棘刺锚参抗肿瘤因子的纯化及其抗肿瘤作用

目的纯化棘刺锚参抗肿瘤因子(Protankyra bidentata Antitumor Factor,PBATF),并探讨其抗肿瘤活性。方法棘刺锚参为原料,采用盐溶液抽提,硫酸胺分级沉淀,DEAE-Sepharose CL-6B离子交换层析,Sephacryl S-300分子筛层析,ZORBAX GF-250HPLC层析,得到PBATF。采用SDS-PAGE电泳和HPLC鉴定其纯度。采用MTT方法测定PBATF对肿瘤细胞生长的影响,克隆形成实验测定对肿瘤细胞集落形成的影响。采用荷瘤小鼠试验测定PBATF对体内肿瘤生长的影响。结果从棘刺锚参纯化获得PBATF,达到较高纯度。PBATF对7901人胃癌细胞、Hela细胞、NCI非小细胞肺癌细胞均具有显著的生长抑制效应,而对929小鼠成纤维细胞和小牛主动脉血管内皮细胞只在高浓度时有抑制作用。PBATF对Hela细胞的集落形成与生长具有明显的抑制作用,试验浓度时对皮肤成纤维细胞的集落形成无明显影响。PBATF对小鼠Lew-is肺癌有明显的疗效,结论获得了高纯度的PBATF,能够显著抑制体内外肿瘤生长。5mg·kg-1剂量具有56.89%的抑瘤率,1mg·kg-1剂量的抑瘤率为52.00%,0.5mg·kg-1剂量的抑瘤率为33.61%。     

Camptothecin antitumor agents

The discovery of the natural product 20(S)-Camptothecin as a highly promising anticancer lead compound in the early 1960s; the identification of topoisomerase I as the molecular target of camptothecin compounds almost 20 years later; the approval and clinical success of irinotecan and topotecan as the first representatives of this novel class of chemotherapeutics another decade later; and the recent efforts to improve drug potency, stability, bioavailability and tumor selectivity: this is the story of camptothecin antitumor agents which will be reviewed.     

Experimental antitumor activity of BMY-28090, a new antitumor antibiotic

Summary BMY-28090 is a novel actinomycete fermentation derived antitumor agent. The cytotoxic effect of BMY-28090 was evaluated in two murine and eight human tumor cell lines in vitro. Following 72-hour exposures, BMY-28090 was cytotoxic for all of these cell lines with IC50 values of < 0.02 to 3.25 g/ml. BMY-28090 was evaluated for in vivo antitumor activity in a variety of experimental murine tumor and human tumor xenograft models. Initial testing against the murine tumor models was performed using BMY-28090 as the water insoluble free base whereas subsequent antitumor tests were performed using water soluble lactate or succinate salts. BMY-28090 administered ip demonstrated good, reproducible antitumor activity against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma and M5076 sarcoma. The water soluble preparations of BMY-28090 were active iv against sc implanted B16 melanoma and M5076 sarcoma as well as subrenal capsule (src) M5076 sarcoma; activity against src implanted B16 was marginal. BMY-28090 lactate was also evaluated for activity against src implanted MX-1 human mammary tumor xenografts in nude mice and the HCT116 human colon tumor xenografts in immune-suppressed BDF mice. At maximum tolerated doses administered ip, BMY-28090 was active against the MX-1 xenograft in two of three tests, causing > 90% inhibition of tumor growth. BMY-28090 administered iv at maximally tolerated doses had marginal activity against the HCT116 xenografts, producing 61% and 68% inhibition of tumor growth in two tests. The results of these studies demonstrated that BMY-28090 has a broad spectrum of in vitro cytotoxicity against both murine and human tumor cell lines. Moreover, BMY-28090 had in vivo antitumor activity against murine leukemias, murine solid tumors and human tumor xenografts, including tumors located distal to the site of drug administration.A preliminary report of some of this research was presented at the Annual Meeting of the American Association for Cancer Research, Los Angeles, CA, May 1986 (1090).

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叶酸受体介导的抗肿瘤靶向前药研究进展

叶酸受体(folate receptor,FR)在大部分人体肿瘤细胞表面过度表达,而在正常细胞表面则很少表达,甚至不表达。这就使得利用FR介导的抗肿瘤药物靶向作用于FR呈阳性的肿瘤细胞成为可能,从而减少传统抗癌药物对正常细胞的毒副作用。另外,前药在克服药物用药障碍、增强化学及代谢稳定性、增加口服或者局部给药的吸收度、增强血脑屏障渗透性、延长作用时间、提高生物利用度,以及减轻不良反应等应用中,已成为一种有效策略而被广为接受。本文主要对FR介导的抗肿瘤靶向前药的作用机制进行综述,并介绍近几年研究者设计并合成的叶酸修饰的靶向前药。     

