Effect of Brahma Rasayana on antioxidant systems and cytokine levels in mice during cyclophosphamide administration

Intraperitoneal administration of cyclophosphamide (CTX) 25 mg/kg.b.wt. dose/mouse for 10 days was found to suppress the tissue and serum level of reduced glutathione (GSH), blood glutathione peroxidase (GPX) and tissue levels of superoxide dismutase (SOD) and catalase (CAT). Tissue levels of glutathione reductase (GR) and glutathione-S-transferase (GST) were unaltered by CTX treatment while serum and tissue lipid peroxide levels were significantly increased. Oral administration of Brahma Rasayana BR-50 mg/dose/mouse for 10 days and 30 days significantly enhanced the tissue levels of SOD, CAT, GST, GPX, serum and tissue GSH and significantly reduced the serum and tissue lipid peroxidation. BR treatment was also found to enhance the serum cytokine level of interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and granulocyte macrophage-colony stimulating factor (GM-CSF) in normal and CTX treated mice. The results are indicative of the use of BR to reduce the oxidant stress induced by CTX treatment and its effect in cellular function.     

Amelioration of cisplatin induced nephrotoxicity in mice by ethyl acetate extract of a polypore fungus,Phellinus rimosus

Pretreatment of ethyl acetate extract of Phellinus rimosus (Berk) Pilat protected cisplatin induced nephrotoxicity in mice. Single dose of the extract (25 and 50 mg/kg body weight) decreased cisplatin induced serum creatinine and urea levels. The cisplatin depleted renal antioxidant defence system, such as activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and concentration of reduced glutathione (GSH), were restored by the treatment of the extract. The enhanced renal antioxidant defence system prevented cisplatin induced tissue lipid peroxidation. The experimental results suggest that ethyl acetate extract of P. rimosus protected cisplatin induced nephrotoxicity, possibly by enhancing renal antioxidant status. The extract did not interfere with the antitumor efficacy of cisplatin.     

Montelukast attenuates side effects of cisplatin including testicular, spermatological, and hormonal damage in male rats

In the current study, the protective effect of montelukast (ML) on cisplatin induced reproductive toxicity in rats was investigated. Twenty-eight rats were equally divided into four groups; first group was kept as control. In the second group, ML was orally administered at the dose of 10 mg/kg/day for 10 days. In the third group, CP was intraperitoneally administered at the dose of 7 mg/kg a single injection, and in fourth group, CP and ML were given together at the same doses. Although CP induced oxidative stress via significant increase in the formation of TBARS, it caused a significant decline in the levels of GSH, CAT, GPx, and SOD in rats. In contrast, ML prevents these effects of CP through cause an increase in GSH, CAT, GPx, and SOD levels and a decrease in formation of TBARS. In addition, sperm motility and serum testosterone levels significantly decrease and histopathological damage increases with CP treatment. However, the effects of CP on sperm motility, serum testosterone level, oxidative and histopathological changes are eliminated by ML treatment. In conclusion, the current study demonstrated that the reproductive toxicity caused by CP may be prevented by ML treatment. Thus, it was judged that co-administration of ML with CP may be useful to attenuate the negative effects of CP on male reproductive system.     

异甘草酸镁对奥沙利铂引起荷瘤裸鼠肝脏损伤的干预研究

目的：研究异甘草酸镁对奥沙利铂导致荷瘤裸鼠肝损伤模型的保护作用。方法：建立结肠癌HCT116细胞裸鼠皮下移植瘤模型,随机分成2组,每组8只,对照组为奥沙利铂组,实验组为奥沙利铂＋异甘草酸镁组。6天后处死裸鼠,腹主动脉取血测谷草转氨酶（AST）及谷丙转氨酶（ALT）的表达;取肝脏组织制作肝脏病理切片观察肝脏损伤情况,并制备肝脏组织匀浆,用比色法测量超氧化物歧化酶（SOD）、还原型谷胱甘肽（GSH）及髓过氧化物酶（MPO）的表达情况。结果：成功建立了结肠癌HCT116细胞裸鼠皮下移植瘤模型;实验组肝窦血管损伤的发生率降低;血液中AST及ALT的表达实验组较对照组明显降低（P＜0．01）;肝脏SOD、GSH的表达实验组较对照组明显升高（P＜0．05）;MPO的表达实验组较对照组明显降低（P＜0．05）。结论：异甘草酸镁可以在一定程度上降低奥沙利铂引起的肝窦血管损伤发生率。     

