乌贼墨对小鼠NK细胞杀伤活性的影响和抑瘤作用的研究

研究乌贼墨对小鼠脾细胞NK细胞杀伤活性的诱生作用及NK细胞杀伤性的持续时间，并探讨乌贼墨对荷瘤鼠脾细胞NK细胞杀伤活性的影响及抑制肿瘤生长的作用。用5％的乌贼墨给小鼠灌胃，连续5d后取不同时间的小鼠脾细胞，应用乳酸脱氢酶释放法检测NK细胞杀伤活性，结果表明，口服乌贼墨后可使小鼠NK细胞杀伤活性增强，实验组与对照组比较有显著性差异（P＜0．01），诱生后24h杀伤活性明显增强，2周左右恢复正常水平，乌贼墨可使荷瘤鼠NK细胞杀伤活性增强，瘤体明显小于阴性对照组，病理学分析证明小鼠瘤组织出血坏死及炎细胞浸润程度明显高于对照组，阳性对照组小鼠免疫功能损伤严重。     

扇贝裙边糖胺聚糖抗肿瘤作用和对荷瘤小鼠免疫功能的影响

目的：研究扇贝裙边糖胺聚糖（SS-GAG）的抗癌作用及对荷瘤小鼠免疫功能的影响。方法：建立小鼠移植性S180实体瘤模型，观察SS-GAG的抑瘤率以及对荷瘤小鼠的体质量、肝质量、白细胞计数、脾指数、胸腺指数的影响，同时观察SS-GAG对荷瘤小鼠细胞免疫活性的影响。结果：SS-GAG可明显抑制S180实体瘤的生长，SS-GAG与环磷酰胺联用可使化疗药物的抗癌作用增强并能有效提升减少的白细胞；能显著增强荷瘤小鼠腹腔巨噬细胞的吞噬能力和杀伤活性，增强荷瘤小鼠脾淋巴细胞的转化增殖和NK细胞活性。结论：SS-GAG可显著抑制肿瘤生长，与环磷酰胺联用时有减毒增效作用；并能增强荷瘤小鼠的免疫功能。     

白术对化疗荷瘤小鼠减毒增效作用的研究

目的 研究白术对化疗后荷瘤小鼠免疫功能的影响。方法 以S180荷瘤C57BL／6小鼠为模型，系统地研究白术对瘤重和脾细胞功能的影响。结果 白术对荷瘤鼠化疗所引起的免疫功能低下具有明显的恢复作用，可显著提高化疗荷瘤鼠T细胞转化能力．明显促进化疗荷瘤鼠白细胞介素2（IL-2）分泌水平。结论 白术能够拮抗肿瘤抗原和化疗所引起的免疫抑制。     

枸杞多糖抗肿瘤作用免疫学机理的探讨

目的:探讨枸杞多糖对荷瘤小鼠免疫功能的调节作用.方法:60只小鼠随机分为6组:正常对照组、荷瘤对照组、环磷酰胺(Cy)阳性对照组和5,10,20 mg·kg -1 ·d -1 枸杞多糖(LBP)组,每组10只,各组分别给予相应剂量,灌胃给药后,检测胸腺重量及巨噬细胞吞噬功能、脾细胞抗体、CTL杀伤功能.结果:一定剂量的LBP能显著抑制移植性肿瘤S180的生长,且能明显增强荷瘤鼠巨噬细胞率和吞噬指数,增加脾细胞抗体生成,提高荷瘤鼠的脾细胞转化功能和CTL的杀伤能力,均以10 mg·kg -1 ·d -1 LBP效果最佳.结论:LBP显著提高荷瘤小鼠的非常异性免疫、体液免疫和细胞免疫功能,且能显著提高荷瘤小鼠CTL的杀伤能力.这可能是枸杞多糖抗移植性肿瘤的机理之一.     

