Effects of smoking on spontaneous and induced sister chromatid exchanges in lymphocytes

Spontaneous and mitomycin C-induced sister chromatid exchanges (SCEs) in lymphocytes were analyzed in 24 non-smokers and 24 sex- and age-matched smokers. Mean spontaneous SCE frequency for non-smokers was 9.8 SCEs/cell, and that for smokers was 11.5 SCEs/cell. The difference was statistically significant (P less than 0.001 by t-test). These results suggest that spontaneous SCE frequency in lymphocytes is useful for evaluation of biological effects of environmental mutagens. However, we could not find any effects of smoking on the sensitivities of lymphocytes to mitomycin C in vitro. The effects of mutagens on humans may be independent of one another.     

Investigation of Potential Genotoxic Effects of Low Frequency Electromagnetic Fields on Escherichia coli*

Abstract— Exposure of growing cells of Escherichia coli strain AB1157 to a frequency of 1 Hz with field strengths of 1 or 3 kV m^?1 did not affect spontaneous or ultraviolet light (UV)-induced mutation frequencies to rifampicin resistance. Neither did growth in the presence of charge alter the sensitivities of strains AB1157, TK702 umuC or TK501 umuC uvrB to UV. Similarly, although the resistance of strains TK702 umuC and TK501 umuC uvrB to UV was increased by the presence of plasmid pKM101, which carries DNA repair genes, pregrowth of plasmid-containing strains in electric fields did not increase UV resistance. Finally, growth in a low frequency field in the presence of sub-inhibitory concentrations of mitomycin C did not affect mitomycin C-induced mutation frequencies. It is concluded that low frequency electromagnetic fields do not increase spontaneous mutation, induce DNA repair or increase the mutagenic effects of UV or mitomycin C.     

Neanthes arenaceodentata, a cytogenetic model for marine genetic toxicology

Genetic toxicants are present in polluted marine environments and may represent a long-term threat to populations of marine organisms. A cytogenetic model is useful to study the effects of these toxicants. The polychaete, Neanthes arenaceodentata, was chosen as such a model because it has a suitable karyotype, is easily cultured, and represents an ecologically important group of organisms. This paper presents details of an in vivo application of sister chromatid exchange (SCE) analysis, a sensitive cytogenetic technique, to this marine worm. In earlier studies, N. arenaceodentata exhibited a dose response to mitomycin C (MMC) at concentrations comparable to those that elicited responses in in vivo mammalian systems. Exposure to 5 × 10⁻⁷ MMMC for 48 h increased the frequency of SCE in the worm from a baseline value of 0.14 exchanges/chromosome to 0.5 exchanges/chromosome. Positive SCE responses in the worm have also been demonstrated in this study for other known, direct-acting mutagens such as 5-bromodeoxyuridine and methylmethanesulfonate, as well as for compounds that need metabolic activation luch as benzo[a]pyrene, dimethylnitrosamine and cyclophosphamide. These results imply that N. arenaceodentata can metabolize promutagens and suggest that the worm may be sensitive to a broad spectrum of genetic toxicants. The significance of these findings, as well as directions for future research, are discussed.     

Long-term follow-up study of gastric cancer patients treated with surgery and adjuvant chemotherapy with mitomycin C.

A group of 496 cases was used in a controlled trial to study the possible value of mitomycin C as an adjuvant to curative surgery for gastric cancer. Patients assigned to receive the drug were given mitomycin C, 0.8 mg/kg body weight intravenously, twice a week for 5 weeks immediately after surgery. The control group was treated with surgery alone. Sixty-six patients were excluded from the study because of non-curative surgery. There was no over-all difference in survival and cancer death rates at 5 and 10 years between treated and control groups. However, a survival rate 18.6% higher at 5 years was observed in the subset of patients who had moderately advanced lymphatic metastases, and a survival rate 26.4% higher at 5 years was observed in the subset of patients who had involved serosa. The difference in cancer death rate was 14.5 and 24.0% in each subset, respectively. These significant differences persisted at 10 years. The effect of chemotherapy seemed to result from the successful inhibition of peritoneal dissemination and local recurrence. An adverse effect was observed in patients in the early stages cancer. These results suggest that mitomycin C could be useful as an adjuvant to curative surgery for moderately advanced stages of gastric cancer.     

Inhibition of mitomycin C-induced sister chromatid exchanges by vitamin C in vivo.

