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Sample records for mice bearing sarcoma-180

  1. Prolonged survival time of sarcoma 180-bearing mice treated with lipid microspheres-entrapped antitumor marine coral prostanoids.

    PubMed

    Honda, A; Mori, Y; Yamada, Y; Nakaike, S; Hayashi, H; Otomo, S

    1988-09-01

    Antitumor marine coral prostanoids (clavulone II and chlorovulone I) were entrapped into lipid microspheres of 0.2 micron diameter to make lipo-drugs. Daily treatment with lipo-chlorovulone I (1.6 mg/kg/day, i.p.) and lipo-clavulone II (12.5 mg/kg/day, i.p.) on days 1 through 5 markedly prolonged the survival time (135% ILS and 73% ILS, respectively) of mice inoculated with sarcoma 180 as compared with that of a corresponding dose of respective free chlorovulone I and clavulone II. These results suggest that lipid microspheres may be used as drug delivery carriers for antitumor coral prostanoids in vivo.

  2. Anticancer activity of subfractions containing pure compounds of Chaga mushroom (Inonotus obliquus) extract in human cancer cells and in Balbc/c mice bearing Sarcoma-180 cells.

    PubMed

    Chung, Mi Ja; Chung, Cha-Kwon; Jeong, Yoonhwa; Ham, Seung-Shi

    2010-06-01

    The Chaga mushroom (Inonotus obliquus) has been used in folk medicine to treat cancers. However, limited information exists on the underlying anticancer effects of the major component of I. obliquusin vivo. We hypothesize that the pure compounds (3beta-hydroxy-lanosta-8,24-dien-21-al, inotodiol and lanosterol, respectively) separated from I. obliquus would inhibit tumor growth in Balbc/c mice bearing Sarcoma-180 cells (S-180) in vivo and growth of human carcinoma cells in vitro. To test this hypothesis, the growth inhibition of each subfraction isolated from I. obliquus on human carcinoma cell lines (lung carcinoma A-549 cells, stomach adenocarcinoma AGS cells, breast adenocarcinoma MCF-7 cells, and cervical adenocarcinoma HeLa cells) was tested in vitro. Then, after S-180 implantation, the mice were fed a normal chow supplemented with 0, 0.1 or 0.2 mg of subfraction 1, 2 or 3 per mouse per day. All of the subfractions isolated from I. obliquus showed significant cytotoxic activity against the selected cancer cell lines in vitro. Subfraction 1 was more active than subfraction 2 and subfraction 3 against the A549, AGS and MCF-7 cancer cell lines in vitro. In in vivo results, subfraction 1 isolated from I. obliquus at concentrations of 0.1 and 0.2 mg/mouse per day significantly decreased tumor volume by 23.96% and 33.71%, respectively, as compared with the control. Subfractions 2 and 3 also significantly inhibited tumor growth in mice bearing S-180 as compared with the control mouse tumor. Subfraction 1 isolated from I. obliquus showed greater inhibition of tumor growth than subfractions 2 and 3, which agrees well with the in vitro results. The results suggest that I. obliquus and its compounds in these subfractions isolated from I. obliquus could be used as natural anticancer ingredients in the food and/or pharmaceutical industry.

  3. Anticancer activity of subfractions containing pure compounds of Chaga mushroom (Inonotus obliquus) extract in human cancer cells and in Balbc/c mice bearing Sarcoma-180 cells