Antioxidant potential by arabinoxylan rice bran, MGN-3/biobran, represents a mechanism for its oncostatic effect against murine solid Ehrlich carcinoma

We have recently examined the oncolytic effect of arabinoxylan rice bran, MGN-3/biobran, against solid Ehrlich carcinoma (SEC)-bearing mice via immune-modulation and apoptosis [N.K. Badr El-din, E. Noaman, M. Ghoneum, In vivo tumor inhibitory effects of nutritional rice bran supplement MGN-3/biobran on Ehrlich carcinoma-bearing mice, Nutr. Cancer 60 (2) (2008) 235-244]. In the present study, we examined the antioxidant system as another possible mechanism through which MGN-3 exerts its oncostatic potential. Female albino mice were inoculated intramuscularly in the right thigh with Ehrlich ascites carcinoma (EAC) cells. MGN-3 (25mg/kg body weight) was injected intraperitoneally (i.p.) six times a week for 25 days into mice at either day 4 or day 11 post-EAC cell inoculation. Tumor growth, lipid peroxidation (LPx), glutathione (GSH) contents, the activity of the antioxidant scavenger enzymes, and alterations in gene expression were examined. MGN-3 efficiently suppressed the growth of tumors, which was associated with normalization of the LPx levels and augmentation of GSH contents. MGN-3 enhanced the activity of the endogenous antioxidant scavenging enzymes - superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and glutathione-S-transferase (GST) - in blood, liver, and tumor tissue. Similarly it up-regulated the expression of GPx, SOD1 and CAT mRNA in the liver. The effect of MGN-3 was more pronounced when treated early, at day 4 of tumor cell inoculation, as compared to later treatment at 11 days. In conclusion, MGN-3-induced oncostatic activity by modulating lipid peroxidation, augmenting the antioxidant defense system and protecting against oxidative stress.     

喹乙醇对HepG2细胞抗氧化系统的影响

目的：观察喹乙醇对人肝癌细胞（HepG2）抗氧化系统的影响,探讨喹乙醇诱导HepG2细胞氧化性损伤的机制。方法：分别将0、200、400、800μg/ml的喹乙醇作用于HepG2细胞24h后,检测各组细胞内抗氧化酶/物的变化;另设800μg/ml的喹乙醇作用于HepG2细胞3h后,再用超氧化物歧化酶（SOD）（100μg/ml）、过氧化氢酶（CAT）（100μg/ml）及SOD（100μg/ml）＋CAT（100μg/ml）分别作用细胞3h的各实验组,采用分子探针2’,7’-二氯荧光黄双乙酸盐（2,7-dichlorodihydrofluorescein diacetate,DCFDA）检测各组处理后细胞内活性氧含量的变化。结果：不同浓度的喹乙醇作用HepG2细胞24h后,细胞总ATPase、Na＋K＋-ATPase及Ca2＋Mg2＋-ATPase和细胞内SOD、谷胱甘肽（GSH）及谷胱甘肽过氧化物酶（GSH-PX）活性随喹乙醇浓度的升高而下降（P〈0.05或P〈0.01）,且具有一定的剂量-效应关系,细胞内CAT活性较对照组下降（P〈0.01）,但无剂量-效应关系,而细胞内丙二醛（MDA）水平随喹乙醇浓度的升高而增加（P〈0.05或P〈0.01）,且呈一定的剂量-效应关系。经喹乙醇（800μg/ml）处理细胞后,再分别用CAT、SOD及SOD＋CAT处理的各组,其ROS含量与单纯喹乙醇（800μg/ml）组相比分别减少80%（P〈0.01）、40%及95%（P〈0.01）。结论：喹乙醇可使体外培养HepG2细胞的抗氧化系统受到一定的破坏,且产生的ROS形式以H2O2为主。     