住院患者抗肿瘤药物的用药分析

目的 分析解放军总医院住院患者抗肿瘤药物的应用情况及其发展趋势,为临床科室合理用药提供依据.方法 对我院住院患者2007-2009年抗肿瘤药物的用药金额、分类、用药频度(DDDs)等统计分析.结果 我院住院患者2007、2008、2009年抗肿瘤药的用药金额分别为9170.3万元、13 601万元、18 749.8万元,呈快速增长趋势;多西他赛虽然DDDs较小,但增长较快,销售额3年稳居首位;单抗类抗肿瘤药销售金额呈快速增长趋势;中成药的DDDs构成比最高;抗代谢药消耗金额构成比相对稳定;抗肿瘤抗生素类、烷化剂和激素类在整个抗肿瘤药中所占的构成比较小并且逐年呈下降趋势.结论 目前我院住院患者抗肿瘤药物使用基本合理,中成药在我院肿瘤治疗方面起到了很好的辅助作用.新型高效、低毒、靶向类的药物及植物药将成为以后抗肿瘤治疗的主要趋势.     

叶酸受体介导的抗肿瘤药物研究进展

   叶酸受体在大多数人体肿瘤细胞表面过度表达,而在正常细胞中的存在很少,甚至检测不到,这就使叶酸受体介导的抗肿瘤药物可以靶向性地作用于叶酸受体呈阳性的肿瘤细胞,减少传统抗癌药物对正常细胞的毒副作用,提高药物的选择性。本文对叶酸受体介导的抗肿瘤药物的作用机制进行综述,介绍近几年研究者设计并合成的叶酸-药物缀合物及其活性测试的结果。     

Experimental antitumor activity of BMY-28175 a new fermentation derived antitumor agent

Summary BMY-28175 is a novel antitumor antibiotic produced in fermentation by Actinomadura verrucosospora. The cytotoxic effects of BMY-28175 were determined using murine and human tumor cell lines in vitro. Following 72 hour exposure, the drug had IC50 values 1.5 to 13.5 ng/ml in a microtiter assay. BMY-28175 was evaluated for antitumor activity against several experimental murine and human tumor models. The drug administered ip was active against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma, M109 lung carcinoma, C26 colon carcinoma, M5076 sarcoma and Lewis lung carcinoma. In addition, BMY-28175 administered iv was active against iv implanted P388 and L1210 leukemias. BMY-28175 was active against sc implanted B16 melanoma (increased lifespan and/or inhibition of primary tumor growth) in about 60% of the tests. The growth of sc implanted M109 was inhibited by BMY-28175 in a single experiment. BMY-28175 was also active against the MX-1 human mammary xenograft implanted in the subrenal capsule of nude mice. The optimal dose for BMY-28175 in these various studies ranged from 0.16 g/kg per injection with consecutive daily (qd1-9) administration, to 51.2 g/kg with single dose administration. The results of these studies indicate that BMY-28175 is one of the most potent antitumor agents yet observed, with a broad spectrum of activity against tumors of murine and human origin and activity against tumors located distal to the site of drug administration.     

烯二炔类大分子抗肿瘤抗生素C1027抗菌与抗肿瘤活性差异的研究

Ｃ１０２７具有极强杀伤肿瘤细胞活性,作用靶点在ＤＮＡ,但Ｃ１０２７ 的抗菌活性不强,如能了解差别出现的原因,就可进一步掌握Ｃ１０２７的抗菌作用机制,并为将来在临床上确定其应用范围打下良好基础。对Ｃ１０２７ 的抗肿瘤活性与抗菌活性的差异的初步研究结论如下：大分子Ｃ１０２７ 与小分子博莱霉素Ａ５ 相比,对肿瘤细胞抑制作用明显高于后者;对细菌的抑制作用却明显低于博莱霉素Ａ５;对支原体的抑制作用略大于博莱霉素Ａ５ 。Ｃ１０２７（１００～０．０１ｍ ｇ／Ｌ）对大肠埃希氏菌Ｂ原生质体ＤＮＡ合成几乎无抑制作用,同对大肠埃希氏菌Ｂ菌体的ＤＮＡ合成抑制作用相比,差别不大。细胞壁并非阻碍Ｃ１０２７损伤大肠埃希氏菌ＢＤＮＡ的主要因素。     

DNA拓扑异构酶与抗肿瘤

DNA拓扑异构酶是真核细胞和原核细胞中的基本酶,广泛分布于细胞核内,在复制、转录、翻译、重组及染色体单体分离等过程中控制、维持和修饰DNA拓扑结构。研究发现,拓扑异构酶在肿瘤组织中高表达,许多抗肿瘤药物的作用机制与抑制拓扑异构酶有关。     

