克癌新丸对小鼠肝癌H22移植瘤生长及免疫的影响

目的：探讨克癌新丸对小鼠肝癌H₂₂移植瘤生长的抑制作用及对荷瘤小鼠免疫的影响。方法：在ICR小鼠右腋皮下注射小鼠肝癌H₂₂细胞,建立小鼠移植性肿瘤模型,通过瘤重计算抑瘤率,观察克癌新丸对H₂₂移植瘤生长的抑制作用;采用腹腔巨噬细胞吞噬试验、淋巴细胞转化试验、Elisa法测定血清细胞因子TNF-α、IL-2、IL-12的水平及利用Western-blot检测瘤组织中IL-2、TNF-α的蛋白表达,观察克癌新丸对H₂₂移植瘤小鼠免疫的影响。结果：在200,400,800 mg· kg^-1时克癌新丸对H₂₂的抑瘤率分别为23.12%,38.71%和48.92%,且能提高H₂₂移植瘤小鼠的胸腺和脾指数;克癌新丸能增强H22移植瘤小鼠腹腔巨噬细胞的吞噬功能,促进淋巴细胞转化,提高血清细胞因子TNF-α、IL-2、IL-12的水平,上调瘤组织中IL-2、TNF-α的蛋白表达。结论：克癌新丸明显抑制H₂₂移植瘤的生长,具有较强的体内抗肿瘤活,其机制可能与增强移植瘤小鼠的免疫有关。     

顺铂脂质体的制备及其体内外评价

目的 制备抗肿瘤药物顺铂脂质复合物脂质体(CDDP-MM),以期降低顺铂的毒副作用,并保持其疗效。方法 使用逆相蒸发法制备CDDP-MM;以SD大鼠为实验动物考察CDDP-MM的体内药动学行为;以H₂₂荷瘤小鼠为模型,以市售注射用顺铂为参比,考察CDDP-MM的体内抗肿瘤效果及其毒副作用。结果 所制备的CDDP-MM平均粒径为109.8 nm,包封率高达90%。大鼠体内药动学结果表明,与注射用顺铂相比,CDDP-MM最大血药浓度(c_max)提高2.93倍(P<0.001),t_1/2α延长65.50倍(P<0.01);AUC_0-24显著增大41.26倍(P<0.01),CDDP-MM显著改善了注射用顺铂的体内药动学行为。小鼠体内抗肿瘤活性结果表明CDDP-MM的抑瘤率为82.5%,与注射用顺铂组相比小鼠体重显著增加(P<0.000 1),肾毒性下降。结论 CDDP-MM显著改善顺铂的体内药动学行为且可以有效抑制肿瘤生长、显著降低顺铂的胃肠道毒性和肾毒性。     

LncRNA CYTOR对大鼠背脊髓神经元细胞损伤及炎性因子的影响

目的 探讨LncRNA CYTOR对大鼠背脊髓神经元细胞损伤及炎性因子的影响及其可能作用机制。方法 采用过氧化氢(H₂O₂)诱导大鼠背脊髓神经元细胞建立细胞损伤模型，随机分为：con组、H₂O₂组、H₂O₂+pcDNA组、H₂O₂+pcDNA-LncRNA CYTOR组、H₂O₂+pcDNA-LncRNA CYTOR+miR-NC组、H₂O₂+pcDNA-LncRNA CYTOR+miR-136-5p组。qRT-PCR检测LncRNA CYTOR、miR-136-5p的表达量；MTT法与流式细胞术分别检测细胞增殖及凋亡；ELISA法检测IL-6、IL-21的水平；双荧光素酶报告实验检测LncRNA CYTOR与miR-136-5p的靶向关系；Western blot检测Bax、Bcl-2蛋白表达量。结果 与con组比较，H     

