抗肿瘤新药琥珀酸瓦他拉尼合成工艺改进

目的优化琥珀酸瓦他拉尼的合成工艺。方法以苯并呋喃酮为原料,与4-吡啶甲醛缩合后,依次经过重排、取代、成盐反应合成了琥珀酸瓦他拉尼。结果琥珀酸瓦他拉尼的总收率32.9%,高于文献报道的收率22.2%。结论改进后的工艺,缩短了反应时间,操作简单,适合工业化生产。     

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.     

Development of mitoxantrone

Summary Mitoxantrone (Novantrone®; dihydroxyanthracenedione) belongs to a new structural class of antineoplastic agents, the anthracenediones. It was the outcome of a program in synthetic chemistry, at the Medical Research Division of the American Cyanamid Company, which started from a molecule with structural features predicted to favor intercalation with double stranded DNA.The initial lead compound had immunomodulatory effects and was subsequently found also to possess significant activity against transplantable murine tumors. A large series of analogues was synthesized and mitoxantrone was selected for clinical trial on the basis of its potency and excellent antitumor activity in mice. It is a cytotoxic agent that will kill both proliferating and non-proliferating cells.A variety of experiments conducted with both intact cells and cell-free systems have revealed mitoxantrone's ability to bind to single stranded and double stranded RNA and DNA. The drug inhibits cellular RNA and DNA synthesis to about the same extent and causes chromosomal aberrations. In vivo experiments using murine models have demonstrated good activity for mitoxantrone against a variety of transplantable tumors including both leukemias and solid types, in many cases giving putative cures. Surprisingly, it is effective when given up to 30 days before tumor implantation. Combination studies with standard anticancer agents gave evidence of therapeutic synergy in a number of cases.Preclinical studies in several animal models indicate that mitoxantrone does not have the cumulative cardiotoxic liability associated with anthracycline antibiotics such as doxorubicin.     

抗肿瘤药物舒尼替尼的新合成方法

目的 研究抗肿瘤药物舒尼替尼的新合成路线。方法 以4-氟-2-碘苯胺（3）为原料,经氯乙酰化、膦酰化、Horner-Emmons-Wittig反应得N-[2-(二乙胺基)乙基]-5-[(E)-2-(4-氟-2-碘代-苯胺基甲酰基)-乙烯基]-2,4-二甲基-1H-吡咯-3-甲酰胺（6）;6在醋酸钯和三乙胺的作用下,通过分子内5-exo型环合反应得舒尼替尼。结果与结论 新中间体及舒尼替尼结构经核磁共振谱和质谱确证,合成路线未见报道。     

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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结肠癌靶向米托蒽醌脂质体的制备及其抗肿瘤活性研究

目的:比较透明质酸(HA)修饰的脂质体(HA-LP)与普通脂质体(LP)的抗转移及抗肿瘤活性。方法:采用薄膜水化法制备空白脂质体,通过透明质酸上的羧基与膜材中DSPE的氨基反应将HA连接在脂质体上,运用硫酸铵梯度法包载模型药物米托蒽醌;通过透射电镜表征脂质体形态;免疫荧光法检测结肠癌细胞(CT26 cells)中透明质酸受体CD44表达情况;高内涵扫描仪检测结肠癌细胞对脂质体的摄取情况;划痕实验考察2组脂质体抑制细胞转移的能力;体内抗肿瘤实验考察2组脂质体的抑瘤效果。结果:所制备的脂质体形态均一,包封率均大于95%。免疫荧光结果显示,结肠癌细胞中CD44受体高度表达。相同的药物浓度下,HA-LP相较于未修饰的脂质体具有明显增加的细胞摄取。划痕实验结果表明,HA可能与受体CD44存在某种相互作用,抑制了结肠癌细胞的转移,表现出HA-LP具有更强的抗转移活性。体内抗肿瘤结果显示,HA-LP对小鼠荷结肠癌实体瘤的抑瘤率为62.1%,显著高于普通脂质体组(46.6%,P<0.05)。结论:HA-LP与细胞膜上的受体CD44作用,显著增加了其细胞摄取,并抑制了结肠癌细胞的转移,体内抑瘤结果同样显示,具有肿瘤靶向功能的HA-LP具有更强的抑制肿瘤生长的能力。     

米托蒽醌隐形阳离子脂质体的制备及体内外抗肿瘤活性

目的:制备米托蒽醌隐形阳离子脂质体(YM),并研究其制剂学性质及体内外抗肿瘤作用。方法:膜材料中引入2-二油酰基羟丙基-3-N,N,N-三甲铵氯(DOTAP)和聚乙二醇2000-二硬脂酰磷脂乙醇胺(DSPE-PEG₂₀₀₀)分别作为阳性和隐形膜材,采用硫酸铵梯度法制备YM,并以泄漏率为指标,考察其稳定性;高内涵扫描仪考察2 h时其在B16F10细胞中的摄取情况;MTT 法测定其对B16F10细胞的增殖影响;B16F10皮下移植瘤模型研究其体内抗肿瘤作用。结果:YM的粒径和Zeta电位分别为(118.2±4.6)nm和(31.6±4.9)mV;载药量和包封率分别为(6.5±0.2)%和(96.2±1.8)%;血清中48 h累积泄漏率<30%,稳定性良好;YM的细胞摄取量是普通长循环脂质体(CM)的10倍,IC₅₀与CM相比显著降低(P<0.05),体内抑瘤率为58.8%,显著高于CM组的42.7%。结论:YM稳定性良好,具有较好的体内外抗肿瘤活性。     