Novel antiproliferative antitumor agents

Small molecules with potent and selective antitumor activity continue to be identified by screening in cellular assays and to be entered into clinical development, and in some cases small molecules are progressed despite the fact that the mechanism of action is unknown. Current examples of drugs with unknown mechanism of action include LY-573636 (Eli Lilly & Co), CHS-828 and SPC-595 (Sunesis Pharmaceutical Co Ltd). Early discovery and the elucidation of structure-activity relationships may be in part facilitated by the fact that the compounds must be relatively soluble and permeable to cells to demonstrate activity, although the challenges of optimizing absorption, distribution, metabolism and excretion/pharmacokinetic properties, toxicity and clinical activity remain similar to compounds developed under the 'targeted therapy' paradigm.     

Cardiotoxicity of antitumor drugs

Many antitumor drugs cause "on treatment" cardiotoxicity or introduce a measurable risk of delayed cardiovascular events. Doxorubicin and other anthracyclines cause congestive heart failure that develops in a dose-dependent manner and reflects the formation of toxic drug metabolites in the heart. Cardiovascular events may occur also with other chemotherapeutics, but the dose or metabolism dependence of such events are less obvious and predictable. Drugs targeted to tumor-specific receptors or metabolic routes were hoped to offer a therapeutic gain while also sparing the heart and other healthy tissues; nonetheless, many such drugs still cause moderate to severe cardiotoxicity. Targeted drugs may also engage a cardiotoxic synergism with "old-fashioned" chemotherapeutics, as shown by the higher than expected incidence of anthracycline-related congestive heart failure that occurred in patients treated with doxorubicin and the anti HER2 antibody Trastuzumab. Mechanism-based considerations and retrospective analyses of clinical trials now form the basis for a new classification of cardiotoxicity, type I for anthracyclines vs type II for Trastuzumab. Such a classification may serve a template to accommodate other paradigms of cardiotoxicity induced by new drugs and combination therapies. Of note, laboratory animal models did not always anticipate the mechanisms and/or metabolic determinants of cardiotoxicity induced by antitumor drugs or combination therapies. Toxicologists and regulatory agencies and clinicians should therefore join in collaborative efforts that improve the early identification of cardiotoxicity and minimize the risks of cardiac events in patients.     

Designed enediyne antitumor agents

The enediynes remain among the most potent antitumoral agents to have been discovered in the past decade. Following prodrug activation, the enediynes undergo cycloaromatization reactions resulting in formation of highly reactive diradical intermediates. The diradical species engage in atom-transfer chemistry to produce neutral arene products, in the process inducing damage to key macromolecules. Several of the naturally occurring members of the enediyne family of antibiotics have entered clinical trials, and this has prompted the design of synthetic enediynes, where the enediyne lquo;warheadrquo; is conjugated to a targeted delivery vehicle. This review will describe ecent efforts using chemical synthesis to identify and improve the target specificity of designed enediynes, and to establish efficient methods to achieve prodrug activation. Finally, new horizons will be examined, including the use of post-cycloaromatized enediyne templates as recognition elements for unique DNA and RNA microenvironments.     

PD 116,152, a new phenazine antitumor antibiotic. Structure and antitumor activity

A new, highly substituted phenazine with antitumor activity was isolated from the culture broth of a Streptomyces sp. This compound, whose structure was determined by spectroscopic methods and verified by X-ray diffraction analysis, was found to be methyl 6-formyl-4,7,9-trihydroxy-8-methyl-1-phenazinecarboxylate.     

Tetrocarcins, novel antitumor antibiotics. II. Isolation, characterization and antitumor activity

Novel antitumor antibiotics, tetrocarcin complex composed of three components (A, B and C) were isolated from the culture broth of Micromonospora chalcea KY11091 through various procedures. Tetrocarcins showed marked activity against experimental tumors such as mouse sarcoma 180 and mouse leukemia P388. Multiple injections showed better therapeutic effect against tumors. Mode of action of tetrocarcin A against Bacillus subtilis was found to be through the inhibition of RNA synthesis.     

Fused azepinones with antitumor activity

Based on the observation that some simple [1]benzazepin-2-ones exhibit in vivo antitumor activity, studies directed to several new structure classes with this partial motif have been reported recently, comprising 7,12-dihydro-indolo[3, 2-d][1]benzazepin-6(5H)-ones (paullones), 5H-qui nolino[3, 2-d][1]benzazepin-6(7H)-ones, 2,4-diaryl-5H-pyrido[3, 2-d][1]benzazepin-6(7H)-ones, spiro[1-benzazepine-4,1 -cyclohexane] deriva-tives, and naphthannelated benzazepinones. For the syntheses of these heterocyclic compounds, 1H-[1]benzazepine-2,5(3H,4H)-diones were employed as readily available starting materials. In each of the mentioned series, entities with in vitro antitumor activity have been detected. Considering potency and in vitro cell line selectivity, both the 2,4-diaryl-5H-pyrido[3, 2-d][1]benzazepin-6(7H)-ones and the paullones are apparently suitable for a further development. A biological mechanism probably related to the anti proliferative activity has been established only for the paullones. These compounds represent a novel class of selective inhibitors of cyclin-dependent kinases, a family of enzymes whose function seems to be deregulated in many human tumors.     