多抗甲素对小白鼠网状内皮系统吞噬功能的影响

多抗甲素是甲型链球菌,(Alpha-hemolytic Streptococci)经发酵提炼而成的一种多糖类物质。它对小白鼠网状内皮系统(RES)吞噬功能具有良好的激活作用,并随给药剂量和次数的增加而逐渐增强。多抗甲素增强RES吞噬活性主要是激活其细胞本身的功能。它还可明显地提高S-180荷瘤小鼠RES的吞噬功能。     

蒲薏颗粒对化疗荷瘤小鼠的增效减毒及免疫功能的影响

目的 研究蒲薏颗粒对荷瘤小鼠化疗增效、减毒及免疫调节作用。方法 建立小鼠恶性肿瘤转实体瘤模型,观察蒲薏颗粒与化疗药物合用对瘤体重量、血液白细胞(WBC)数、骨髓有核细胞数的影响;对肿瘤坏死因子(TNF-a)的影响以及对荷瘤小鼠免疫功能的影响。结果 蒲薏颗粒能增强化疗药物抑瘤作用、拮抗化疗药物对WBC及骨髓有核细胞的抑制;提高荷瘤小鼠TNF-a含量;增强免疫功能。结论 蒲薏颗粒对荷瘤小鼠具有化疗增效、减毒及免疫增强的作用。     

蒲薏颗粒对化疗荷瘤小鼠的增效减毒及免疫功能的影响

目的研究蒲薏颗粒对荷瘤小鼠化疗增效、减毒及免疫调节作用。方法建立小鼠恶性肿瘤转实体瘤模型,观察蒲薏颗粒与化疗药物合用对瘤体重量、血液白细胞（WBC）数、骨髓有核细胞数的影响;对肿瘤坏死因子（TNF-a）的影响以及对荷瘤小鼠免疫功能的影响。结果蒲薏颗粒能增强化疗药物抑瘤作用、拮抗化疗药物对WBC及骨髓有核细胞的抑制;提高荷瘤小鼠TNF-a含量;增强免疫功能。结论蒲薏颗粒对荷瘤小鼠具有化疗增效、减毒及免疫增强的作用。     

海力特抗肿瘤作用及其对免疫功能的影响

观察海力特(Hailite)的抗肿瘤作用及对机体免疫功能的影响。结果表明,海力特60,120mg·kg~(-1)对小鼠S_(180)实体瘤及小鼠肝癌H_(22)均有明显抑制作用(P<0.01);海力特10,20,40,80mg·kg~(-1)能明显促进小鼠腹腔巨噬细胞吞噬功能及提高血清溶血素含量,并能显著增强T淋巴细胞增殖活性及NK细胞杀伤靶细胞的活性,明显增加脾脏T细胞产生IL-2的能力。     

灵龙颗粒剂的抗肿瘤作用及对免疫功能的影响

目的观察灵龙颗粒剂(简称LLE)抗动物移植性肿瘤和裸鼠人肺癌与体外抑瘤作用及其对荷瘤小鼠免疫功能的影响.方法体内抗肿瘤实验采用腋下接种肿瘤细胞及实体瘤称重的方法;腹腔接种瘤液观察荷瘤动物存活率;裸鼠腋下接种人肺腺癌及实体瘤称重;体外抗肿瘤实验采用直接观察肿瘤细胞增殖的MTT法;2,4-二硝基氟苯诱发的DTH反应采用小鼠耳片差重法;淋巴细胞转化实验采用MTT法检测;TNF-α活性检测采用L929细胞杀伤实验.结果LLE(13.1,17.5,35.0g生药*kg-1)对移植性动物肿瘤S180及H22的抑瘤率分别为47.7%,66.1%,82.0%及67.0%,73.3%,76.4%;使荷EAC肿瘤小鼠的生存期延长; LLE(17.5,35.0g生药*kg-1)对裸鼠人肺腺癌有较强的抑制作用,抑瘤率为60.5%和77.8%;该药还显示一定的体外抑瘤作用;LLE对荷S180及H22小鼠的DTH反应有增强作用;对淋巴细胞转化有明显促进作用;LLE可有效增加荷瘤小鼠腹腔巨噬细胞TNF-α的产生.结论ig LLE对荷瘤小鼠具有显著的抗肿瘤作用,且能拮抗荷瘤所致的免疫功能的抑制.     

