硒对顺铂毒性和肿瘤生长的影响及其与金属硫蛋白的关系探讨

观察硒利生对顺铂毒性和小鼠肿瘤生长的影响，发现硒利生对顺铂致死毒性，肾脏和造血系统毒性均有不同程度保护作用，其效果优于亚硒酸钠和现已证实可诱导金属硫蛋白（ＭＴ）合成、降低顺铂毒性的有效药物次硝酸铋。经ＭＴ测定结果表明，硒利生的ＭＴ诱导作用最强（Ｐ＜０．０１），亚硒酸钠次之。由此证明了诱导体内ＭＴ增加是应用微量元素药物解救顺铂引起的重金属中毒的环节之一，但两者均不引起肿瘤中ＭＴ升高。体内抑瘤实验和体外细胞毒实验提示，硒利生对肿瘤生长没有促进作用，也不降低顺铂疗效。     

诱导生物合成金属硫蛋白减轻顺铂对小鼠的致死毒性

本研究对比了预先给予小鼠多种无机和有机含金属（Ｚｎ，Ｓｅ，Ｇｅ，Ｂｉ和Ａｓ）药物及中药十全大补膏等对顺铂致死毒性的影响。结果表明除复方甘铋镁、氧化锗及十全补膏外，其余药物对顺铂的致死毒笥均有一定保护作用。尤其是甘草锌、硒利生及锗－１３２对顺铂致死毒笥有较好保护作用（Ｐ＜０．０１）。它们的效果优于其无机化合物硫酸锌、亚硒酸钠、氧化猪及药物次硝酸饿（０．０５＜Ｐ＜０．１）。经金属硫蛋白（ＭＴ）测定结果     

金属硫蛋白水平与顺铂所致肾脏病理改变的相关性研究

本文作者应用硒利生、亚硒酸钠、甘草锌诱导合成金属硫蛋白的方法观察其对顺铂所致肾脏病理改变的影响，并对肾脏中ＭＴ含量与肾脏病理改变之间的相关性进行了分析。发现顺铂所致肾脏损害的病理变化总积分值在应用上述药后可明显降低，其中以硒利生组保护作用最明显，以下依次为亚硒酸钠组和甘草锌组。     

富硒大蒜对体内外人胃癌细胞生长的影响

目的 比较富硒大蒜、普通大蒜、亚硒酸钠以及普通大蒜与亚硒酸钠混合（蒜硒联合）处理影响人胃癌细胞生长的能力。方法 利用细胞计数、流式细胞术、Western blot和裸鼠瘤体积测定等方法,观察富硒大蒜水溶物对离体培养的MGC803胃癌细胞系及其在裸鼠皮下生长的影响。结果 （1）在离体条件下,富硒大蒜对MGC803细胞增殖有明显抑制作用,与等蒜量普通大蒜作用强度相似;等硒量亚硒酸钠抑制作用最弱,蒜硒联合抑制作用最强。（2）富硒大蒜、普通大蒜和亚硒酸钠处理24h后,未同步化的细胞G1期增多,已同步化的细胞S期增多;蒜硒联合处理则使未同步化和已同步化细胞G2＋M期增多。（3）4种处理24h后,同步化细胞的Cdk2-CyclinE和Cdk4-CyclinD1复合物蛋白含量均降低。（4）饲喂Balb/C裸小鼠含1．67％富硒大蒜粉（含硒2μg/g)的饲料,对移植瘤生长的抑制率达29．92％;0．83％富硒大蒜、1．67％普通大蒜和4．38μg/g亚硒酸钠（含硒2μg/g)处理组未见明显抑制作用。（5）0．83％富硒大蒜处理可诱发裸鼠单核细胞包裹肿瘤。结论 富硒大蒜能够抑制MGC803细胞在体外的生长,主要作用在于蒜。富硒大蒜对裸鼠移植胃癌有抑制作用,作用比普通大蒜和亚硒酸钠强。     

维生素A和亚硒酸钠对菜油烟冷凝物致小鼠毒性作用的影响

本文报道了维生素Ａ和亚硒酸钠对菜油烟冷凝物致小鼠毒性作用的影响。结果表明：①菜油烟冷凝物组小鼠的体重明显低于补充维生素Ａ组和亚硒酸钠组（Ｐ＜０．０１）；②菜油烟冷凝物组小鼠的心脏器系数高于补充维生素Ａ和亚硒酸钠组（Ｐ＜０．０５）；③补充维生素Ａ和亚硒酸钠后，可显著地降低菜油烟冷凝物所致的小鼠微核率和精子畸形率（Ｐ＜０．００１和Ｐ＜０．０１），而单纯菜油组则无致小鼠微核率和精子畸形率升高的作用（Ｐ＞０．０５）。     