盐酸表柔比星联合维生素K2的药效学考察

目的考察不同剂量盐酸表柔比星(epirubicin hydrochloride,EPI)脂质体联合维生素K₂(Vitamin K₂,VK₂)纳米乳的抗肿瘤效果。方法制备唾液酸(sialic acid,SA)修饰的EPI脂质体(EPISAL)、维生素K₂纳米乳(VK₂-E)、SA修饰的维生素K₂纳米乳(VK₂-SAE),并对制剂进行了表征和稳定性及药动学考察。使用S180肉瘤为模型,采用多个参数综合评价VK₂-E、VK₂-SAE分别联合不同剂量EPI-SAL的体内抗肿瘤效果。结果剂量分别为0.75、1.5、3.0 mg·kg^-1EPI-SAL,5 mg·kg^-1VK₂-E和5 mg·kg^-1VK₂-SAE的单独使用均具有一定的抗肿瘤作用;当不同剂量的EPI-SAL与VK₂-E、VK₂-SAE联合治疗后,效果均优于EPI-SAL的单独治疗;其中EPI-SAL与VK₂-SAE的联合治疗效果优于EPI-SAL联合VK₂-E;值得注意的是,低剂量的EPI-SAL与VK₂-SAE联用后,体内抗肿瘤效果与单独使用高剂量EPI-SAL的治疗效果相当。结论VK₂可以协同EPI发挥抗肿瘤作用,进而减少EPI的使用剂量,可降低EPI剂量过大带来的心脏毒性等副作用。     

麝香及其代用品人工麝香对H2O2诱导人脐静脉内皮细胞损伤保护作用比较研究

目的：研究麝香（TR）及其代用品人工麝香（RG）对H₂O₂诱导人脐静脉内皮细胞（HUVECs）损伤保护作用及机制。方法：将对数期生长的HUVECs细胞随机分为5组：空白对照、H₂O₂、H₂O₂+NAC、H₂O₂+TR和H₂O₂+RG。HUVECs细胞在H₂O₂作用2 h后,采用MTS法检测细胞增殖光密度值并计算存活率,利用试剂盒测定细胞外液LDH漏出量、细胞内MDA含量、SOD和GSH-Px活力。对HUVECs细胞进行伊红染色,然后用光学显微镜观察细胞形态变化。结果：与H₂O₂组相比较,麝香（50 μg·mL^-1）增加了细胞存活率（P<0.05）;使LDH漏出量和MDA含量显著降低（P<0.05,P<0.001）;使SOD和GSH-Px活力显著提高（P<0.01,P<0.05）;抑制了H₂O₂对HUVECs细胞形态的改变,减少了细胞内ROS水平。人工麝香（50 μg·mL^-1）对HUVECs细胞也有保护作用,但不具有统计学意义。结论：麝香对H₂O₂诱导的人脐静脉内皮细胞损伤具有保护作用,作用机制可能与有效改善细胞内抗氧化酶的活性,减轻氧化应激损伤有关。此外,麝香对人脐静脉内皮细胞的保护作用略强于人工麝香。     

SP94修饰的肝靶向阳离子基因载体的制备及其体外评价

目的：研究适配体SP94修饰的阳离子基因载体H₃R₅,合成新型肝靶向纳米复合物SP94-H₃R₅/miR195,增加对肝癌细胞的靶向性,提高基因的转染效率。方法：经半胱氨酸修饰的SP94与H₃R₅末端的半胱氨酸发生氧化反应,组装得到SP94-H₃R₅,利用¹H-NMR鉴定SP94-H₃R₅载体的结构,通过电位粒度仪测定纳米复合物的电位和粒径,利用琼脂糖凝胶电泳考察载体对miR195的压缩能力。以体外培养的人肝癌SK-Hep-1为研究对象,CCK8法检测SP94-H₃R₅和H₃R₅对细胞增殖的抑制作用,采用激光共聚焦显微镜考察肝癌细胞对纳米复合物的摄取,以pEGFP为报告基因考察基因转染效率,Western blot 实验检测SK-Hep-1细胞VEGF的蛋白表达。结果：SP94-H₃R₅具有生物相容性,可以压缩miR195形成稳定的纳米复合物,SP94-H₃R₅/miR195与H₃R₅/miR195相比可以更多地被SK-Hep-1摄取（P<0.01）,SP94-H₃R₅转染效率高于非靶向载体H₃R₅,对VEGF的阻滞作用也更高（P<0.01）。结论：SP94-H₃R₅兼具纳米材料的被动靶向作用和适配体的主动靶向作用,有潜力成为肝癌治疗中的新型载体。     

奈达铂联合氟尿嘧啶治疗晚期食管癌的疗效观察

目的 比较奈达铂（NDP）与顺铂（DDP）联合氟尿嘧啶（5-Fu）对晚期食管癌的疗效及其不良反应.方法 61例晚期食管癌患者随机为分观察组（奈达铂组）30例,对照组（顺铂组）31例.奈达铂组给予NDP 80～100 mg/m2,静脉滴注,第1天,5-Fu 0.5 g/m2,静脉滴注,第1～5天 顺铂组给予DDP 80～100 mg/m2,分3 d静脉滴注,5-Fu 0.5 g/m2静脉滴注,第1～5天.每4周为一个化疗周期,2个化疗周期后评定疗效并比较.结果 观察组有效率56.7%,显著高于对照组的29.0%（P〈0.05） 观察组的胃肠道不良反应显著低于对照组（P〈0.05）,但骨髓毒性显著高于对照组（P〈0.05）.结论 NDP联合5-Fu对晚期食管癌有一定的疗效,较DDP联合5-Fu方案有一定优势,临床耐受性较好,可作为一线药物推荐.     