鲨鱼软骨粉对S_(180)荷瘤小鼠免疫细胞调节功能的影响

目的研究鲨鱼软骨粉(SCP)对S180荷瘤小鼠免疫细胞功能的影响。方法鲨鱼软骨粉300、200、100mg·kg-1小鼠灌胃给药10 d。MTT法检测其对S180荷瘤小鼠脾淋巴细胞增殖功能的影响;流式细胞仪检测T淋巴细胞亚群的变化;ELISA法测定荷瘤小鼠血清中细胞因子TNF-α、IFN-γ含量。结果 SCP能提高小鼠脾淋巴细胞的增殖活性;不同程度地提高小鼠脾细胞CD4+细胞数,增加CD4+/CD8+细胞比值;明显提高小鼠巨噬细胞的吞噬活性;促进外周血清中TNF-α和IFN-γ的分泌水平。结论 SCP能提高T细胞介导的细胞免疫应答,提高巨噬细胞调节免疫应答的功能,促进TNF-α、IFN-γ等细胞因子的分泌,从而发挥其抗肿瘤作用。     

应用流式细胞术研究平阳霉素与异博定合用对S-180细胞周期的影响

本文应用流式细胞术等方法研究了经抗癌药物平阳霉素和钙拮抗剂异博定单独或联合处理的体外培养S-180细胞的周期运形情况。发现无毒剂量的异博定使平阳霉素对S-180细胞G_2M期的阻断作用和对细胞增殖的抑制作用增强,使平阳霉素IC_(50)值降低。其结果为阐明异博定增强抗癌药物作用的机制提供了依据。     

Synthesis and evaluation of substituted naphthalimide nitrogen mustards as rationally designed anticancer compounds

Bromonapmustine 4a and chloronapmustine 4b, two new nitrogen mustards of substituted naphthalimides, have been synthesized as mixed-function anticancer compounds from 4-bromo- and 4-chloro-N-(2-hydroxyethyl)-naphthalimide respectively following a three-step process. Their chemical alkylating activity exceeded that of nor-HN2. Their antitumour efficacy were assessed in vivo in two murine ascites tumours, namely Ehrlich ascites carcinoma (EAC) and Sarcoma-180 (S-180) by measuring the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. Two standard clinical drugs, namely endoxan (cyclophosphamide) and 5-fluorouracil (5-FU) were used as positive controls for comparison. Both of them have displayed substantial and reproducible antitumoural activity in these tumours comparable with 5-FU. These compounds inhibit the synthesis of DNA and RNA in S-180 tumour cells. These were further screened in vitro in 3 different human tumour cell lines but no significant activity was observed in those lines.     

联合化疗对腺样囊性癌细胞作用的实验研究

目的观察体外应用羟基喜树碱(HCPT)、平阳霉素(PYM)两种药物单用和两两联合应用对人腺样囊性癌Acc-M细胞的生长抑制作用.方法采用MTT法研究用药前后细胞增殖活性的影响,用流式细胞仪观察细胞凋亡及细胞周期变化.结果①两种药单用及两药合用对细胞均有很好的抑制作用,且以HCPT和PYM合用最强.②HCPT和PYM单用和合用可使细胞的群体倍增时间显著延长,克隆形成率降低,细胞凋亡率增加,以联合用药为佳.结论HCPT、PYM单独及联合用药均对Acc-M细胞在体外有很好的抑制作用且与以联合应用效果更佳.     