催化性抗氧化剂AEOL-10150对氮芥诱导小鼠急性肝损伤的保护作用

目的： 探讨催化性抗氧化剂AEOL-10150对氮芥诱导小鼠肝损伤的保护作用及其机制。方法： 实验对象为C57BL/6小鼠,采用腹腔单次注射盐酸氮芥（2 mg/kg）构建急性肝损伤模型,染毒后0.5和6 h分别给予AEOL-10150（5 mg/kg）进行治疗干预,染毒3 d后处死小鼠,收集眼球血液和肝组织,观察肝组织大体改变和HE染色后进行组织病理学检测;检测血清谷丙转氨酶（ALT）和谷草转氨酶（AST）活性,肝组织活性氧（ROS）水平、丙二醛（MDA）含量和还原型谷胱甘肽（GSH）含量,肝组织氧化还原调控分子Nrf-2的mRNA表达水平,肝组织髓过氧化物酶（MPO）活性,血清炎症因子TNF-α、IL-1β含量。结果： 2 mg/kg的氮芥单次腹腔注射3 d后可以成功诱导小鼠肝组织氧化损伤和炎症反应。与氮芥染毒组小鼠相比,AEOL-10150治疗组动物肝组织病理损伤程度减轻,血清ALT和AST活性降低,同时肝组织ROS水平和MDA含量显著减少,伴有GSH含量增加和Nrf-2的mRNA和蛋白表达水平降低（均为P<0.05）。此外,AEOL-10150治疗组小鼠的肝组织MPO活性及血清TNF-α、IL-1β浓度较氮芥染毒组显著降低（均为P<0.05）。结论： AEOL-10150能够有效减轻氮芥诱导的小鼠急性肝损伤,其机制可能与直接抗氧化作用及抗炎效应有关。     

Hepatoprotective effect of andrographolide against hexachlorocyclohexane-induced oxidative injury

Many plant products are known to exert antioxidative effects by quenching various free radicals and singlet molecular oxygen. Andrographis paniculata (Kalmegh) is used extensively in the Indian traditional system of medicine as a hepatoprotective and hepatostimulative agent and has been reported to have antioxidant effects against different hepatotoxins. The present study aims to analyze antioxidant properties of an active component, andrographolide (ANDLE), extracted from A paniculata. This study investigates the effect of andrographolide on the hepatocellular antioxidant defense system and lipid peroxidation of control mice, mice treated with hexachlorocyclohexane (BHC) only, and andrographolide + BHC. Glutathione (GSH), glutathione-s-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GSH-Px), gamma-glutamyl transpeptidase (gamma-GTP), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (LPO) are studied by spectrophotometric methods. The BHC experimental model forms an irreversible liver tumor in male mice. The activities of GSH, GR, GSH-Px, SOD, and CAT show significant (P 相似文献   

巴西蜂胶抗大鼠急性放射性肝损伤的实验研究

目的：探讨巴西蜂胶对30Gy高能X线上腹部照射后大鼠急性放射性肝损伤的防护作用。方法：40只SD大鼠随机分为4组：A组（生理盐水＋假放疗组）;B组（蜂胶＋假放疗组）;C组（蜂胶＋放疗组）;D组（生理盐水＋放疗组）。实验大鼠接受高能X线上腹部照射30Gy,并于照射后4天采血、处死,观察大鼠肝细胞凋亡情况、肝脏病理改变,检测血清ALT、AST水平变化,观察肝脏组织的SOD、GSH活性变化。结果：C组与D组比较,大鼠肝细胞凋亡指数、血清ALT、AST水平显著降低,病理损伤减轻,肝脏组织中SOD、GSH均显著增高（P〈0.05）。结论：巴西蜂胶可清除自由基,减少辐射所致肝细胞凋亡,进而对急性放射性肝损伤起一定的防护作用。     

Effect of methotrexate on homocysteine and other sulfur compounds in tissues of rats fed a normal or a defined,choline-deficient diet