    PubMed Central

    Chung, Mi Ja; Chung, Cha-Kwon; Jeong, Yoonhwa

    2010-01-01

    The Chaga mushroom (Inonotus obliquus) has been used in folk medicine to treat cancers. However, limited information exists on the underlying anticancer effects of the major component of I. obliquus in vivo. We hypothesize that the pure compounds (3β-hydroxy-lanosta-8,24-dien-21-al, inotodiol and lanosterol, respectively) separated from I. obliquus would inhibit tumor growth in Balbc/c mice bearing Sarcoma-180 cells (S-180) in vivo and growth of human carcinoma cells in vitro. To test this hypothesis, the growth inhibition of each subfraction isolated from I. obliquus on human carcinoma cell lines (lung carcinoma A-549 cells, stomach adenocarcinoma AGS cells, breast adenocarcinoma MCF-7 cells, and cervical adenocarcinoma HeLa cells) was tested in vitro. Then, after S-180 implantation, the mice were fed a normal chow supplemented with 0, 0.1 or 0.2 mg of subfraction 1, 2 or 3 per mouse per day. All of the subfractions isolated from I. obliquus showed significant cytotoxic activity against the selected cancer cell lines in vitro. Subfraction 1 was more active than subfraction 2 and subfraction 3 against the A549, AGS and MCF-7 cancer cell lines in vitro. In in vivo results, subfraction 1 isolated from I. obliquus at concentrations of 0.1 and 0.2 mg/mouse per day significantly decreased tumor volume by 23.96% and 33.71%, respectively, as compared with the control. Subfractions 2 and 3 also significantly inhibited tumor growth in mice bearing S-180 as compared with the control mouse tumor. Subfraction 1 isolated from I. obliquus showed greater inhibition of tumor growth than subfractions 2 and 3, which agrees well with the in vitro results. The results suggest that I. obliquus and its compounds in these subfractions isolated from I. obliquus could be used as natural anticancer ingredients in the food and/or pharmaceutical industry. PMID:20607061

  4. Methylglyoxal induced activation of murine peritoneal macrophages and surface markers of T lymphocytes in sarcoma-180 bearing mice: involvement of MAP kinase, NF-kappa beta signal transduction pathway.

    PubMed

    Pal, Aparajita; Bhattacharya, Iman; Bhattacharya, Kaushik; Mandal, Chitra; Ray, Manju

    2009-06-01

    Methylglyoxal profoundly stimulates host's immune response against tumor cell by producing reactive oxygen intermediates (ROI's) and reactive nitrogen intermediates (RNI's) [Bhattacharyya, N., Pal, A., Patra, S., Haldar, A.K., Roy, S., Ray, M., 2008. Activation of macrophages and lymphocytes by methylglyoxal against tumor cells in the host. Int. Immunophar. 8 (11), 1503-1512]. Present study indicated that methylglyoxal stimulates iNOS activation by p38 MAPK-NF-kappa beta dependent pathway and ROS production by ERK and JNK activation in sarcoma-180 tumor bearing mice. Proinflammatory cytokines, for macrophage activation, IL-6 and IL-1 beta were also increased. Production of TLR 4 and TLR 9, which acts through the same signaling pathway, were also upregulated. Hence, concluded that methylglyoxal augmented the IL-6 and IL-1 beta, expression of TLR 4 and TLR 9 and produced MAPKs, important regulators of ROIs and RNIs. Methylglyoxal treatment also increased M-CSF, an upregulator of macrophage production. CD8 and CD4 molecules, associated with T(C) and T(H) cells respectively, were also increased. Overall methylglyoxal treatment is important for enhancement of macrophages and lymphocyte activation or immunomodulation against sarcoma-180 tumor.

  5. Immunostimulatory activities of a low molecular weight antitumoral polysaccharide isolated from Agaricus blazei Murill (LMPAB) in Sarcoma 180 ascitic tumor-bearing mice.

    PubMed

    Niu, Ying-Cai; Liu, Ji-Cheng; Zhao, Xue-Mei; Su, Fu-Qin; Cui, Hong-Xia

    2009-07-01

    LMPAB is a linear beta-(1-3)-glucan we isolated from polysaccharide extract of Agaricus blazei Murill (AbM). Effects of LMPAB on splenic natural killer (NK) cell activity, splenocyte proliferation, index of spleen and thymus, IFN-gamma expression in spleen and the concentration of IL-12, IL-18 and TNF-alpha in serum of S180 ascitic tumor-bearing mice were detected. The results showed that intraperitoneal injection of LMPAB (100 mg x kg(-1) x d(-1)) significantly increased the thymus index. LMPAB augmented splenic NK cell activity in a dose-dependent manner (50-200 mg x kg(-1) x d(-1)). The concanavalin A (3 microg/ ml) stimulated splenocyte proliferation was significantly enhanced by LMPAB at dosages of 50, 100 or 200 mg x kg(-1) x d(-1). Further studies showed that LMPAB (50, 100 or 200 mg x kg(-1) x d(-1), 14d) significantly increased the production of IL-12, TNF-alpha, IL-18 and the expression IFN-gamma as determined by ELISA and immunohistochemistry, respectively. These results clearly indicate that the anti-tumor effects of LMPAB are closely associated with up-regulation of activity of NK cells, expression of IFN-gamma in spleen and the systemic level of IL-12, IL-18 and TNF-alpha in tumor-bearing mice.