Immunological studies on the antitumor components of the basidiocarps ofAgrocybe cylindracea

The effects of cylindan, a polysaccharide isolated from the basidiocarps ofAgrocybe cylindracea, on murine sarcoma 180 tumor and murine immune cells were examined after intraperitoneal administration. Cylindan exhibited a marked life extension effect in mice against ascite forms of sarcoma 180 and Lewis lung carcinoma at a dose of 50 mg/kg/day, although it did not show any direct cytotoxicity against sarcoma 180, X5563, and MM46 murine tumor cells. Cylindan increased numbers of bone marrow stem cells as well as peritoneal exudate cells in flow cytometry using monoclonal antibodies. The tumor bearing mice group apparently showed the increase of macrophages and cytotoxic T lymphocytes in mouse spleen cells during the early stage of tumor growth. But during the later stage, the control group decreased immune cells and cylindan restored the decreased immune cells in the tumor bearing mice to the normal level. In non-specific immune response, cylindan stimulated the bacterial phagocytosis and acid phosphatase production in macrophages. It also activated components of the alternative complement pathway and natural killer activity against YAC-1 lymphoma. In humoral immunity, cylindan had a mitogenic effect against splenocytes and increased the number of plasma cells as token of stimulation of the differentiation of B lymphocytes. In cellular immunity, cylindan restored the depressed response of delayed type hypersensitivity in the tumor bearing mice to 60% of the normal level and increased the interleukin-2 (IL-2) responsiveness in the IL-2 dependent CTLL-2 cells. These results suggest that cylindan did not show direct cytotoxic effects on tumor cells but restored the decreased immune response of the tumor bearing mice.     

Liposomal formulation of glycosphingolipids from Sphingomonas paucimobilis induces antitumour immunity in mice

Natural Killer T (NKT) cells play an important role in host’s anti-tumour immune response. Glycosphingolipids (GSLs) isolated from Sphingomonas paucimobilis have the ability to stimulate NKT cells. In this study, the activity of free GSLs or GSLs-incorporated liposomes (glycosphingosomes) was investigated against dimethyl-α-benzanthracene (DMBA)-induced tumours in mice. The anti-tumour immunity of GSLs- or glycosphingosomes-loaded bone marrow-derived dendritic cells (BMDCs) was investigated in tumour-bearing mice. The Immunotherapeutic potential of co-administration of liposomal doxorubicin (Lip-Dox) and GSLs or glycosphingosomes was assessed by measuring cytokine levels and VEGF in the tumour tissues. Pretreatment with glycosphingosomes significantly delayed the frequency of tumour formation. Immunotherapy with glycosphingosomes-loaded BMDCs increased serum IFN-γ level and survival rate in mice. The effect of immunotherapy was dependent on effector functions of NK cells because the depletion of NK cells abolished the effects of immunotherapy. There was reduced tumour growth with low expression of VEGF in the group of mice treated with glycosphingosomes and Lip-Dox combination. Moreover, the splenocytes secreted higher levels of IFN-γ, IL-12 and lower TGF-β level. The results of this study indicate that glycosphingosomes can induce better antitumour immunity and may be considered a novel formulation in antitumour therapy.     

Effects of heptaminol AMP amidate on suppressor and helper function of murine T cells

Heptaminol AMP amidate (HAA), a newly developed nucleotide derivative, was found to restore the immunosuppression in mice due to the induction of suppressor T (Ts) cells by concanavalin A (Con A) (50 micrograms/body). HAA also inhibited Con A-mediated in vitro induction of Ts cells. On the contrary, the administration of HAA in mice primed with keyhole lympet hemocyanin (KLH) (30 micrograms/body) caused an enhanced induction of antigen specific helper T (Th) cells. Effects of HAA on Ts and Th cells were found to be dependent on their level of induction. The administration of HAA also increased the spleen cell number and augmented the plaque forming cell response to some extent in cyclophosphamide treated mice. The present results suggested that HAA-mediated immunopotentiation was possible by a combined suppressive effect on Ts cells and enhancing effect on Th cells.     

Antitumour effect of OM-174 and cyclophosphamide on murine B16 melanoma in different experimental conditions

We report that OM-174, a purified water soluble diphosphorylated and triacetylated lipid A derived from E. coli, is able to reduce tumour progression and to prolong the survival of mice in the B16 melanoma experimental model. At the doses employed in our study OM-174 had an antitumour activity comparable to that of a single high dose of CY. More striking effects were achieved by means of the combination of the two agents in a protocol consisting of a single administration of CY (200 mg/kg) followed by five injections of OM-174 (1 mg/kg). Immunological studies of treated and control mice revealed that the antitumour activity of OM-174, alone or in combination with CY, is mediated by the stimulation of natural killer (NK) and cytotoxic T lymphocyte (CTL) responses as well as by a significant increase in the absolute number of NK1.1, CD4 and CD8 positive cells. OM-174 is thus candidate for association with cytostatic drugs in chemo-immunotherapy protocols.     

