 的抗肿瘤活性。H1 (12 5 ,6 2 5mg·kg- 1 )和H2(6 2 5 ,31 2 5mg·kg- 1 )能显著抑制小鼠移植性S 180实体瘤的生长 ,而且H1 和H2 与环磷酰胺合用 ,可以明显改善环磷酰胺所致的免疫器官萎缩和造血系统的损伤。     

CD3AK细胞的诱导及其体外抗肿瘤活性的实验研究

本研究采用抗ＣＤ３单克隆抗体辅以少量的基因重组人白细胞介素２和植物血凝素诱导外周血淋巴细胞，成功地研制出具有抗瘤活性的ＣＤ３ＭｃＡｂ激活的杀伤细胞。     

白花蛇舌草不同提取工艺对抗肿瘤活性的影响

目的 为研制低毒高效的抗癌制剂，确定不同的白花蛇舌草提取物（汤剂，亲脂提取物，粗多糖）的抗肿瘤作用。方法 采用水提取法，醇提取法，脱脂水提醇沉法分别制备了白花蛇舌草汤剂，亲脂提取物和粗多糖，用S-180细胞植入小鼠作为模型。进行了抑制肿瘤的试验。结果 白花蛇舌草的水提液（汤剂）对S-180肿瘤细胞没有明显的抑制作用。白花蛇舌草水溶性的多糖和亲脂提取物对S-180肿瘤细胞具有显著的抑制作用；在抑瘤的同时，多糖部分具有对化学损伤的保护作用；水溶性的多糖和亲脂提取物合并给药并未显示协同抗肿瘤活性。结论 白花蛇舌草的脂溶性部位和多糖具有良好的抗肿瘤应用前景。分别提取比简单的水提取效果好。     

Measurement of tumour reactive antibody and antibody conjugate by competition, quantitated by flow cytofluorimetry

Binding of unlabelled monoclonal antibody preparations has been assessed by cometition at saturation with fluorochrome labelled homologous antibody for binding to antigen bearing target cells. The extent of competition was measured by quantitative flow cytofluorimetry, and simple mathematical procedures have been developed to allow the interpretation of competition data in terms of antibody binding activity. In the system studied, non-specific (non-competitive) fluorescence was minimal, but an iterative method to calculate its contribution to the measured signal is given. This approach has the advantage that the antibody preparation to be tested does not need to be labelled or modified; this is particularly important when evaluating the binding activity of therapeutic antibody conjugates. Comparison with a well characterized standard antibody preparation provides a rapid, sensitive and accurate quality control procedure. This test is also simple to perform, requiring only the mixing of labelled and unlabelled antibodies with target cells, a single incubation, followed by analysis without washing of the target cells.     

肿瘤专科医务人员对抗肿瘤生物类似药认知的调查分析

目的 调查肿瘤专科医务人员对抗肿瘤生物类似药的认知情况，为其临床合理使用提供保障。方法 采用问卷调查法，调查对象为我院40个科室的医师、护师和药师，使用自行设计的问卷对医务人员的一般资料、对生物类似药概念和特征的认知、抗肿瘤生物类似药临床使用的认知、抗肿瘤生物类似药相关药学服务的认知情况进行调查。结果 共发放问卷206份，有效回收201份，问卷有效回收率为97.57%。有79例（39.31%）知道生物类似药的定义，52例（25.87%）知道生物类似药的特征，53例（26.37%）知道抗肿瘤生物类似药适应证外推，其中内科知道生物类似药概念和特征的比例最高；有41例（20.40%）认为抗肿瘤生物类似药与参照药可以互换，41例（20.40%）认为抗肿瘤生物类似药之间可以互换，154例（76.62%）倾向于使用参照药，其原因主要是安全性（94例，46.77%）和有效性（113例，46.22%）；有193例（96.02%）认为制定“抗肿瘤药物超说明书用药管理制度”有必要，177例（88.06%）认为药师在抗肿瘤生物类似药临床应用中发挥了作用，并给出了开展抗肿瘤生物类似药相关药学服务的建议；有90例（44.78%）建议配置，137例（68.16%）建议处方审核，155例（77.11%）建议药学监护，120例（59.70%）建议处方点评，92例（45.77%）建议血药浓度监测。结论 我院肿瘤专科医务人员对抗肿瘤生物类似药的认知程度较低，药师应积极、准确地向医务人员传递抗肿瘤生物类似药相关信息，并提供全程化药学服务，以促进其安全、有效、经济、合理的使用。