  6. Immunomodulation of macrophages by methylglyoxal conjugated with chitosan nanoparticles against Sarcoma-180 tumor in mice.

    PubMed

    Chakrabarti, Adrita; Talukdar, Dipa; Pal, Aparajita; Ray, Manju

    2014-01-01

    Methylglyoxal (MG), the potent anticancer agent has been conjugated to a nontoxic, biocompatible polymer, chitosan, to protect it from in vivo enzymatic degradation. This polymeric complex, 'Nano-MG' shows remarkable antitumor property and elicits macrophage-mediated immunity in tumor bearing mice on intravenous (0.4 mg/kg body wt/day) treatment more efficiently than MG (20mg/kg body wt/day). These activated macrophages appear more in numbers in the peritoneum and produce more superoxide and nitrite. Moreover, immunomodulatory cytokines and surface receptors of these macrophages like iNOS, IFN-γ, TNF-α, IL-1β, IL-6, M-CSF, TLR-4 and TLR-9 also exhibit marked up-regulation in Sarcoma-180 tumor bearing mice after Nano-MG treatment compared to untreated tumor bearing counterpart. Hence, Nano-MG acts as an immunostimulant in tumor bearing mice to combat cancer at conspicuously lower dose, probably due to its longer circulation time in blood.

  7. Anticancer effect of Jinlongshe granules on in situ-transplanted human MKN-45 gastric cancer in nude mice and xenografted sarcoma 180 in Kunming mice and its mechanism

    PubMed Central

    Yu, Zhi-Hong; Wei, Pin-Kang; Xu, Ling; Qin, Zhi-Feng; Shi, Jun

    2006-01-01

    AIM: To study the antitumor effect of Chinese compound Jinlongshe (JLS) granules on sarcoma 180 and MKN-45 human gastric cancer cell lines in vivo and its mechanism. METHODS: After establishment of S180 sarcoma (S180) and MKN-45 gastric cancer model of nude mice, the tumor-bearing mice were divided into 5 groups at random. Three experimental groups were respectively given the aqueous extract of JLS granules at doses of 120 g, 60 g and 20 g /(kg per 6/wk, i.g) for 3 wk in S180 and 6 wk in nude mice model. Positive control was given cyclophosphamide (Cy) at a dose of 50 mg/(kg per 3 /wk, i.g) for 3 wk in S180 models and 5- Fluorouracil (5-FU) 20 mg/(kg per 3 /wk, i.g) for 3 wk in nude mice model. Negative control was given normal saline (NS) at a dose of 0.18 g/(kg per 6/wk, i.g) respectively. After 3 wk in mice bearing S180 tumor and 6 wk in nude mice model, the experimental animals were sacrificed and the masses of tumor were weighed, and the rates of tumor inhibition of each treated group were calculated respectively. To determine the antitumor mechanisms, the morphological changes, cell cycle and apoptosis were observed in MKN-45 nude mice model. Annexin V-FITC/PI double staining FCM assay was used to further determine the live cells, apoptotic cells, necrotic cells and debris. RESULTS: The inhibitory rates of JLS granules at the doses of 20 g/kg, 60 g/kg and 120 g/kg were 50.31%, 55.94% and 68.13% (P < 0.01) in nude mice models and 40.90%, 50.32% and 58.46% (P < 0.01) in S180 model. The inhibitory rate of Cy was 85.22% in S180 models and the inhibitory rate of 5-FU was 53.43% in nude mice model (P < 0.01). Nuclear chromatin and margination were observed under a transmission electron microscope (TEM). The G0/G1 phase was arrested, typical apoptotic peak appeared, the apoptotic rate was 22.81%-38.54% in three JLS granule-treated groups. Annexin V-FITC/PI double staining FCM assay showed that the apoptotic cells were 4.36%, 3.08%and 7.08% in three dosages, most

  8. Anti-tumor effects and apoptosis induction by Realgar bioleaching solution in Sarcoma-180 cells in vitro and transplanted tumors in mice in vivo.