尖吻蝮蛇血凝酶对心肺转流术下心脏瓣膜置换术患者凝血功能的影响

目的观察尖吻蝮蛇血凝酶对心肺转流术（CPB）下心脏瓣膜置换术患者凝血功能的影响和安全性。方法择期CPB下行心脏瓣膜置换术患者80例,随机分为对照组;H₁组:手术开始前20 min给药;H₂组:心肺转流开始后20 min给药;H₃组:心肺转流结束肝素拮抗后给药,每组20例,H₁^H₃组均注射尖吻蝮蛇血凝酶2 U,对照组于手术前20 min注射等量0.9%氯化钠注射液。分别于术前20 min（T₀）、术后即刻（T₁）、术后24 h（T₂）测定4组的凝血功能[凝血酶原时间（PT）、活化部分凝血酶时间（APTT）、凝血酶时间（TT）、血浆纤维蛋白原（Fib）]、血小板（PLT）;记录术后24 h内心包纵隔引流量、机械通气时间、重症加强护理病房（ICU）停留时间、实际住院天数及住院费用、输血量等各临床指标以及二次开胸、过敏、肝肾功能异常、深静脉血栓形成及精神神经症状等不良事件的发生情况。结果与对照组比较,T₁、T₂时H₁、H₂和H₃组PT、APTT、TT降低（P<0.05）,与T0时比较,各组患者T₁、T₂时PT、APTT、TT升高;与H₁组比较,H₃组T₁、T₂时PT、TT降低（P<0.05）。H₁、H₂和H₃组术后24 h内心包纵隔引流量和机械通气时间低于对照组（P<0.05）,各组不良事件发生率无明显差异。结论应用尖吻蝮蛇血凝酶可改善心肺转流术下心脏瓣膜置换术患者的低凝状态,且使用安全。     

EZH2选择性抑制剂GSK126对胶质瘤细胞增殖的影响

目的研究Zeste基因增强子人类同源2（EZH2）抑制剂GSK126对胶质瘤细胞系U87和LN229细胞增殖的影响。方法 GSK126处理U87和LN229细胞后,采用CCK-8和平板克隆实验检测该抑制剂对胶质瘤细胞增殖的影响,用流式细胞仪测定其对细胞周期的影响,Western blot检测H3K27me3、p21、cyclin E和CDK2的表达。结果经GSK126处理后,U87和LN229细胞增殖能力下降（P<0.05）;GSK126处理能够诱导细胞停滞于G₀/G₁期（P<0.05）,p21蛋白表达量上升,而H3K27me3、cyclin E和CDK2表达量下调（P<0.05）。结论 GSK126能显著抑制胶质瘤细胞增殖,并通过上调p21表达来阻滞细胞周期。     

TM208-羟丙基-β-环糊精包合物的制备及其在大鼠体内的药动学研究

目的:4-甲基哌嗪-1-二硫代甲酸-(3-氰基-3,3-二苯基)丙酯盐酸盐(TM208)是我院合成的新抗肿瘤化合物,极难溶于水。本实验的研究目的是研制TM208-羟丙基-β-环糊精(HP-β-CD)包合物,并研究其在大鼠体内的药动学。方法:以共沉淀法制备TM208-HP-β-CD包合物,比较原药与包合物的紫外吸收光谱,X-射线衍射图谱,差示扫描量热图谱的变化;两组SD大鼠分别单剂量口服TM208混悬剂和TM208-HP-β-CD包合物,用HPLC法测定血药浓度;应用3P87药动学程序计算药动学参数。结果:TM208与TM208 HP-β-CD包合物紫外光谱一致; TM208经包合后晶体衍射峰消失;差示扫描量热法测定结果显示形成包合物后一种新物相峰出现;TM208在形成包合物后溶解度增大了700倍;大鼠单剂量给予TM208混悬剂和TM208-HP-β-CD包合物后,TM208的主要药动学参数C_(max)分别为(1．31±0．22)和(2．84±1．23)μg·mL~(-1),T_(max)分别为(10．2±4．18)和(3．31±0．541)h。AUC_(0～4(?)h)分别为(42．5±11．5)和(67．7±20．I)μg·mL~(-1)·h。统计分析结果显示,包合后TM208达峰时间显著缩短,峰浓度显著提高,相对生物利用度为159．3％。结论:TM208制备成HP-β-CD包合物后,在水中溶解度极显著增加,体内吸收速度与程度显著提高。     