Summary Methotrexate (MTX) affects homocysteine (Hcy) metabolism in both cultured cells and patients, and this may be explained by a lack of the 5-methyltetrahy-drofolate required for salvage of Hcy to methionine. We here report the effect of MTX on Hcy in serum and Hcy, S-adenosylhomocysteine (AdoHcy), S-adenosylmethionine (AdoMet) and reduced glutathione (GSH) in tissues of rats fed either a normal or a defined, choline-deficient (CD) diet. The CD diet alone did not affect the amounts of Hcy in serum and tissues, but decreased the amount of AdoMet in most tissues and increased the GSH content in the liver. MTX increased the amount of Hcy about 2-fold in serum, liver and kidney, and decreased the amount of AdoMet in liver and kidney, whereas the AdoHcy content in these tissues was essentially unaffected. Accordingly, both choline deficiency and MTX treatment reduced the AdoMet to AdoHcy ratio. The increased GSH in the liver induced by CD diet seemed to be abolished by MTX. In the spleen MTX had only a marginal effect on the Hcy and AdoMet content and decreased the GSH content. It is concluded that the increase in serum Hcy during MTX exposure probably reflects a disturbance of the Hcy metabolism in some tissues, and especially in the liver. Altered metabolism of other sulfur-containing metabolites may only partly be related to the inhibition of Hcy salvage, and some metabolic effects of MTX may be modulated by tissue-specific metabolic pathways as well as by the diet.Supported by grants from the Norwegian Cancer Society and the Norwegian Society for Fighting Cancer     

川芎嗪对辐射所致小鼠氧化应激损伤的保护作用

目的:研究川芎嗪对辐射所致小鼠氧化损伤的预防和治疗作用。方法:采用~(60)Co-γ射线5 Gy全身单次照射小鼠造模,分别于照射前(预防)和照射后(治疗)每天腹腔注射川芎嗪31.2 mg/kg,连续给药10 d,并设生理盐水阴性对照组,检测各组小鼠肝组织中丙二醛(MDA)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、还原型谷胱甘肽(GSH)、谷胱甘肽过氧化物酶(GPx)及总抗氧化力(T-AOC)的变化。结果:与阴性对照组比较,~(60)Co-γ射线照射可显著增加小鼠肝组织中MDA的含量(P0.05),降低SOD、GSH、GPx的活性(P0.05),使肝组织T-AOC下降(P0.05),但对CAT的活性无显著影响(P0.05)。与照射组比较,照射前和照射后给予川芎嗪,均可降低小鼠肝组织MDA含量(P0.05),使SOD、GSH、GPx的活性升高(P0.05)、肝组织T-AOC升高(P0.05),对CAT的活性仍无显著影响(P0.05)。结论:川芎嗪具有较好的抗氧化作用,预防和治疗性用药均可降低辐射所致小鼠的氧化应激损伤。     

Pu-erh Tea Powder Preventive Effects on Cisplatin-Induced Liver Oxidative Damage in Wistar Rats

Background: Chemotherapy is one of the major means for control of malignancies, with cisplatin (CDDP) as one of the main agents, widely used for the treatment of various malignant solid tumors. However, prevention of hepatotoxicity from cisplatin is one of the urgent issues in cancer chemotherapy. In this study, we aimed to investigate the effects of pu-erh tea on hepatotoxicity through body weight and tissue antioxidant parameters like, liver coefficient, serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), malondialdehyde(MDA) and glutathione (GSH) levels, and light microscopic evaluation by histological findings. Materials and Methods: The rats were randomly divided into five groups: Control (n=10), cisplatin (3 mg/kg p.i., n=10), cisplatin+pu-erh (0.32 g/kg/day i.g., n=10), cisplatin+pu-erh (0.8 g/kg/day i.g., n=10) and cisplatin+pu-erh (1.6 g/kg/day i.g., n=10). Pu-erh tea powderwas administrated for 31 consecutive days. The rats were sacrificed at the end on the second day after a single dose of cisplatin treatment for measuring indices. Results: Pu-erh tea powder exhibited a protective effect by decreasing MDA and GSH and increasing the SOD and GSH-PX levels and GSH-PX/MDA ratio in camparison with the control group. Besides, pu-erh tea was also able to alleviate the pathological damage to some extent. Conclusion: Pu-erh tea powder is protective against cisplatin-induced liver oxidative damages, especially at themedium dosage (0.8 g/kg/d).     