    PubMed

    Xie, Qin-Jian; Cao, Xin-Li; Bai, Lu; Wu, Zheng-Rong; Ma, Ying-Ping; Li, Hong-Yu

    2014-01-01

    Realgar which contains arsenic components has been used in traditional Chinese medicine (TCM) as an anticancer drug. However, neither Realgar nor its formula are soluble in water. As a result, high dose of Realgar has to be administered to achieve an effective blood medicine concentration, and this is associated with adverse side effects. The objective of the present study was to increase the solubility of a formula using hydrometallurgy technology as well as investigating its effects on in vitro and in vivo cell proliferation and apoptosis in Sarcoma-180 cell line. Antiproliferative activity of Realgar Bioleaching Solution (RBS) was evaluated by MTT assay. Further, effects of RBS on cell proliferation and apoptosis were studied using flow cytometry and transmission electron microscopy. Kunming mice were administered RBS in vivo, where arsenic specifically targeted solid tumors. The results indicated that RBS extract potently inhibited the tumor growth of Sarcoma-180 cell line in a dose-dependent manner. Flow cytometry and transmission electron microscopy further indicated that RBS significantly induced cell apoptosis through the inhibition of cell cycle pathway in a dose-dependent manner. Further, on RBS administration to mice, arsenic was specifically targeted to solid tumors RBS could substitute for traditional Realgar or its formula to work as a potent tool in cancer treatment.

  9. Antitumour potential of a polysaccharide-rich substance from the fruit juice of Morinda citrifolia (Noni) on sarcoma 180 ascites tumour in mice.

    PubMed

    Furusawa, Eiichi; Hirazumi, Anne; Story, Stephen; Jensen, Jarakae

    2003-12-01

    An immunomodulatory polysaccharide-rich substance (Noni-ppt) from the fruit juice of Morinda citrifolia has been found to possess both prophylactic and therapeutic potentials against the immunomodulator sensitive Sarcoma 180 tumour system. The antitumour activity of Noni-ppt produced a cure rate of 25%-45% in allogeneic mice and its activity was completely abolished by the concomitant administration of specific inhibitors of macrophages (2-chloroadenosine), T cells (cyclosporine) or natural killer (NK) cells (anti-asialo GM1 antibody). Noni-ppt showed synergistic or additive beneficial effects when combined with a broad spectrum of chemotherapeutic drugs, including cisplatin, adriamycin, mitomycin-C, bleomycin, etoposide, 5- fl uorouracil, vincristine or camptothecin. It was not beneficial when combined with paclitaxel, cytosine arabinoside, or immunosuppressive anticancer drugs such as cyclophosphamide, methotrexate or 6-thioguanine. Noni-ppt also demonstrated beneficial effects when combined with the Th1 cytokine, interferon gamma, but its activity was abolished when combined with Th2 cytokines, interleukin-4 or interleukin-10, thereby suggesting that Noni-ppt induces a Th1 dominant immune status in vivo. The combination of Noni-ppt with imexon, a synthetic immunomodulator, also demonstrated beneficial effects, but not when combined with the MVE-2 copolymer, a high molecular weight immunomodulator. It was also not effective when combined with interleukin-2 or interleukin-12. Copyright 2003 John Wiley & Sons, Ltd.

  10. High dose concentration administration of ascorbic acid inhibits tumor growth in BALB/C mice implanted with sarcoma 180 cancer cells via the restriction of angiogenesis

    PubMed Central

    Yeom, Chang-Hwan; Lee, Gunsup; Park, Jin-Hee; Yu, Jaelim; Park, Seyeon; Yi, Sang-Yeop; Lee, Hye Ree; Hong, Young Seon; Yang, Joosung; Lee, Sukchan

    2009-01-01

    To test the carcinostatic effects of ascorbic acid, we challenged the mice of seven experimental groups with 1.7 × 10-4 mol high dose concentration ascorbic acid after intraperitoneal administrating them with sarcoma S-180 cells. The survival rate was increased by 20% in the group that received high dose concentration ascorbic acid, compared to the control. The highest survival rate was observed in the group in which 1.7 × 10-4 mol ascorbic acid had been continuously injected before and after the induction of cancer cells, rather than just after the induction of cancer cells. The expression of three angiogenesis-related genes was inhibited by 0.3 times in bFGF, 7 times in VEGF and 4 times in MMP2 of the groups with higher survival rates. Biopsy Results, gene expression studies, and wound healing analysis in vivo and in vitro suggested that the carcinostatic effect induced by high dose concentration ascorbic acid occurred through inhibition of angiogenesis. PMID:19671184