The aim of this experiment was to test the modulation of genotoxicity produced by vitamin C (V-C) challenged against mitomycin C (MMC) in vivo, by analyzing the sister chromatid exchanges (SCE) and cell proliferation kinetics. We used the mouse bone marrow cytogenetic method, and tested three dosages of V-C (3, 5, and 7 g/kg of body weight), along with the appropriate positive (2 mg MMC/kg body weight) and negative V-C controls. The results showed that V-C caused a strong inhibition of SCEs induced by MMC in the three dosages administered. The highest dose (7 g/kg) caused an SCE inhibition of 70.02%, while the lower ones caused an inhibition of 54.61% and 52.30%, respectively. It was also clear that V-C per se does not increase the level of SCEs in mouse bone marrow cells. On the other hand, V-C induced a slight decrease in cell proliferation that was stronger when combined with MMC. Our data suggest that V-C effectively inhibit the SCE damage in vivo, but caution must be taken because of the observed cytotoxicity.     

Sister chromatid exchanges in breast cancer patients who underwent chemotherapy

The study aimed to determine the effects of cytostatic and genotoxic drugs used to treat breast cancer on sister chromatid exchange (SCE). SCE values were examined in 25 female patients with breast cancer in pre-treatment, treatment process and remission period as well as in 22 nonsmoker women via peripheral blood culture technique. The SCE values of patient and control group were analyzed via "Mann-Whitney U test". Whilst SCE values of patient group ??were 8.25 ± 3.67, 10.19 ± 2.95 and 11.52 ± 3.33 in pre-treatment, treatment process and remission periods respectively, it was 7.01 ± 1.24 in control group. When overall SCE values of patients group in pre-treatment period were compared with those of control group, no significant difference was observed (p > 0.05), whereas highly significant differences were observed between treatment process and remission period of patient groups and control group in terms of SCE values (p < 0.01). If patients are exposed to any cytostatic and clastogenic drugs, the increase in the exchange values was considered remarkable. These findings reinforced the availability of sister chromatid exchange technique in directing of treatment and monitoring the genetic abnormalities caused by genomic instability which may occur due to the drugs used for treatment.     

Detectability in vivo of stabilized intercalating agents with the alkaline elution technique. Comparison with in vivo sister chromatid exchange introduction

The purpose of the work reported here was to investigate, with the alkaline elution technique, the capability of in vivo administered actinomycin D, daunomycin and mitomycin C to induce DNA damage, DNA interstrand cross-linking and DNA-protein cross-linking. The ability of these compounds to induce increases in sister chromatid exchange (SCE) in the bone marrow cells of mice was also investigated. Actinomycin D and daunomycin were active in inducing single strands breaks, while mitomycin C was inactive. Mitomycin C showed a clear DNA interstrand cross-linking activity, while this activity was absent in actinomycin D and daunomycin. All three compounds were positive for SCE induction, but mitomycin C was by far the most active compound. Our results seem to suggest that stabilized intercalating agents are often detectable with the alkaline elution technique, after treatment in vivo. However, they cannot be evaluated with the simple alkaline elution technique only. It is convenient to add to the basic method the modification for detecting cross-links. Finally, DNA interstrand cross-linking and sister chromatid exchanges could be correlated.     

Assessment of antioxidant / anticarcinogenic activity of plant extracts by a combination of molecular methods

Cancer chemoprevention is considered to be a promising approach for cancer control, as it has been identified by both epidemiological and molecular studies that environmental factors are the major causes of cancer. Chemoprevention can be defined as the use of agents to prevent, inhibit or reverse the process of carcinogenesis. Several epidemiological studies have shown that fruits, vegetables and common beverages, as well as herbs and plants, are rich sources of chemopreventive compounds. In the present report, a battery of in vitro methods for the identification of chemopreventive agents are presented. These methods include: i) inhibition of bleomycin-induced mutations in Salmonella typhimurium TA102 cells, ii) inhibition of bleomycin-induced sister chromatid exchanges (SCEs) in human peripheral blood lymphocytes, iii) protection from mitomycin C-induced DNA strand breakage and iv) inhibition of topoisomerase I DNA relaxation. The first three methods are also used for the identification of agents which prevent reactive oxygen species (ROS)-mediated DNA damage.     