In-Vitro Anticancer and Antioxidant Activities of Eremina desertorum (Forsskal, 1775) Snail Mucin

Objectives: The aim of the present research is to elucidate the anti-oxidant and anti-tumor activities of the mucin extracted from Ereminia desertorum snails´ mucus against two types of tumor cell lines; human colon adenocarcinoma (CACO-2) cells and human hepatoma (HepG-2) cells. Methods: Both cell lines were treated with Ereminia desertorum snails´ mucin and the oxidative markers were measured in culture media and cells by biochemical and gene expression analysis using RT-PCR. The tumor suppressor gene expression was also evaluated using RT-PCR. Results: The culture media of HepG-2 or CACO-2 cells treated with the extract have high significant increased levels of catalase, SOD, GSH and total antioxidants. Apart from SOD in CACO-2 cells that didn’t differ from untreated cells. Also, Gene expression levels (2^-ddct) of the antioxidant markers in HepG-2 cells; GSTA-1, catalase, SOD, and GPx increased in mucin- treated cells. Also, these antioxidant genetic markers were up-regulated in CACO-2 cells by treatment with mucin extract. Gene expression levels (2^-ddct) of tumor suppression genes (p53, Rb, APC, and PTEN) in both HepG-2 and CaCO-2 cells were increased in mucin extract-treated cells. Conclusion: The present study highlighted the anti-oxidant and the anti-cancer activities of the mucin extracted from E. desertorum snails´ mucus that could attract attention to such natural product as a possible source of therapeutic compounds against liver and colon cancers.     

Effects of L-2-oxothiazolidine-4-carboxylate on the cytotoxic activity and toxicity of cyclophosphamide in mice bearing B16F10 melanoma liver metastases

Glutathione (GSH) is the major non-protein thiol in cells that plays a critical role against damage from electrophilic agents such as alkylating drugs. Selective therapeutic GSH elevation in normal but not in tumour cells has been suggested as a means of protecting host tissues against more intense doses of chemotherapy. The present study investigated the response of B16 melanoma to treatment with the cysteine pro-drug L-2-oxothiazolidine-4-carboxylate (OTZ), alone and in combination with cyclophosphamide (CY). We found that OTZ decreased the GSH levels and proliferation rate of B16 melanoma cells in vitro, sensitizing them to the cytotoxic action of the activated metabolite of CY, acrolein (AC). In contrast to OTZ, the cysteine deliverer N-acetylcysteine (NAC) enhanced B16 melanoma cell proliferation by increasing GSH levels, and markedly decreased the sensitivity of these tumour cells to AC. In vivo studies showed the antitumoral activity of OTZ in B16 melanoma liver metastasis-induced mice, increasing their life span. We also observed that, whereas with CY treatment the GSH levels in peripheral blood mononuclear cells (PBMCs) were reduced and a dose-dependent leukopenia was produced, OTZ significantly increased PBMC GSH content, reducing toxicity and enhancing the survival of mice bearing established melanoma liver metastases treated with lethal dose CY. These results suggest a critical role for OTZ in protecting against alkylator agent-induced immunosuppression, which may allow the dose escalation of these cytostatic drugs to improve their therapeutic benefit in the treatment of malignant melanoma.     

Analysis of Antioxidant Potential of <i>Trigonella foenum-graecum</i> (L.) Extract Against Tumorigenesis