  11. In vivo growth inhibition of sarcoma 180 by latex proteins from Calotropis procera.

    PubMed

    Oliveira, Jefferson S; Costa-Lotufo, Letícia V; Bezerra, Daniel P; Alencar, Nylane M N; Marinho-Filho, José Delano B; Figueiredo, Ingrid Samantha T; Moraes, Manoel O; Pessoa, Claudia; Alves, Ana Paula N N; Ramos, Márcio V

    2010-08-01

    Latex of Calotropis procera has been described as a relevant source of pharmacologically active proteins, including proteins with anticancer activity. A previous in vitro study of laticifer proteins (LP) from C. procera reported that they had selective cytotoxic effects on human cancer cell lines. The aim of this study was to determine the effects of LP in vivo using mice transplanted with sarcoma 180. Biochemical, hematological, histopathological, and morphological analyses were performed in animals given LP by oral or intraperitoneal routes. LP significantly reduced tumor growth (51.83%) and augmented the survival time of animals for up to 4 days. Tumor growth inhibitory activity was lost when LP fraction was submitted to proteolysis, acidic treatment, or pretreated with iodoacetamide. However, LP retained its inhibitory activities on sarcoma 180 growth after heat treatment. Thus, it seems that heat-stable proteins are involved in tumor suppression. Biochemical parameters, such as the enzymatic activity of aspartate aminotransferase and alanine aminotransferase and urea content in serum were not affected in treated mice. It is worth noting that LP completely eliminated the 5-FU-induced depletion of leukocytes in mice even when given orally. The active proteins were recovered in a single fraction by ion exchange chromatography and still exhibited anticancer activity. This study confirms the pharmacological potential of proteins from the latex of C. procera to control sarcoma cell proliferation.

  12. Antitumor activity of milk kefir and soy milk kefir in tumor-bearing mice.

    PubMed

    Liu, Je-Ruei; Wang, Sheng-Yao; Lin, Yuh-Yih; Lin, Chin-Wen

    2002-01-01

    The effects of oral administration of milk and soy milk kefirs on tumor growth in tumor-bearing mice and the mucosal immunoglobulin A response in mice were studied. Oral administration of milk and soy milk kefirs to mice inoculated with sarcoma 180 tumor cells resulted in 64.8% and 70.9% inhibition of tumor growth, respectively, compared with controls. In addition, oral administration of the two kefir types induced apoptotic tumor cell lysis. Total immunoglobulin A levels for tissue extracts from the wall of the small intestine were also significantly higher for mice fed a milk kefir or a soy milk kefir regimen for 30 days. These results suggest that milk and soy milk kefirs may be considered among the more promising food components in terms of cancer prevention and enhancement of mucosal resistance to gastrointestinal infection.

  13. Anticancer and Immunopotentiating Activities of Crude Polysaccharides from Pleurotus nebrodensis on Mouse Sarcoma 180

    PubMed Central

    Cha, Youn Jeong; Alam, Nuhu; Lee, Jae Seong; Lee, Kyung Rim; Shim, Mi Ja; Lee, Min Woong; Kim, Hye Young; Shin, Pyung Gyun; Cheong, Jong Chun; Yoo, Young Bok

