Immunotoxins and other conjugates containing saporin-s6 for cancer therapy

Ribosome-inactivating proteins (RIPs) are a family of plant toxins that permanently damage ribosomes and possibly other cellular substrates, thus causing cell death. RIPs are mostly divided in two types: Type 1 RIPs that are single-chain enzymatic proteins, and type 2 RIPs that consist of an active A chain (similar to a type 1 RIP) linked to a B chain with lectin properties. RIP-containing conjugates have been used in many experimental strategies against cancer cells, often showing great efficacy in clinical trials. Saporin-S6, a type 1 RIP extracted from Saponaria officinalis L. seeds, has been extensively utilized to construct anti-cancer conjugates because of its high enzymatic activity, stability and resistance to conjugation procedures, resulting in the efficient killing of target cells. This review summarizes saporin-S6-containing conjugates and their application in cancer therapy, considering in-vitro and in-vivo studies both in animal models and in clinical trials. The review is structured on the basis of the targeting of hematological versus solid tumors and on the antigen recognized on the cell surface.     

Novel conventional therapies in onco-hemathology

Cytogenetic, molecular and phenotyping features of malignant hematologic diseases succeeded in improving their management by a more accurate stratification of patients according to several groups of risk and by providing a rational for targeted therapy. Three major types of treatment (excluding cellular therapy) are currently available in onco-hematology: conventional chemotherapy, small molecules for targeted therapy and monoclonal antibodies. Conventional chemotherapy with optimization of doses and multidrug-based regimens allowed to substantially improve survival of patients and keeps a place of choice in treatment of these diseases. Targeted treatments came from the cytogenetic and molecular characterization of hemopathies. Thus, the kinase Bcr-Abl, as a result of the translocation t(9;22)(q34;q11), has been successfully targeted by tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Molecular abnormalities like internal-tandem duplication/point activating mutations in FLT3 in some acute myeloblastic leukemia or epigenetic dysregulations in some blood malignancies can also be targeted by small molecules. Hematopoietic malignant cells are phenotypically characterized by expression of cluster of differentiation (CD) on their surface. These CD are detected by flow cytometry using specific antibodies. Monoclonal antibodies targeting different CD have been developed for treatment. Rituximab, an anti-CD20 antibody, was the first monoclonal antibody successfully developed for treatment of malignant hematologic diseases. Since rituximab, many other monoclonal antibodies are being developed. Trends in malignant hematologic diseases presented here will include treatments, which have at least entered phase I/II clinical trials in adult or childhood leukemia. They include some novel drugs of conventional chemotherapy like second-generation nucleoside analogues. We will give an overview of the small molecules targeting the different cellular pathways and we will highlight those appearing as the most promising like novel TKIs. The large field of monoclonal antibodies will be also approached focusing on antibodies developed in leukemias.     

胡桃楸抗肿瘤作用及其机制研究概况

对胡桃楸的抗肿瘤机制进行整理分析。通过维普,SciFinder等数据库,查阅国内外文献。研究表明胡桃楸抗肿瘤作用的机制主要包括影响细胞周期、抑制DNA拓扑异构酶、诱导肿瘤细胞凋亡、提高免疫、损伤线粒体结构、改变细胞膜的结构和生化性质等。胡桃楸及其提取物具有的众多抗肿瘤靶向药物的特征,笔者认为其开发应用价值广阔,值得更进一步的深入研究,以期获得更高效低毒的产品。     

Biotransformation,a Promising Technology for Anti-cancer Drug Development

With the high morbidity and mortality caused by cancer, finding new and more effective anti-cancer drugs isvery urgent. In current research, biotransformation plays a vital role in the research and development of cancerdrugs and has obtained some achievements. In this review, we have summarized four applications as follows:to exploit novel anti-cancer drugs, to improve existing anti-cancer drugs, to broaden limited anti-cancer drugresources and to investigate correlative mechanisms. Three different groups of important anti-cancer compoundswere assessed to clarify the current practical applications of biotransformation in the development of anti-cancerdrugs.     

In vitro Investigation of Cytotoxic and Apoptotic Effects of Cynara L. Species in Colorectal Cancer Cells

Apoptotic and cytotoxic activity of plant extracts obtaining from naturally growing Cynara syriaca in Turkeyand cultivated C cardunculus against DLD1 colorectal cancer cells was determined. Extracts from wild andcultivated Cynara species were obtained from their vegetative parts and receptacles using hexane and applied withfive different dose (0.1-1 mg/ml) as well as apigenin for MTT tests for three time periods (24, 48 and 72 hours).After cells were treated with IC50 doses for each extract total DNA and RNA were isolated for determination ofthe cause of cell death. From isolated RNAs, cDNA were synthesized and amplification of p21, BCL-2 and BAXgene regions was carried out. Consequently, we found that pro-apoptotic (BAX) gene expression and a cell cycleinhibitor (p21) were induced in the presence of our artichoke extracts. In contrast, anti-apoptotic BCL-2 geneexpression was reduced compared to the control group. In addition DNA fragmentation results demonstratedDLD1 cell death via apoptosis.     