多靶点抗肿瘤药物索拉非尼的研究进展

索拉非尼(sorafenib)是小分子的多靶点口服抗癌新药,不仅能抑制RAF-MEK-ERK通路,还能抑制VEGFR,PDGFR,Flt-3c,-Kit等多种受体型酪氨酸激酶的活性,从而达到抑制肿瘤细胞增殖和肿瘤新生血管生成的作用。美国FDA先后批准其用于晚期肾癌和肝癌的治疗,推荐剂量为400 mg,bid。与安慰剂比较,索拉非尼可明显延长患者的无进展生存期和总生存期。索拉非尼的主要不良反应有手足综合征、高血压、腹泻、皮疹、乏力。大多数不良反应可通过减少药物用量或停药而得到缓解。     

新型抗肿瘤药槐定碱

目的：槐定碱是从苦豆子中提取的单体生物碱,纯度高达99.5%以上.研究表明,其对动物移植瘤S-180等有30%～60%稳定的抑癌率;对癌细胞有一定直接杀伤作用;能影响癌细胞周期的G1和G2期,减少其增殖,并引起癌细胞凋亡;对癌细胞TOPO异构酶Ⅰ有抑制作用.体内过程符合二房室模型,分布广泛迅速,消除迅速,以原型经肾脏排泄.临床对恶性滋养细胞肿瘤有显著疗效,对恶性淋巴瘤和消化道肿瘤也有一定疗效,且毒性较低.     

抗肿瘤药物苹果酸舒尼替尼的合成

目的 合成抗肿瘤药物苹果酸舒尼替尼。方法 以乙酰乙酸叔丁酯为起始原料，通过Knorr吡咯合成法、脱叔丁氧羰基、Vilsmeier甲酰化、酯水解反应得中间体5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸（6），6与碳酰二咪唑反应生成酰基咪唑，不经分离直接用“一锅煮”方法与5-氟吲哚啉-2-酮和2-(二乙氨基)乙二胺缩合，最后成盐得到苹果酸舒尼替尼。 结果与结论 合成的苹果酸舒尼替尼经核磁共振、质谱和元素分析确证结构，总收率达28%。     

Toxicity of a particulate formulation for the intraperitoneal application of mitoxantrone

Mitoxantrone (MXN) has demonstrated therapeutic efficacy in the intraperitoneal treatment of malignancies. However, severe local toxicity is dose limiting. Therefore, a particulate formulation of MXN, the drug incorporated in albumin microspheres, was evaluated concerning tolerability. Survival rates as well as alterations in body weight, food intake, water intake, urine volume, urine specific gravity, urine protein content, and complete blood count were observed following single or multiple intraperitoneal injections of MXN solution, dispersions containing MXN-loaded microspheres or unloaded microspheres, and the injection vehicle to female and male Sprague–Dawley rats. Applied MXN dosage was equivalent to 30 mg/m² body surface area. Unloaded microspheres were well tolerated without signs of toxicity. Application of MXN solution or MXN-loaded microspheres resulted in similar survival rates (56% 9 weeks after single injection) and in a comparable bone marrow toxicity (mainly leucopenia). Body weight, food and water intake as well as urine volume were decreased following application of MXN solution, whereas a progressive gain in weight and no remarkable alterations in nutrition and urine excretion were noted after administration of MXN-loaded and unloaded microspheres, or of the injection vehicle. In conclusion, intraperitoneal injection of MXN incorporated in albumin microspheres exhibits in part less toxicity than conventional treatment.     

高喜树碱类抗肿瘤药物研究进展

在近年来研究的拓扑异构酶抑制剂中,高喜树碱类化合物是对喜树碱类化合物结构改造非常成功的衍生物,其活性等较喜树碱类强。本文主要就高喜树碱类在肿瘤治疗中的优越性及研究进展进行简要综述。     

Epoxomicin, a new antitumor agent of microbial origin.

An actinomycete strain No. Q996-17 produced a novel compound, epoxomicin, which exhibited in vivo antitumor activity against B16 melanoma. Structural studies indicated that it is a new member of the epoxy-beta-aminoketone group, and is closely related to eponemycin.     