    2012-01-01

    Pleurotus nebrodensis is an edible and commercially available mushroom in Korea. This study was conducted in order to evaluate the anticancer and immunopotentiating activities of crude polysaccharides, extracted in methanol, neutral saline, and hot water (hereafter referred to as Fr. MeOH, Fr. NaCl, and Fr. HW, respectively) from the fruiting bodies of P. nebrodensis. β-Glucan and protein contents in Fr. MeOH, Fr. NaCl, and Fr. HW extracts of P. nebrodensis ranged from 23.79~36.63 g/100 g and 4.45~6.12 g/100 g, respectively. Crude polysaccharides were not cytotoxic against sarcoma 180, HT-29, NIH3T3, and RAW 264.7 cell lines at a range of 10~2,000 µg/mL. Intraperitoneal injection with crude polysaccharides resulted in a life prolongation effect of 11.76~27.06% in mice previously inoculated with sarcoma 180. Treatment with Fr. NaCl resulted in an increase in the numbers of spleen cells by 1.49 fold at the concentration of 50 µg/mL, compared with control. Fr. HW improved the immuno-potentiating activity of B lymphocytes through an increase in alkaline phosphatase activity by 1.65 fold, compared with control at 200 µg/mL. Maximum production of nitric oxide (14.3 µM) was recorded in the Fr. NaCl fraction at 200 µg/mL. Production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) was significantly higher, compared to control, and IL-6 production was highest, in contrast to TNF-α, IL-1β, and positive control, concanavalin at the tested concentration of the various fractions. Results of the current study suggest that polysaccharides extracted from P. nebrodensis have a strong anticancer effect and may be useful as an ingredient of biopharmaceutical products for treatment of cancer. PMID:23323048

  14. Whole-body autoradiographic study of the distribution of 195mPt in healthy and tumor-bearing mice treated with labeled cisplatin

    SciTech Connect

    Benard, P.; Desplanches, G.; Macquet, J.P.; Simon, J.

    1983-05-01

    195mPt-labeled cisplatin was administered iv and ip to control mice and to mice bearing Sarcoma 180. The delivered dose was 8 mg/kg and the injected activity was 80 muCi/kg. Whole-body autoradiography was performed at various times after treatment. For all animals, concentration of radioactive material was observed in the kidneys as early as 5 minutes after treatment. Most of the delivered radioactivity was present in the urine-bladder for the first 4 hours after the injection. Autoradiography also showed concentration of 195mPt in the bile ducts. These results suggest that a lower but significant part of the delivered radioactivity was also eliminated in the bile, which may explain in part the presence of the isotope in the gut lumen. In addition, 195mPt-equivalents were observed in the kidney parenchyma, the cartilages, the teeth, the skin, and the hair. Only trace amounts of 195mPt were present in the hypophysis and the testes. The distribution of radioisotope in healthy and tumor-bearing animals was comparable. Measurable uptake occurred in the Sarcoma 180 tumor.

  15. Binding and cytotoxicity of Ricinus communis lectins to HeLa cells, Sarcoma 180 ascites tumor cells and erythrocytes.

    PubMed

    Oda, T; Aizono, Y; Funatsu, G

    1984-08-01

    The binding of Ricinus communis lectins to HeLa cells, Sarcoma 180 ascites tumor cells and human erythrocytes was studied in detail. Scatchard plots of binding of 125I-lectins to these cells gave biphasic lines except for HeLa cells at 0 degree C. The association constants of lectins for the three cell types at 37 degrees C were lower than those at 0 degree C. The numbers of total binding sites were estimated to be 7 to 16 X 10(7) per HeLa cell, 3 to 4 X 10(7) per Sarcoma 180 ascites tumor cell and 0.4 to 1 X 10(6) per erythrocyte. A fraction, 16 to 27% of the total amount of cell-bound lectin at 37 degrees C, appeared to be bound irreversibly as judged by non-removal on washing with 0.1 M lactose, whereas no lectin was irreversibly bound at 0 degree C. In the case of erythrocytes, no lectin became irreversibly bound even at 37 degrees C. The toxicity of lectins on HeLa cells and Sarcoma 180 ascites tumor cells was investigated. The toxicity of ricin D was 50 times for Sarcoma 180 ascites tumor cells and 140 times for HeLa cells as much as that for castor bean hemagglutinin. As to the sensitivities of both cell types to these lectins, it became apparent that Sarcoma 180 ascites tumor cells were more susceptible than HeLa cells.

  16. Antitumor effect of culinary-medicinal oyster mushroom, Pleurotus ostreatus (Jacq.: Fr.) P. Kumm., derived protein fraction on tumor-bearing mice models.