上海地区人群中的芳香烃受体基因多态性与膀胱癌易感性无关

目的:研究芳香烃受体(AHR)基因两个多态性位点:G_(1712)A(R_(554)K)和G_(1768)A(V_(57S)Ⅰ),在中国人群中的分布频率及与膀胱癌易感性的关系.方法:我们建立了基于等位基因特异性PCR(Allele-Specific PCR,AS-PCR)的基因型鉴定方法,并对三组人群进行了基因型鉴定:一个作为对照的本地正常人群,一个有膀胱癌致癌剂联苯胺职业暴露史的膀胱癌病人组,和一个无明显芳香胺类物质接触史的膀胱癌病人组.结果:我们在本地区正常人群中没有发现G_(1768)位点的多态性;在对照人群中,G_(1721)多态性位点的基因型分布频率与已报道的一个高加索人群有显著差异(P<0.01);该多态性位点在不同性别中的分布差异不显著(P=0.54).在所研究的三个人群中,其基因型分布频率相近.结论:AHR基因G_(1768)位点在上海地区的人群中表现为野生型单态性;G_(1721)A多态性基因型分布在该人群和高加索人群中有显著差异;在该地区人群中,G_(1721)位点的多态性并不是构成致膀胱癌的危险因子.     

Chromosomal aberrations,sister chromatid exchanges,and micronuclei in lymphocytes of oncology department personnel handling anti-neoplastic drugs

Objective: Concern exists regarding the possible hazards to the personnel handling anti-neoplastic drugs. The purpose of the present study was to assess the genotoxicity induced by anti-neoplastic agents in oncology department personnel. Materials and methods: To do this, the frequency of chromosomal aberrations (CAs) induced in peripheral blood lymphocytes was assessed at G₀ phase of the cell cycle using metaphase analysis, cytokinesis block-micronucleus (MN) assay and sister chromatid exchange (SCE) assay. These cytogenetic end points were measured among 71 nurses in oncology department and 10 drugstore personnel handling and preparing anti-neoplastic drugs. The results were compared to those of 74 matched nurses for age and sex not exposed to any anti-neoplastic agents. Results: There was no significant difference between the age of study subjects and control group (p?>?0.05). The results showed that the mean frequency of cytogenetic damages in terms of CAs [chromatid breaks (p?=?0.01), chromosome breaks (p?=?0.005), total CAs (p?=?0.001)], MN formation (p?=?0.001), and SCE (p?=?0.004) in lymphocytes of personnel handling anti-neoplastic drugs were significantly higher than those in control unexposed group. Conclusion: Results of the present study demonstrate the cytogenetic damage in peripheral blood lymphocytes of oncology department personnel. Suitable training and proper knowledge when handling anti-neoplastic drugs are emphasized to avoid potential health hazards caused by cytostatic agents.     

Sister-chromatid exchanges in lymphocytes from 12 chromium platers: a 5-year follow-up study

To detect the mutagenic effects of hexavalent chromium (Cr) in humans, sister-chromatid exchange (SCE) frequency in lymphocytes and urinary Cr was determined in 66 blood-urine paired samples from 12 male Cr-platers during 5 years (1984-1989). Multiple regression of SCE frequency on age, urinary Cr and smoking habits was analyzed in all 66 samples. Neither age (P = 0.204) nor urinary Cr (P = 0.056) was a significant predictor for SCE frequency. Although urinalysis revealed obvious exposure to Cr in the platers, exposure was unable to influence SCE frequency. Smoking habits were a highly significant (P less than 0.001) positive predictor for SCE frequency, and smoking of one cigarette per day was associated with an increase of 0.054 SCEs/cell in SCE frequency. SCE frequency significantly fluctuated from year to year in 3 subjects. The smoking habits of these 3 subjects did not change during the follow-up period. The results suggest that there are other unknown factors influencing SCE frequency in addition to smoking habits.     

Mechanism of autophagy induction and role of autophagy in antagonizing mitomycin C-induced cell apoptosis in silibinin treated human melanoma A375-S2 cells

The aim of this study was to elucidate the molecular mechanisms mediating silibinin-induced autophagy in A375-S2 cells. In the present study it was found that silibinin-induced autophagy through increasing the conversion of LC3 I to LC3 II and up-regulating Beclin-1 expression, which was concomitant with p53 suppression and NF-κB activation. P53 inhibitor, pifithrin-α (PFT-α), increased autophagy and enhanced the expression of NF-κB. Moreover, inducing p53 accumulation with MG132 reduced autophagic ratio, and repressed the expression and activation of NF-κB expression. NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC) suppressed autophagy. Autophagic specific inhibitor 3-methyladenine (3-MA) treatment reversed silibinin-induced p53 suppression as well as NF-κB activation, suggesting that there was a positive feedback loop between p53 inhibition-mediated NF-κB activation and autophagy. In addition, we also found that 3-MA efficiently abrogated silibinin's cyto-protective effect against mitomycin C-induced cell death, and reversed the suppressive efficacy of silibinin on p53 expression, suggesting that autophagy contributed to silibinin's cyto-protective effect against mitomycin C-induced cell death in A375-S2 cells.     