Inhibition of proliferation and induction of apoptosis by trimethoxyl stilbene (TMS) in a lung cancer cell line

Trimethoxyl stilbene (TMS) is a derivative of resveratrol, a compound shown to inhibit development of a variety of tumor types. We aimed to evaluate the effect of TMS on cell proliferation and apoptosis in the A549 non-small cell lung cancer cell line. Growth inhibition rate and colony formation was measured and apoptosis was determined with Hoechst 33258 staining. Protein expression levels of caspase-3, STAT3, STAT5b, JAK2, NF-κB, and IκB were examined by Western blotting. Furthermore, localization of NF-κB protein was also explored. TMS inhibited proliferation (IC50 8.6 μmol/L) and induced apoptosis of the cells in a concentration-dependent manner., also inducing apoptosis accompanied by up-regulated expression and cleavage activation of caspase-3, up-regulation of IκB and down-regulation of NFκB, STAT3, STAT5b, and JAK2 signal transduction. TMS has potential as a new drug for treatment of non-small cell lung cancer patients with anti-proliferation and apoptosis inducing effect of TMS to A549 cells apparently related to its inhibitory effect on STATs and NF-κB signal transduction. Up-regulation of caspase-3 further supports the potential clinical use of TMS for the treatment of non-small cell lung adenocarcinoma.     

低氘水抗肿瘤作用的研究进展

目的氘是致癌的重要诱发因素之一,通过采用先进的制造技术去除天然水中的氘,降低氘含量可制得贫氘水,又称低氘
水、超轻水或无氘水。有研究表明,水中氘浓度体积分数减少65%能够抑制肿瘤生长,国外临床实验证实服用低氘水（10~
20ppm）的肿瘤患者能使肿瘤停止生长,显著提高患者的生存时间和生活质量。目前,抗癌化疗药物种类繁多,但都存在一定局
限性,而低氘水使用方便,没有毒副作用。基于低氘水的显著优势,本文主要对低氘水的抗癌作用的研究进展作一综述。
     

Anti-GD2 immunotherapy for neuroblastoma

Introduction: Current therapeutic approaches for high-risk neuroblastoma (HR-NB) include high-dose chemotherapy, surgery and radiotherapy; interventions that are associated with long and short-term toxicities. Effective immunotherapy holds particular promise for improving survival and quality of life by reducing exposure to cytotoxic agents. GD2, a surface glycolipid is the most common target for immunotherapy.

Areas covered: We review the status of anti-GD2 immunotherapies currently in clinical use for neuroblastomas and novel GD2-targeted strategies in preclinical development.

Expert commentary: Anti-GD2 monoclonal antibodies are associated with improved survival in patients in their first remission and are increasingly being used for chemorefractory and relapsed neuroblastoma. As protein engineering technology has become more accessible, newer antibody constructs are being tested. GD2 is also being targeted by natural killer cells and T-cells. Active immunity can be elicited by anti-GD2 vaccines. The rational combination of currently available and soon-to-emerge immunotherapeutic approaches, and their integration into conventional multimodality therapies will require further investigation to optimize their use for HR-NB.     

雷公藤红素抗癌作用的研究进展

通过检索近年来与雷公藤红素相关的国内外文献,并对其进行分析、归纳、总结,从雷公藤红素的抗肿瘤作用机制及相关的靶点、通路等方面进行综述.1995年至今,多方面研究表明雷公藤红素有抗肿瘤作用,其作用机制包括诱导肿瘤细胞凋亡、影响血管生成、影响肿瘤相关的蛋白、通过肿瘤坏死因子及核因子-κB信号通路、以细胞微管为靶点、调节热休克反应等等,但对其体内过程等方面的研究还很少.应进一步针对雷公藤红素体内作用进行研究,为其抗肿瘤作用的发挥奠定坚实的基础.     

Re-challenge chemotherapy with gemcitabine plus carboplatin in patients with non-small cell lung cancer

Despite recent improvements to current therapies and the emergence of novel agents to manage advanced non-small cell lung cancer(NSCLC),the patients′overall survival remains poor.Re-challenging with first-line chemotherapy upon relapse is common in the management of small cell lung cancer but is not well reported for advanced NSCLC.NSCLC relapse has been attributed to acquired drug resistance,but the repopulation of sensitive clones may also play a role,in which case re-challenge may be appropriate.Here,we report the results of re-challenge with gemcitabine plus carboplatin in 22 patients from a single institution who had previously received gemcitabine plus platinum in the first-line setting and had either partial response or a progression-free interval of longer than 6 months.In this retrospective study,the charts of patients who underwent second-line chemotherapy for NSCLC in our cancer center between January 2005 and April 2010 were reviewed.All the patients who received a combination of gemcitabine and carboplatin for re-challenge were included in the study.These patients were offered second-line treatment on confirmation of clear radiological disease progression.The overall response rate was 15%and disease control rate was 75%.The median survival time was 10.4 months,with 46%of patients alive at 1 year.These results suggest that re-challenge chemotherapy should be considered in selected patients with radiological partial response or a progression-free survival of longer than 6 months to the initial therapy.