亚硒酸钠对肿瘤细胞生长增殖和细胞内环核苷酸水平的影响

把ＨＬ－６０细胞与含或不含亚硒酸钠（１５μｍｏｌ／Ｌ）的培养液一起培养，用放名法测定ｃＡＭＰ和ｃＧＭＰ，以探讨亚硒酸钠对肿瘤细胞内环核苷酸水平的影响。研究发现１５μｍｏｌ／Ｌ的亚硒酸钠能显著地抑制ＨＬ－６０细胞的生长增殖，并降低静息的肾上腺（５０μｍｏｌ／Ｌ）ｃＧＭＰ的水平，但对ｃＡＭＰ水平无影响。研究结果提示，亚硒酸钠的抗肿瘤作用可能是通过降低细胞内ｃＧＭＰ水平而发挥。     

亚硒酸钠拮抗氯化汞致小鼠微核作用的研究

亚硒酸钠拮抗氯化汞致小鼠微核作用的研究周纯先，肖棣，王帮霞，王允滋（蚌埠医学院卫生学教研室蚌埠２３３００３）应用微核试验方法，对亚硒酸钠（Ｎａ２ＳｅＯ３）拮抗氯化汞（ＨｇＣｌ２）致小鼠骨髓多染红细胞微核作用进行了研究。试验选用昆明种小鼠，体重１８─２...     

亚硒酸钠和维甲酸联合对HL－60细胞生长、分化的影响

以人早幼粒白血病细胞（ＨＬ－６０）为实验对象，观察了亚硒酸钠和维甲酸联合作用对其生长、分化的影响。结果表明：５．８μｍｏｌ／Ｌ亚硒酸钠和０．１μｍｏｌ／Ｌ维甲酸联合可显著抑制细胞生长，且细胞毒性并无增加，强于两者的单独作用。而且可明显诱导细胞向粒系细胞分化，在处理５天后有７２％的细胞进行分化。单用０．１μｍｏｌ／Ｌ维甲酸只有３９％的细胞分化成熟。ＮＢＴ还原实验表现出类似结果。     

亚硒酸钠对平阳霉素致突变性的防护作用

平阳霉素是具有放射线样作用的药物，为寻找和探讨相应措施防护其化学致癌作用。本文对平阳霉素致小鼠骨髓嗜多染红细胞（ＰＣＥ）微核作用及亚硒酸钠对平阳霉素致微核效应的拮抗作用进行了检测。结果表明平阳霉素首次染毒４８小时后微核率最高，且染毒后１周时间内仍未恢复至正常水平。随着亚硒酸钠投予量的增加平阳霉素引起微核率下降，有明显的剂量效应关系。在０２５ｍｇ／ｋｇ和０．５ｍｇ／ｋｇ两个剂量条件下与阳性对照组均有显著性差异，说明亚硒酸钠对平阳霉素的致微核效应有一定的防护作用。     

亚硒酸钠与维生素E对三甲基胆蒽诱发肉瘤的影响

用三甲基胆蒽皮下诱发小鼠肉瘤，观察亚硒酸钠与维生素Ｅ对此肉瘤发生的影响。结果表明，亚硒酸钠组小鼠，延缓肉瘤发生时间，与对照组比较肉瘤发生率由５３．３％降至２７．７％，维生素Ｅ组，无降低肉瘤发生作用。亚硒酸钠与维生素Ｅ联合应用组肉瘤发生率与亚硒酸钠组相似，亚硒酸钠组能明显升高小鼠血中谷胱甘肽过氧化物酶的活性及血中硒的含量，维生素Ｅ无此作用。结果说明亚硒酸钠与维生素Ｅ虽都为抗氧化剂，并都被认为有防癌作用，但它们对本实验三甲基胆蒽皮下诱发肉瘤的作用似不相同。     

DETOXIFYING EFFECT OF LISHENG－SE ON CDDP AND ITS RELATION TO METALLOTHIONEIN INDUCTION

徐卓立，郭军华，宋三泰，卢淑娟，吴德政ＤＥＴＯＸＩＦＹＩＮＧＥＦＦＥＣＴＯＦＬＩＳＨＥＮＧ－ＳＥＯＮＣＤＤＰＡＮＤＩＴＳＲＥＬＡＴＩＯＮＴＯＭＥＴＡＬＬＯＴＨＩＯＮＥＩＮＩＮＤＵＣＴＩＯＮ￥ＸｕＺｈｕｏｌｉ；ＧｕｏＪｕｎｈｕａ；ＳｏｎｇＳａｎｔａｉ；...     