6-(1-Alkenoyloxyalkyl)-5,8-dimethoxy-1,4-naphthoquinone derivatives: Synthesis and evaluation of antitumor activity

Thirty six 5,8-dimethoxy-1,4-naphthoquinone derivatives, which bear unsaturated alkyl side chain with ester bond, were synthesized and tested cytotoxic activity on L1210 cells and antitumor activity against ICR mice bearing S-180 cells. It could be recognized that the cytotoxicities of naphthoquinones with R₁ being methyl and propyl (IV1∼24) were not enhanced by replacing the alkanoyls with alkenoyls. In contrast, the introduction of the alkenoyl moieties on the compounds with R₁=hexyl (IV25∼36) resulted in the enhancement of their cytotoxicities. Replacement of alkanoyl group with an alkenoyl group generally increased the T/C value of the mice bearing S-180 cells.     

Antitumor activity of methanol extract from roots of Agrimonia pilosa Ledeb

To evaluate the antitumor activity of Agrimonia pilosa LEDEB., the effects of the methanol extract from roots of the plant (AP-M) on several transplantable rodent tumors were investigated. AP-M significantly prolonged the life span of S180-, Meth-A fibrosarcoma- and MM-2 mammary carcinoma-bearing mice by intraperitoneal (i.p.) pre- or postmedication. AP-M also inhibited the growth of S-180 solid type tumor. On the other hand, the prolongation of life span induced by AP-M on S-180 ascites type tumor-bearing mice was markedly minimized or abolished by the pretreatment of cyclophosphamide. AP-M showed considerably strong cytotoxicity on MM-2 cells in vitro, but the effect was diminished to one-tenth by the addition of serum to the culture. Against the host animals, the peripheral white blood cells in mice were significantly increased from 2 to 5 days after the i.p. injection of AP-M. On 4th day after the injection of AP-M, the peritoneal exudate cells which possessed the cytotoxic activity on MM-2 cells in vitro were also increased to about 5-fold those in the non-treated control. The spleen of the mice was enlarged, and the spleen cells possessed the capacity to uptake 3H-thymidine. However, AP-M did not show direct migration activity like other mitogens against spleen cells from non-treated mice. These results indicate that the roots of Agrimonia pilosa contain some antitumor constituents, and possible mechanisms of the antitumor activity may be some host-mediated actions and direct cytotoxicity.     

Drug Interaction Effects on Antitumour Drugs (VIII): Prevention of Ifosfamide-Induced Urotoxicity by Disulfiram and its Effect on Antitumour Activity and Acute Toxicity of Alkylating Agents in Mice

Abstract: To reduce the side-effects and to enhance the antitumour activities of antitumour agents, we have been investigating their combined use with routine drugs. In the present study, we examined the effects of disulfiram (DSF) in combination with ifosfamide (IFX). DSF prevented IFX-induced bladder damage in a dose-dependent manner in tumour-free ddY mice when orally administered simultaneously with antitumour agent, but failed to diminish the acute lethal toxicity or leukocytotoxicity of IFX. Diethyldithiocarbamate (DDTC) prevented IFX-induced bladder damage when administered simultaneously with IFX or 1 to 5 hr afterwards. The antitumour activity of IFX in ddY-mice inoculated with Sarcoma 180 or in C₅₇BL/6J mice inoculated with EL-4 leukaemia was not impaired when it was given simultaneously with DSF or 3 hr before DDTC. Thus, neither DSF nor DDTC impaired the antitumour effect of IFX and both diminished its adverse effects. The bladder protection of DSF and DDTC appeared resulted from adduct formation with acrolein and not from inhibition of the metabolic activation of IFX.