炼焦工业职业肺癌流调病因及抗肺癌阻断实验研究

本研究包括太钢公司炼焦和煤气工人及土焦区居民肺癌发病率的流行病学调查。流调对象有焦工１１１７名和煤气工３５０名，以及４９０，０００名生活在土焦地区的居民。焦工及土焦区居民肺癌标化死亡比（ＳＭＲ）与山西省及太原市同龄人群的肺癌死亡率进行了对比，并与国内外类似的报道加以比较。研究结果表明，焦工及土焦区居民的肺癌危险度均显著高于文献报道。对研究结果分析证实与下列诸因素有密切关系：①设备陈旧；②工艺原始落后；③向外环境释放大量致癌原，如多环芳烃（ＰＣＨ）；④劳动个体缺乏防护衣具和防护措施；⑤居民长期生活在污染严重的环境中。对上述地区进行了监测并且采集大气样品，进行了多项动物实验，以深入阐述肺癌病因学，并且观察了抗癌复合剂的阻断治疗效果。     

体外药敏试验指导下的结直肠癌个体化化疗的临床研究

目的 研究大肠癌体外化疗药物敏感性与临床疗效的关系,为临床肿瘤化疗个体化提供依据。方法 用改进的MTT法测定53例结、直肠癌组织的化疗药物敏感性,并依药敏结果选择化疗方案,观察临床近期疗效和远期生存率。结果 53例结、直肠癌组织对8种化疗药物的敏感顺序为5-氟脲嘧啶(5-Fu)、顺铂(DDP)、丝裂霉素(MMC)、阿糖胞苷(ARA-C)、长春新碱(VCR)、氨甲喋呤(MTX)、阿霉素(ADM)、卡氮芥(BCNU),除DDP、5-Fu、MMC的敏感率高于文献报道的单药有效率外,其余与文献报道有效的单药基本一致。体外敏感性与临床近期疗效的总符合率为91.7％(11/12),药敏试验组和按经验给药组的3年生存率无明显区别,但药敏试验组5年生存率明显高于按经验给药组(P<0.05)。结论 MTT法测定化疗药物敏感性可帮助临床医师制定合理的化疗方案,按药敏试验结果指导化疗可能会有助于提高大肠癌患者的远期存活率。     

Generation of photoemissive species by mitomycin C redox cycling in rat liver microsomes

Generation of reactive oxygen species during redox cycling is thought to be involved in the chemotherapeutic action of quinone anticancer drugs. A clinically used agent which contains a quinone moiety is mitomycin C (Mit C). With isolated rat liver microsomes we detected photoemissive species during Mit C-induced redox cycling. After addition of reduced glutathione (GSH) a large increase in Mit C-induced chemiluminescence was observed. The increase of photoemission in deuterium oxide as well as greater than 90% of intensity at wavelengths greater than 610 nm suggest that singlet oxygen is a photoemissive species generated by this system. Glutathione disulfide (GSSG) accumulates during the reaction. We propose that superoxide anion radicals formed during redox cycling of Mit C react with GSH. Generation of glutathionyl radicals followed by oxygen addition then leads to the formation of photoemissive species and GSSG.     

Genotoxic effects after in vivo exposure of vegetable extracts containing heavy metals from the Dhapa area of Calcutta, India. I. Effects of cauliflower, spinach and radish.

Several reports have indicated that the sewage-fed vegetables of the Dhapa area, near the city of Calcutta, contain a very high amount of heavy metals. Currently 800 ha of land is being utilised throughout the year to cultivate more than eight types of vegetables, with a production of about 147 tonnes per day. A major population of Calcutta consumes these vegetables grown in the Dhapa area. Recently there has been huge pressure on the State Government to ban vegetables grown in the Dhapa area for human consumption. For this reason, we have studied the genotoxic effects of some of the most commonly used vegetable extracts from the Dhapa area after in vivo acute exposure in mice as measured by chromosomal aberrations (CA) and sister chromatid exchanges (SCE) to find out the minimum threshold dose to induce CA and SCE. Three different concentrations of the three most commonly used vegetable extracts (cauliflower, spinach, radish) were fed by gavage to mice for the study of CA and SCE. A significant increase in CA was observed only at the highest concentration of all the vegetable extract-treated groups when compared with the solvent control. A significant increase in SCE were observed in the middle and high doses of spinach and only the high dose of cauliflower and radish extract-treated series when compared with distilled water control. The lowest dose was equivalent to approximately 1 kg of vegetables consumed by a human (60 kg body weight) in a day. The middle and high doses of each vegetable extract were much higher than the normal amount of vegetables that a human can consume per day. So the minimum dose for inducing SCE and CA was much higher than the amount a human can consume in a day. Therefore this study indicates that these vegetables are safe for human consumption up to a certain limit, and attention should be given to reducing the heavy metal contents in the soil and sewage of the Dhapa area to thus reduce the heavy metal concentrations in the vegetables.     