The effect of sodium selenite on cell proliferation and transformation of primary rat tracheal epithelial cells.

The effects of sodium selenite (Na2SeO3) on cell proliferation and the development of preneoplastic transformed variants were studied in primary cultures of rat tracheal epithelial cells. Results revealed a biphasic effect of Na2SeO3 on cell proliferation: at concentrations between 6 x 10(-8) and 6 x 10(-6) M, it stimulated and at concentrations of approximately 2 x 10(-5) and above it inhibited cell proliferation (presumably due to toxicity). Nontoxic concentrations of Na2SeO3 (6 x 10(-8) -6 x 10(-7) M) significantly reduced the spontaneous transformation frequency. Transformation induced by the tobacco-specific nitrosamine 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was effectively inhibited by nontoxic as well as toxic concentrations of Na2SeO3. Treatment of cultures with Na2SeO3 after cessation of NNK exposure, i.e. during the selection period, also significantly reduced the transformation frequency. These experiments show that the inhibition of transformation by Na2SeO3 is not the result of an antiproliferative effect. They further indicate that the inhibitory effect occurs even when the chemical treatment occurs during the 'postinitiation' phase. Thus the inhibition of transformation by Na2SeO3 cannot solely be explained by its effects on drug metabolism.     

Possible role of glutathione in mitochondrial apoptosis of human oral squamous cell carcinoma caused by inorganic selenium compounds

Selenium (Se) is a very effective anti-cancer agent. We studied the effects of inorganic Se compounds on induction of apoptosis by which Se compounds exert cancer chemopreventive activity. With the use of HSC-3 human oral squamous cell carcinoma cells, the present study showed that treatment with Se for 72 h, in the form of SeO2 and Na2SeO3, but not Na2SeO4, markedly induced apoptosis in a dose-dependent manner. Treatment of HSC-3 cells with 100 microM SeO2 resulted in the caspase-3-like and -9-like activation. Se compounds induced a loss of mitochondrial membrane potential (DeltaPsim), but did not induce the generation of reactive oxygen species. Treatment with SeO2 for 18 h resulted in 80% loss of reduced glutathione (GSH), which is known to be involved in the metabolism of Se. Treatment with N-acetyl-L-cysteine, or exogenous GSH, prevented the SeO2-induced apoptosis. Treatment with GSH led to the partial reverse in reduction of DeltaPsim caused by SeO2, while buthionine sulfoximine augmented the SeO2- or Na2SeO3-induced apoptosis.These results suggest that modulation of the mitochondrial redox equilibrium by Se contributes to the mitochondrial pathway, regulating caspase-9-mediated apoptosis without a concurrent increase in ROS.     

Effect of Na2SeO3 on the damages of genetic materials induced by MNNG in children's foreskin fibroblasts in vitro

In order to study the effect of selenium on anticarcinogenesis, micronuclei (MN) and chromosome aberrations (CA) were used as the indexes to reflect the damages on the genetic materials induced by MNNG in children's foreskin fibroblasts in vitro. In the MN test, the final concentrations of Na2SeO3 were 10(-7), 10(-6), 10(-5) and 10(-4) M and MNNG, 10(-5)M. In the CA test, Na2SeO3 were used in 10(-7), 10(-6) and 10(-5)M and MNNG, 10(-6)M as the final concentrations. Relative to the time of MNNG treatment, the cells were exposed to Na2SeO3 4 hours before and at the same time as with the carcinogen. The results showed that the MN% (number of cells out of one thousand MN) was reduced from 4.31 +/- 0.91% to 1.55 +/- 0.54% and 1.54 +/- 0.54% (P less than 0.05), respectively. The CA% (the percentage of the cell with CA) was reduced from 86 +/- 7% to 34 +/- 9% and 33 +/- 9% (P less than 0.05), respectively. However there was no like results when the cells were treated with Na2SeO3 and MNNG simultaneously. Na2SeO3 had no significant protective effects on the cells when the concentration was 10(-7)M. If the dose was 10(-4)M or more, Na2SeO3 became toxic to the cells. The results suggested that the protection of Na2SeO3 on the damages of genetic materials induced by MNNG be time and dose dependent.     