Effect of TM208 on QGY-7703 xenograft tumor growth

A newly synthesized dithiocarbamate derivative, 4-methylpiperazine-1-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride (TM208), has demonstrated anticancer effects with low toxicity in earlier studies; however, the mechanism has yet to be identified. We explored antitumor effects of TM208 and the possible mechanisms by which it inhibited the growth of human hepatocellular carcinoma cell line QGY-7703 xenograft tumors. Cell proliferation was evaluated with the sulforhodamine B assay in vitro. The results suggested that TM208 had slightly antiproliferative activity on QGY-7703 cells. The antitumor effect of TM208 was assessed in nude mice xenografted with QGY-7703 tumors. We found that TM208 significantly inhibited tumor growth but did not cause loss of body weight or leukocytopenia. Western blotting was used to detect the expression of protein kinase C alpha, mitogen-activated protein kinase signal pathways, and cell cycle-related proteins. The results showed that TM208 decreased the expression of protein kinase C alpha, phospho-extracellular signal-regulated kinase-1/2, phospho-p38, cyclin B1, cell division cycle 2 (cdc2), and phospho-cdc2 (Thr161) and increased the expression of phospho-cdc2 (Tyr15). Taken together, our data show that TM208 has little antiproliferative effect on QGY-7703 cells in vitro, whereas it significantly inhibits the growth of QGY-7703 xenograft tumors with low toxicity in vivo. The inhibition of mitogen-activated protein kinase signal pathways and the regulation of the G2/M phase may be responsible for its antitumor effects.     

Studies on the metabolism of 4-methyl-piperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride in rats by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry

4-Methyl-piperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride(TM208) is a newly synthesized compound, which has shown excellent in vivo and in vitro anticancer activity and low toxicity. In this study, the metabolism of TM208 in rats was studied for the first time by high-performance liquid chromatography coupled with tandem mass spectrometry. Following a single oral administration to rats, TM208 was metabolized to eight metabolites (M1–M8). M1 is the desmethyl metabolite and the acylation of M1 with N-acetyl transferase results in M6 (N-acetyl metabolite), M5 is N-formyl metabolite; M4 is phenyl monohydroxylation metabolite, M2 is the sulfine metabolite of TM208, and M3 is also an odd-oxygen added products which the possible oxidation site has described in this paper; M8 is the metabolite resulting from the replacement of ‘–CS’ with ‘–CO’, M7 is a ring-opened piperazine oxidation products to a kind of acid.     

TM208在大鼠肝微粒体中代谢产物与细胞色素P450亚型代谢酶鉴别研究

在大鼠肝微粒体的体外代谢中研究作用于TM208的细胞色素P450亚型代谢酶。以不含细胞色素P450化学抑制剂的样品为对照，研究不同细胞色素P450亚型选择性化学抑制剂对TM208代谢转化率的影响。CYP2D和CYP2B的选择性抑制剂对TM208的代谢表现出浓度依赖性较强抑制作用，CYP1A的选择性抑制剂对TM208的代谢表现出一定抑制作用。CYP3A的选择性抑制剂对TM208的代谢没有表现出明显的抑制作用。TM208在人鼠肝微粒体体外代谢中主要通过CYP2D和CYP2B两种细胞色素P450亚型代谢酶参与代谢。     

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of TM208 on non-small cell lung cancer xenograft