Cancer incidence in New Zealand born residents of New South Wales

Cancer incidence in New Zealand born residents of New South Wales (NSW) has been compared with that in the Australian born population using data from the NSW Central Cancer Registry for the period 1972-84. Indirectly age-standardised incidence ratios (SIR) showed that New Zealand born women living in NSW had higher rates of cancer at all sites combined (SIR = 112) and a significant excess of colorectal cancer (SIR = 126). Although overall cancer rates were similar in men born in New Zealand to those in the Australian born men, the New Zealanders had a significantly higher risk of colorectal (SIR = 124) and testicular cancer (SIR = 227), cancers which are more common in New Zealand than in Australia. While the SIRs for lung cancer in men and melanoma of skin in both sexes were low, no cancer was significantly less common in New Zealand born residents of NSW than in the Australian born.     

经尿道丝裂霉素粘膜下注射预防膀胱癌复发

目的：探讨经尿道丝裂霉素粘膜下注射对降低MTC治疗膀胱癌复发的效果。方法：将经尿道MTC加丝裂霉素粘膜下注射及膀胱灌注,与经尿道MTC后单纯丝裂霉素膀胱灌注的膀胱癌患者进行疗效比较。结果：观察组83例中78例得到随访,11例分别在治疗后6－36个月后复发,复发率为14．1％。对照组47例中,43例得到随访,17例分别在治疗后6－24个月后复发,复发率为39．5％。结论：丝裂霉素粘膜下注射的方法,对提高MTC治疗效果,减少肿瘤复发,延长无瘤间期,有明显效果。并具有：操作简单、安全、恢复快等优点。     

Effects of sorbic acid and its salts on chromosome aberrations, sister chromatid exchanges and gene mutations in cultured Chinese hamster cells

The ability of sorbic acid and its potassium and sodium salts to induce chromosome aberrations, sister chromatid exchanges (SCE) and gene mutations in cultured Chinese hamster V79 cells was examined. Sodium sorbate caused significant induction of chromosome aberrations and SCE, and also induced 6-thioguanine-resistant mutations in a dose-dependent manner. The clastogenic potency of sodium sorbate was found to be less than one hundredth of that of the potent clastogen N-methyl-N'-nitro-N-nitrosoguanidine. The induction of SCE by sodium sorbate was twice the control level, whereas that by methyl methanesulphonate, a potent inducer of SCE, was 14 times the control level. The mutagenic potency of sodium sorbate was less than one-tenth that of ethyl methanesulphonate, a potent inducer of mutation, when compared at an equitoxic level. Sorbic acid and its potassium salt induced chromosome aberrations, but only at the highest doses tested. These compounds also induced 1.2 times the control level of SCE, but neither compound induced 6-thioguanine-resistant mutations. The cytogenetic activity of sodium sorbate was concluded not to be due to the effect of osmotic pressure or an impurity. These results indicate that sodium sorbate is a genotoxic agent, although its potency seems to be weak, and that sorbic acid and potassium sorbate are less genotoxic than the sodium salt.     

Chromosome damage induced by carboplatin (CBDCA)

The chromosome damage induced by carboplatin (CBDCA) was evaluated in vitro. In human lymphocytes 5 μg/ml CBDCA produced a 7-fold increase in the frequency of sister chromatid exchanges (SCE) and a 3-fold increase in the number of cells with structural abnormalities compared with the control. Likewise, at this highest dose a significant increase was induced in the value of micronuclei (MN) and an important delay in the lymphocyte cycle progression was observed. In Chinese hamster ovary (CHO) cells, CBDCA showed a significant increase in chromosome aberrations (CA) at the doses assayed. The increase of SCE, CA and MN by CBDCA remained much lower than that produced by mitomycin C (positive control). The results suggest that CBDCA is a DNA-damaging drug with similar behaviour as an alkylating agent.