Cardiovascular actions of an experimental antitumor agent,homoharringtonine, in anesthetized dogs

Cardiovascular actions of homoharringtonine, a plant extract currently being tested for clinical efficacy as an antitumor agent, were investigated in anesthetized mongrel dogs. Intravenous administration of homoharringtonine (4 mg/M²) produced significant reductions in heart rate, cardiac output, and arterial blood pressure, while myocardial contractility or total peripheral resistance were not altered. These results suggest that the bradycardia could account for decreases in both cardiac output and blood pressure. In additional experiments performed to evaluate the actions of homoharringtonine on cardiac sympathetic neurotransmission it was discovered that this compound caused significant impairment of the tachycardia elicited during stimulation of cardiac sympathetic nerves. The positive chronotropic effects of either norepinephrine or isoproterenol were not altered by homoharringtonine. In these animals in which both vagi and the right cardioaccelerator nerve were sectioned, the hypotensive and bradycardiac effects were of lesser magnitude than that seen in neurally intact animals. These results show that a dose of homoharringtonine comparable to that used in clinical trials produces hypotension and bradycardia which may result from inhibition of sympathetic nerve function caused by the compound.     

Role of pre- and post-replicative mismatch repair in cytotoxicity of methylating antitumor agents (a review)

The review considers modern data on the pre- and post-replicative repair of DNA damage induced by methylating agents such as N-methyl-N-nitrosourea, temozolomide, procarbazine, dacarbazine, and aranoza. These drugs are used in the treatment of various types of tumors including Hodgkin’s disease, brain tumors, disseminated melanoma, and lymphoproliferative diseases. Resistance (both intrinsic and acquired) to methylating agents is an important problem in cancer chemotherapy. The cytotoxicity of methylating agents depends on O6-methylguanine-DNA-methyltransferase (MGMT) activity (prereplicative repair). Several preclinical and clinical studies have demonstrated that postreplicative mismatch repair (MMR) is responsible to a high degree for the tumor cell resistance to the methylating agents. MMR in experimental studies is determined using expression of the main proteins hMLH1, hMSH2, and hMSH6 involved in the activity of the MMR system. Resistance to methylating agents is due to hypermethylation of promoters of the corresponding genes. The deficiency of hMLH1, hMSH2, and hMSH6 in tumors and lymphocytes after pre-operative neoadjuvant chemotherapy may serve as an independent predictor of poor prognosis in the development of disease. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 2, pp. 3–6, February, 2009.     

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.     

Section 2 Clinical experience with fenoprofen,a new antirheumatic agent

Summary

The authors review the studies which have been carried out on fenoprofen. Fenoprofen has been demonstrated to have anti-inflammatory, analgesic and antipyretic activity in both animals and man. It is an effective and well tolerated agent in the symptomatic treatment of patients with rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis, acute gout and non-articular rheumatism. Fenoprofen is also useful in the symptomatic treatment of a variety of conditions associated with pain and fever.

The main adverse reactions have been minor skin rashes and gastro-intestinal disturbances. Although less irritating than aspirin, fenoprofen should be used with caution in patients with a history of peptic ulcer disease. The risk-to-benefit ratio suggests that fenoprofen will be a useful therapeutic agent.     

抗肿瘤新药临床前安全性评价

大多数药物均具有两重性,一方面能治疗疾病,另一方面又具有副反应,抗肿瘤药更是如此。因此,对新的抗肿瘤药物进行安全性评价就显得更加重要。为了更正确地评价抗肿瘤药物的安全性,特提出抗肿瘤药物临床前安全性评价的基本要求和抗肿瘤药物毒理学研究中需要讨论的一些问题。     

Biochemical studies of a new antitumor agent, O2,2'-cyclocytidine

Cyclocytidine, O²,2′-cyclocytidine (cyclo-C), structurally related to 1-β-d-arabinofuranosyl cytosine (ara-C), inhibits the incorporation of ³H-thymidine into DNA of L1210 leukemia cells both in vivo and in vitro, and human normal marrow cells and leukemic cells in vitro; but it has no effect on uridine or l-valine incorporation. The inhibition is proportional to the dose, and on an equimolar basis in vivo, cyclo-C shows a lesser but longer lasting effect than ara-C. Cyclo-C has no effect on thymidine incorporation into DNA of L1210 leukemic cells resistant to ara-C. Cyclo-C is stable in 0.1 M Tris buffer, pH 7.0, at 37° for the incubated 4-hr period, but at pH 9.0 for 1hr, > 90 per cent is hydrolyzed to ara-C. When cyclo-C was incubated at 37° for 60 min with plasma from various species, the supernatant from boiled human plasma, or Eagle's minimum essential medium, the only product found was ara-C. Ara-C was found in dog's plasma and urine 2 hr after the i.v. injection of ¹⁴C-cyclo-C and in mouse urine 1 hr after the injection (i.p.). The above results suggest that cyclo-C is hydrolyzed to ara-C and may thus serve as a reservoir of ara-C. Intermittent treatment with cyclo-C may, therefore, replace the current clinical practice of 5-day continous intravenous infusion of ara-C.