In the present study, we aimed to investigate the anticancer effect of TM208 (4-methylpiperazine-1-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride) on non-small cell lung cancer (NSCLC). Moreover, pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe and simulate the time-course of the drug response in A549 xenograft model. The inhibition rates of two treatment groups (TM208 100 mg/kg group and TM208 150 mg/kg group) in A549 xenograft model were first compared with both vehicle and positive control groups. Subsequently, natural tumor growth model was built and finally PK-PD model was established based on the PD data of the vehicle control group and TM208 treatment groups. In addition, the model was further evaluated, and the anti-cancer efficacy under different regimens was simulated. Our results showed that NSCLC was one potential indication of TM208 and TM208 150 mg/kg QD would be an effective regimen. For parameters about tumor growth, the initial volume was 0.134 cm³ and the growth rate was 0.0869 day^–1. For parameters about drug efficacy, the killing factor was 0.174 mL/μg/dand average transit rate among transit compartments was 0.173 day^–1. Among various regimens in the step of simulation, TM208 900 mg/kg QW, which was a hypothetical regimen without experimental data support yet, showed similar anticancer effect compared with TM208 150 mg/kg QD. In conclusion, the anti-cancer effect of TM208 on NSCLC was demonstrated by the pre-clinical experiment and confirmed by the developed PK-PD model. Moreoever, results from model simulation would be helpful for further translational research of TM208.     

Combination chemotherapy with JTE-522, a novel selective cyclooxygenase-2 inhibitor,and cisplatin against gastric cancer cell lines in vitro and in vivo

COX-2 over-expression occurs in various cancers, but the role of COX-2 in cancer progression remains to be elucidated. We examined the inhibitory effects of a novel selective COX-2 inhibitor, JTE-522 (JT), against gastric cancer cell lines (TMK-1, MKN-45 and MKN-74) alone and in combination with cisplatin (CDDP). The antitumor activity of JTE-522 was evaluated by MTT assay, which revealed that JT alone elicits a dose-dependent antitumor activity in vitro. The JT/CDDP combination elicited a synergistic antitumor effect in MKN-45 cells and an additive effect in the other cell lines. In an in vivo study, 10 mg/kg JT and 12 mg/kg CDDP together elicited a synergistic antitumor activity against MKN-45 cells that were subcutaneously transplanted into nude mice. We conclude that JT is a potent antitumor agent in vitro and in vivo and that, in combination with CDDP, it might be a useful treatment strategy for gastric cancer.     

HPLC-ESI/ITMSn法分析大鼠体内4-甲基哌嗪-1-二硫代甲酸-(3-氰基-3，3-二苯基)丙酯盐酸盐及其主要代谢物

目的研究新化合物4-甲基哌嗪-1-二硫代甲酸-(3-氰基-3，3-二苯基)丙酯盐酸盐(TM208)在大鼠体内的主要代谢产物。方法大鼠ig TM208 500 mg·kg^-1后，收集粪样、尿样和血样，用液相色谱-电喷雾离子阱质谱法测定。根据TM208及其代谢产物的色谱保留时间和电喷雾离子阱质谱(ESI-ITMSⁿ )电离规律及生物体内药物代谢转化规律，推导代谢物的结构。结果在粪样中发现8种I相代谢产物，在尿样和血样中发现5种I相代谢产物，未发现II相代谢产物。结论本法操作简便、快速、灵敏度高、专属性强，是一种研究TM208体内代谢产物的有效方法。     

Docetaxel alone or orally combined with 5-fluorouracil and its derivatives: effects on mouse mammary tumor cell line MM2 in vitro and in vivo

Although docetaxel (Taxotere; TXT), a taxoid anticancer drug, is clinically and experimentally very effective against breast cancer, its antitumor effect is of very short duration. We addressed whether 5-fluorouracil (5-FU) and its derivatives can act synergistically with TXT against mammary tumors, with placing particular stress on their use by oral route. Mouse mammary tumor cell line, MM2, was propagated in culture and as ascites in mice. Carmofur (HCFU) and doxifluridine (5'-DFUR) were used as 5-FU derivatives. In vitro, the cytotoxic effects of antitumor drugs on MM2 cells were examined by MTS assay. In vivo, mice inoculated i.p. with MM2 cells were treated with i.p. injection of TXT and/or oral administration of 5-FU or its derivatives, and observed for curing tumor. In vitro, the synergistic effects were observed in the combination of TXT and 5-FU or HCFU, but not in that of TXT and 5'-DFUR. In vivo, all of these combinations cured tumors far more effectively than TXT alone. The discrepant result of the combination of TXT and 5'-DFUR between in vitro and in vivo was ascribed to up-regulation of pyrimidine phosphorylase in tumor cells in vivo by TXT. Thus, 5-FU, its masked compounds like HCFU and its prodrugs like 5'-DFUR can act synergistically with TXT in the therapy of cancer even when administered by the oral route.     