Background: Trigonella foenum-graecum Linn. has been extensively used for medicinal purposes. The current study deals with in vitro and in vivo correlation of free radical quenching activity and anticancer potential of seed extracts of Trigonella. Materials and methods: Antioxidant activity was evaluated against DPPH, NO and ABTS via in vitro radical scavenging assay. Cytotoxicity effect of Trigonella seed extract was studied in human embryonic kidney HEK 293 cell line by alamar blue assay. In vivo antioxidant activity in Swiss albino mice model was assessed by studying endogenous antioxidant enzymes such as GSH, GPx, SOD and LPO. Antitumor effect was observed by studying parameters like total number of tumors, tumor size in mice. Further, expression of tumor suppressor gene, p53 in treated mice was investigated. Results: In vitro antioxidant assays had shown methanolic extract to possess higher radical scavenging activity than aqueous and to be minimal cytotoxic. In vivo study has shown a significant reduction in total number of tumors and tumor size for the mice group treated with extract in comparison to DMBA-TPA treated group. An increase in the levels of GSH, SOD and GPx was observed with a significant reduction in LPO levels. Expression of p53 was found to be upregulated in Swiss albino mice treated with extract emphasizing possible antitumor effect of Trigonella. Conclusion: The present study helped in understanding the reducing potential and antitumorigenic activity of Trigonella seed extract and its probable therapeutic effect in skin papillomagenesis.     

Cardioprotective effects of fullerenol C(60)(Oh)(24) on a single dose doxorubicin-induced cardiotoxicity in rats with malignant neoplasm

The therapeutic utility of the anthracycline antibiotic doxorubicin is limited due to its cardiotoxicity. Our aim was to investigate the efficacy of fullerenol C(60)(OH)(24) in preventing single, high-dose doxorubicin-induced cardiotoxicity in rats with malignant neoplasm. Experiment was performed on adult female Sprague Dawley rats with chemically induced mammary carcinomas. The animals were sacrificed two days after the application of doxorubicin and/or fullerenol, and the serum activities of CK, LDH and alpha-HBDH, as well as the levels of MDA, GSH, GSSG, GSH-Px, SOD, CAT, GR, and TAS in the heart, were determined. The results obtained from the enzymatic activity in the serum show that the administration of a single dose of 8 mg/kg in all treated groups induces statistically significant damage. There are significant changes in the enzymes of LDH and CK (p < 0.05), after an i.p. administration of doxorubicin/fullerenol and fullerenol. Comparing all groups with untreated control group, point to the conclusion that in the case of a lower alpha-HBDH/LDH ratio, results in more serious the liver parenchymal damage. The results revealed that doxorubicin induced oxidative damage and that the fullerenol antioxidative influence caused significant changes in MDA, GSH, GSSG, GSH-Px, SOD, CAT, GR, and TAS level in the heart (p < 0.05). Therefore, it is suggested that fullerenol might be a potential cardioprotector in doxorubicin-treated individuals.     

INHIBITORY EFFECT OF BOSCHNIAKIA ROSSICA ON DEN-INDUCED PRECANCEROUS HEPATIC FOCI AND ITS ANTIOXIDATIVE ACTIVITIES IN RATS

BoschnikiarossicaFedtsch.etFlerovisaparasiticplantgr0wingonther0otofAlnusplants(BetUlaceae).[']Itisoneofthevaluablemedicinalplantsgr0wingonChangbaiMountainareas,itgrowsgreatlyontheChangbaiMountainatl45orl8O0metersabovesealevel,Jilin,China.Itisals0gr0wsintheDemocraticPeople'sRepublicofKorea(DPRK),JaPanandRussian.Boschiakiarossicawasnamed"BuLaoCa0"(antisenilityplant),becauseithastheeffectsoftonifyingthekidneyandstrengtheningYang,andhasbeenusedasatonicinChina.Weis0latedfouririd0idc0mP…     

Cornus Mas L improves Antioxidant Status in the Liver,Lung, Kidney,Testis and Brain of Ehrlich Ascites Tumor Bearing Mice

Cornelian Cherry (Cornus Mas L) has widespread use due to its anti-inflammatory, anti-carcinogenic and anti-oxidant properties. In this study, the effects of Cornus Mas L (C. mas L) in different dosages on the biochemical values of mice organs were investigated in the Ehrlich Ascites tumor model, which originated from mice breast adenocarcinoma and developed in Balb/C mice. In our study, 32 Balb/C type male mice were used. Ehrlich Ascites Tumor (EAT) cells (1x106 EAT cell) from the stock animal were injected into all the mice in an intraperitoneal way. Experimental groups were given 100 and 200mg/kg C. mas L extract intraperitoneally for 9 days. The weights of the animals were recorded every day and were sacrificed on the 9th day. To estimate tumor proliferation of the lung, brain, kidney, liver, and testis, antioxidant parameters were recorded including, the reduced glutathione (GSH), lipid peroxidation, glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT). Treatments of different doses of C. mas L. meaningfully (p < 0.05) modulated the lung, brain, kidney, liver and testis tissues antioxidant parameters as compared to the control. Our study showed the anti-tumor effect of C. mas L. in assisted tumor development with EAT cells, conceivably moderated by the enhancement of oxidative stress due to numerous mechanisms.     