Effect of bismuth nitrate given in combination withcis-diamminedichloroplatinum(II) on the antitumor activity and renal toxicity of the latter in nude mice inoculated with human bladder tumor

Summary The effects of bismuth nitrate pretreatment on the toxicity and antitumor activity ofcis-diamminedichloroplatinum (cisplatin, CDDP) were examined in nude mice that had been inoculated with human bladder-tumor tissue. Pretreatment with bismuth nitrate depressed the renal toxicity of CDDP without compromising its activity against a transplantable human bladder tumor. Renal metallothionein (MT) and bismuth (Bi) levels in nude mice were markedly increased by Bi preadministration, but no significant MT induction was observed in inoculated human bladder-tumor tissue in which only a trace amount of Bi was incorporated. Furthermore, it was confirmed that tumor platinum (Pt) concentrations in CDDP-treated mice were not affected by Bi pretreatment. Thus, the administration of Bi compounds prior to chemotherapy with CDDP may provide an effective mode of treatment for advanced bladder tumors.     

Modulation of genotoxic activity of tobacco smoke

Tobacco smoke (TS) caused a three- to nine-fold increase in the frequency of his+ revertants in Salmonella typhimurium TA98 but not in TA97a, TA100 or TA102. Activation by a post-mitochondrial fraction obtained from the liver of rats pretreated with Aroclor-1254 or methylcholanthrene was required; fractions from phenobarbital-pretreated or untreated rats had no effect. Vitamins A and E, but not ascorbic acid, inhibited the TS-induced mutagenesis by up to 63%, whereas glutathione and cysteine increased it slightly. Na2SeO3, but neither CoCl2 nor caffeine, inhibited the mutagenic effect of TS by 46-56%. In Chinese hamster ovary cells, both Na2SeO3 and caffeine strongly potentiated the number of chromosomal aberrations induced by TS, while theophilline slightly reduced its clastogenic effect. Treatment of mice with TS for 60 min/day increased the frequency of micronuclei in polychromatic erythrocytes in bone marrow and in fetal liver and the number of NCE micronuclei in peripheral blood by four to five fold. Simultaneous treatment of mice with TS and Na2SeO3 reduced the clastogenic effect of TS. Ascorbic acid had no effect on clastogenicity but reduced toxicity as measured by body weight loss. Both Na2SeO3 and ascorbic acid suppressed the induction of TS-induced hyperplastic and metaplastic changes in bronchial mucosa but had no effect on the number of urethane-induced lung adenomas. Vitamins A and E and ascorbic acid may have a protective effect against the toxic and genotoxic activities of TS.     

亚硒酸钠和维甲酸联合对HL－60细胞生长、分化的影响

 以人早幼粒白血病细胞（HL－60）为实验对象，观察了亚硒酸钠和维甲酸联合作用对其生长、分化的影响。结果表明：5.8μmol/L亚硒酸钠和0.1μmol/L维甲酸联合可显著抑制细胞生长，且细胞毒性并无增加，强于两者的单独作用。而且可明显诱导细胞向粒系细胞分化，在处理5天后有72%的细胞进行分化。单用0.1μmol/L维甲酸只有39%的细胞分化成熟。NBT还原实验表现出类似结果。     

Citrate enhances the protective effect of orally administered bismuth subnitrate against the nephrotoxicity of<Emphasis Type="Italic"> cis</Emphasis>-diamminedichloroplatinum

Attenuation of the renal toxicity ofcis-diamminedichloroplatinum (CDDP) is important in the use of this effective but cytotoxic anticancer agent. We have previously shown that the renal toxicity of CDDP can be efficiently reduced by the induction of metallothionein (MT) by preadministration of bismuth compounds in mice. Bismuth subnitrate (BSN) is used as an antigastric ulcer agent and as an antidiarrheic agent, and is suitable for inducing MT in the kidney in cancer patients. However, due to the low absorption rate of Bi from the gastrointestinal tract, the efficacy of BSN in inducing renal MT is low. In the present study, we examined the effects of citrate as a vehicle for oral administration of BSN on the tissue distribution of Bi and induction of MT in the kidneys and tumors in mice inoculated with Meth-A fibrosarcoma. Renal levels of MT and Bi were markedly increased in the mice given BSN dissolved in citrate solution compared with those given BSN suspended in saline. On the other hand, the use of citrate increased Bi accumulation in the tumor only slightly and did not increase tumor MT levels. Administration of BSN with citrate efficiently depressed the renal toxicity of CDDP, but did not affect its antitumor activity. Since both BSN and citrate are used clinically as pharmaceuticals, the combination regimen of BSN and citrate may be readily applicable as a countermeasure against the adverse side effects of CDDP without affecting its antitumor activity.