The antitumor activities of flavonoids

The flavonoids are polyphenolic compounds found as integral components of the human diet. They are universally present as constituents of flowering plants, particularly of food plants. The flavonoids are phenyl substituted chromones (benzopyran derivatives) consisting of a 15-carbon basic skeleton (C6-C3-C6), composed of a chroman (C6-C3) nucleus (the benzo ring A and the heterocyclic ring C), also shared by the tocopherols, with a phenyl (the aromatic ring B) substitution usually at the 2-position. Different substitutions can typically occur in the rings, A and B. Several plants and spices containing flavonoid derivatives have found application as disease preventive and therapeutic agents in traditional medicine in Asia for thousands of years. The selection of a particular food plant, plant tissue or herb for its potential health benefits appears to mirror its flavonoid composition. The much lower risk of colon, prostate and breast cancers in Asians, who consume more vegetables, fruits and tea than populations in the Western hemisphere do, raises the question of whether flavonoid components mediate the protective effects of diets rich in these foodstuffs by acting as natural chemopreventive and anticancer agents. An impressive body of information exists on the antitumor action of plantflavonoids. In vitro work has concentrated on the direct and indirect actions of flavonoids on tumor cells, and has found a variety of anticancer effects such as cell growth and kinase activity inhibition, apoptosis induction, suppression of the secretion of matrix metalloproteinases and of tumor invasive behavior. Furthermore, some studies have reported the impairment of in vivo angiogenesis by dietary flavonoids. Experimental animal studies indicate that certain dietary flavonoids possess antitumor activity. The hydroxylation pattern of the B ring of the flavones and flavonols, such as luteolin and quercetin, seems to critically influence their activities, especially the inhibition of protein kinase activity and antiproliferation. The different mechanisms underlying the potential anticancer action of plant flavonoids await further elucidation. Certain dietary flavonols and flavones targeting cell surface signal transduction enzymes, such as protein tyrosine and focal adhesion kinases, and the processes of angiogenesis appear to be promising candidates as anticancer agents. Further in vivo studies of these bioactive constituents is deemed necessary in order to develop flavonoid-based anticancer strategies. In view of the increasing interest in the association between dietary flavonoids and cancer initiation and progression, this important field is likely to witness expanded effort and to attract and stimulate further vigorous investigations.     

抗肿瘤多肽研究进展

抗肿瘤活性多肽由于具有相对分子质量小、活性高、毒性低等特点,在肿瘤的临床治疗上有重要的价值。此文按照多肽的来源综述了目前国内外对于一些新的具有抗肿瘤活性的多肽的研究现状。     

Properties of antitumor activity of vinorelbine tartrate, a new vinca alkaloid antitumor agent

Vinorelbine (VNR) is a new vinca alkaloid derivative semi-synthesized by Potier et al. The antitumor activity of VNR was superior to other vinca alkaloid antitumor agents, and the neuro-toxicity of VNR was weaker than those of other vinca alkaloids. In nude mice xenografted human tumor models, VNR showed antitumor activity against eight of eleven tumor models (non-small cell lung cancer: 4/4, breast cancer: 2/3, colon cancer: 0/2, stomach cancer: 2/2). Especially, VNR showed tumor-regressive activity against LC-6 non-small cell lung cancer and MX-1 breast cancer. The antitumor activity of VNR against non-small cell lung cancer was superior to that of vindesine (VDS), which had been one of the key drugs of non-small cell lung cancer in the clinic. In combination chemotherapy, VNR plus cisplatin (CDDP) was better than VDS plus CDDP, which had been one of the standard regimens of non-small cell lung cancer chemotherapy. The potent antitumor effect of VNR with minor neurotoxicity was explained by VNR having stronger activity on mitotic microtubules than axonal microtubules. It was supposed that less activity of VNR against mitotic microtubules would be related to different composition of microtubule-associated TAU isoforms in the two types of microtubules. In non-small cell lung cancer, VNR resulted in a significantly higher response rate than VDS. In combination with CDDP, VNR resulted in longer survival than VDS with a significant log-rank test. In advanced breast cancer, VNR resulted in a high response rate in 1st line and 2nd line treatment. VNR is effective in combination with chemotherapeutic agents such as anthracycline, fluorouracil and Taxol. In Japan, the clinical trial in breast cancer is now ongoing.