Bcl-2 and glutathione depletion sensitizes B16 melanoma to combination therapy and eliminates metastatic disease.

PURPOSE: Advanced melanoma resists all current therapies, and metastases in the liver are particularly problematic. Prevalent resistance factors include elevated glutathione (GSH) and increased expression of bcl-2 in melanoma cells. GSH has pleiotropic effects promoting cell growth and broad resistance to therapy, whereas Bcl-2 inhibits the activation of apoptosis and contributes to elevation of GSH. This study determined the in vivo efficacy of combination therapies administered while GSH and Bcl-2 were individually and simultaneously decreased in metastatic melanoma lesions. EXPERIMENTAL DESIGN: Highly metastatic murine B16 melanoma (B16M-F10) cells have elevated levels of both GSH and Bcl-2. B16M-F10 cells were injected i.v. to establish metastatic lesions in vivo. GSH was decreased using an L-glutamine--enriched diet and administration of verapamil and acivicin, whereas Bcl-2 was reduced using oligodeoxynucleotide G3139. Paclitaxel, X-rays, tumor necrosis factor-alpha, and IFN-gamma were administered as a combination therapy. RESULTS: Metastatic cells were isolated from liver to confirm the depletion of GSH and Bcl-2 in vivo. Reduction of Bcl-2 and GSH, combined with partial therapies, decreased the number and volume of invasive B16M-F10 foci in liver by up to 99% (P<0.01). The full combination of paclitaxel, X-rays, and cytokines eliminated B16M-F10 cells from liver and all other systemic disease, leading to long-term survival (>120 days) without recurrence in 90% of mice receiving the full therapy. Toxicity was manageable; the mice recovered quickly, and hematology and clinical chemistry data were representative of accepted clinical toxicities. CONCLUSIONS: Our results suggest a new strategy to induce regression of late-stage metastatic melanoma.     

Glutathione peroxidase, glutathione-S-transferase, catalase, xanthine oxidase, Cu-Zn superoxide dismutase activities, total glutathione, nitric oxide, and malondialdehyde levels in erythrocytes of patients with small cell and non-small cell lung cancer

Lung cancer is a common pathology with high mortality due to late diagnosis. Glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST), catalase (CAT), xanthine oxidase (XO), Cu-Zn superoxide dismutase (Cu-Zn SOD) activities, total glutathione (TGSH), nitric oxide (NO*), and malondialdehyde (MDA) levels were investigated in erythrocytes of patients with non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), and healthy control group. We aimed to investigate serum GSH, GSH-dependent enzymes activities (GSH-Px and GST), XO, CAT, Cu-Zn SOD activity, and NO*, and MDA levels in patients with NSCLC and with SCLC and correlate with the cancer stage. Erythrocyte MDA, NO*, TGSH levels and erythrocyte SOD, CAT and XO activities were significantly higher in patients with NSCLC and SCLC than in controls. Slightly increased erythrocyte GSH-Px and GST activities were not significantly different from the controls. Erythrocyte MDA level positively correlated with erythrocyte NO* levels in patients with early stage (I+II) in NSCLC groups. Erythrocyte MDA level positively correlated with erythrocyte XO activity in patients with advanced stage (III+IV) in NSCLC groups. However, no other correlation could be found among the parameters in healthy controls and patients with NSCLC and with SCLC. Results obtained in this study indicate significant changes in antioxidant defence system in NSCLC and SCLC patients, which may lead to enhanced action of oxygen radical, resulting in lipid peroxidation.