Inhibition of EGFR autophosphorylation plays an important role in the anti-breast cancer efficacy of the dithiocarbamate derivative TM208

Aim： To investigate the effects of a novel dithiocarbamate derivative TM208 on human breast cancer cells as well as the pharmacoki- netic characteristics of TM208 in human breast cancer xenograft mice. Methods： Human breast cancer MCF-7 and MDA-MB-231 cells were treated with TM208 or a positive control drug tamoxifen. Cell pro- liferation was examined using SRB and colony formation assays. Cell apoptosis was analyzed with Annexin V-FITC/PI staining assay. Protein expression was examined with Western blot, ELISA and immunohistochemical analyses. MCF-7 breast cancer xenograft nude mice were orally administered TM208 （50 or 150 mg.k$1〈1-1） or tamoxifen （50 mg.kgl〈t-~） for 18 d. On d 19, the tumors were collected for analyses. Blood samples were collected from the mice treated with the high dose of TM208, and plasma concentrations of TM208 were measured using LC-MS/MS. Results： Treatment of MCF-7 and MDA-MB-231 cells with TM208 dose-dependently inhibited the cell proliferation and colony formation in vitro （the IC~o values were 36.38＋3.77 and 18.13＋0.76 pmol/L, respectively）. TM208 （20-150pmol/L） dose-dependently induced apoptosis of both the breast cancer cells in vitro. In MCF-7 breast cancer xenograft nude mice, TM208 administration dose-depend- ently reduced the tumor growth, but did not result in the accumulation of TM208 or weight loss. TM208 dose-dependently inhibited the phosphorylation of EGFR and ERK1/2 in both the breast cancer cells in vitro as well as in the MCF-7 xenograft tumor. Conclusion： Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer.     

Synthesis, structure, and antitumor activity of a novel tetranuclear titanium complex

The coordination complex cyclo-tetrakis[bis(1-phenyl-3-methyl-4-benzoylpyrazolon-5-ato++ +)mu-o xotitanium(IV)] has been synthesized and characterized with IR and NMR spectroscopies and X-ray diffraction. The core of this species consists of an eight-membered Ti-mu-oxo ring with alternate short-long Ti-O bond lengths. Besides these two O ligands, each metal is bound octahedrally to four O atoms from two chelating 1-phenyl-3-methyl-4-benzoylpyrazolon-5-ato anions. Several sets of Ti-O bond lengths are present: the shortest are the two Ti-O(oxo) (which are cis to each other), the longest are the two Ti-O(acyl) (cis to each other), and the two Ti-O(pyrazolonato) (trans to each other) are intermediate. The beta-diketonate ligand asymmetry, a feature considered essential in other antitumor Ti compounds, induces the short-long Ti-O(oxo) sequence of bond lengths. The antitumor activity of this compound, encapsulated in a dipalmitoylphosphatidylcholine liposome, has been studied in vitro using TA-3 (mouse mammary adenocarcinoma), HEP-2 (human epithelial larynx carcinoma), and VERO (African green monkey kidney) cell lines and in vivo in CF-1 and AJ female mice ip inoculated with TA-3. In vitro cytotoxicity is greater for TA-3 than for HEP-2 and null for VERO cell lines. In vivo results show a marked increase in survival time (T/C = 293% for AJ and 208% for CF-1), whereas tumor weight decrease was observed for CF-1-treated mice. These results suggest the Ti complex-liposome system may be promising as an antitumor drug.     

Antitumor activity of benzamide riboside and its combination with cisplatin and staurosporine

Benzamide riboside (BR), a new synthetic nucleoside analogue, has demonstrated a potent cytotoxic activity in murine leukemia in vitro. The purpose of the present investigation was to examine the antitumor activity of BR in mice bearing leukemia L1210. The results revealed that BR possesses a potent antitumor activity in vivo. It increases life-span of mice with leukemia. Synergistic cytotoxicity of BR with select DNA damaging agents, cisplatin (cis-Pt) and staurosporine (STP) was examined in MTT chemosensitivity assay, FACS analyses and apoptotic DNA fragmentation on L1210 cells in culture. A simultaneous treatment of leukemia L1210 cells with the combination of BR and STP resulted in synergistic cytotoxicity that correlated with increased apoptotic activity in those cells. On the other hand, treatment of L1210 cells with combination of BR and cis-Pt resulted in antagonistic cytotoxic effect. Finally, to elucidate the synergistic effect of BR and STP in inducing apoptosis, the attention was directed to the activation of cell death processes through various cell cycle signals. This is the first report describing in vivo antitumor activity of BR and its utilization in combination chemotherapy.