    PubMed

    Maiti, Swatilekha; Mallick, Sanjaya Kumar; Bhutia, Sujit Kumar; Behera, Birendra; Mandal, Mohitosh; Maiti, Tapas K

    2011-01-01

    Previously, we reported the in vitro anticancer and immunomodulatory effect of a protein fraction designated as Cibacron blue affinity purified protein (CBAEP) obtained from the culinary-medicinal oyster mushroom, Pleurotus ostreatus. In the present study, we investigated the in vivo antitumor potential of CBAEP in different tumor-bearing mice models and studied the detailed mechanism of tumor regression in Dalton lymphoma (DL)-bearing mice. The lethal dose (LD50) of CBAEP was found to be 55 mg/kg body weight and sublethal doses (5 mg/kg and 10 mg/kg body weight) showed a prolonged tumor survival time in DL, Sarcoma-180, and B16F0 melanoma tumor-bearing mice. Further, CBAEP reduced about 35.68 and 51.43% DL cell growth in 5 and 10 mg/kg body weight, respectively. The in vivo CBAEP treatment showed an apoptotic feature as demonstrated in morphological study and sub-G0/G1 population in cell cycle and Western blot of DL cells. CBAEP also activated immunosuppression condition in DL tumor-bearing host. It also stimulated immune cells in the presence of nonspecific immunostunulator (LPS and ConA) ex vivo as well as enhanced Th1 response with production of TNF-α, IFN-γ, and IL-2. Moreover, it activated tumor-associated macrophages and NK cells. The present findings revealed the potent antitumor property of CBAEP, which might help in developing a new anticancer drug.

  17. Amelioration of doxorubicin-induced myocardial oxidative stress and immunosuppression by grape seed proanthocyanidins in tumour-bearing mice.

    PubMed

    Zhang, Xiao-Yu; Li, Wen-Guang; Wu, Yong-Jie; Gao, Ming-Tang

    2005-08-01

    We have investigated the protective effects of grape seed proanthocyanidins on doxorubicin-induced toxicity in tumour-bearing mice. The intraperitoneal administration of doxorubicin (2 mg kg(-1) every other day, cumulative dosage for 18 mg kg(-1)) significantly inhibited the growth of sarcoma 180, and induced myocardial oxidative stress with decreased superoxide dismutase and glutathione peroxidase activity while increasing malondialdehyde formation in the heart or serum. Doxorubicin-induced myocardial oxidative stress also reduced lactate dehydrogenase and creatine kinase activity in the heart and elevated their levels in the serum. Doxorubicin also affected immune functions of tumour-bearing mice with significantly decreased interleukin-2 (IL-2) and interferon-gamma (INF-gamma) production, and slightly decreased natural killer (NK) cell cytotoxicity, lymphocyte proliferation and CD4+/CD8+ ratio. It markedly increased the percentages of cytotoxic T cells (CD3+CD8+), helper T cells (CD3+CD4+), IL-2R+CD4+, and IL-2R+ cells as compared with untreated tumour-bearing mice. The intragastric administration of proanthocyanidin (200 mg kg(-1) daily) significantly inhibited tumour growth, and increased NK cell cytotoxicity, lymphocyte proliferation, CD4+/CD8+ ratio, IL-2 and INF-gamma production. Moreover, proanthocyanidin strongly enhanced the anti-tumour effect of doxorubicin and the above immune responses, and completely eliminated myocardial oxidative stress induced by doxorubicin. In conclusion, intragastric administration of proanthocyanidin could enhance the anti-tumour activity of doxorubicin and ameliorate doxorubicin-induced myocardial oxidative stress and immunosuppression in tumour-bearing mice.

  18. Sonodynamically-induced cytotoxicity by rose bengal derivative and microbubbles in isolated sarcoma 180 cells

    NASA Astrophysics Data System (ADS)

    Sugita, Nami; Hosokawa, Mami; Sunaga, Naoki; Iwase, Yumiko; Yumita, Nagahiko; Ikeda, Toshihiko; Umemura, Shin-ichiro

    2015-07-01

    It is known that the combination of ultrasound and sonodynamic sensitizer (SDS) is effective in noninvasive tumor treatment, referred to as sonodynamic therapy (SDT). Microbubbles have been used in ultrasound therapy as well. The purpose of this paper is to clarify the effect of microbubbles on SDT. Sarcoma 180 cells were suspended in air-saturated phosphate-buffered saline and exposed to ultrasound with the SDS rose bengal derivative (RBD) in standing wave mode in the presence and absence of microbubbles [sonazoid (SZ)]. The ultrasonically induced cytotoxicity with RBD and SZ was about 20 times higher than without either, and about 80% of the SZ microbubbles were destructed by ultrasonic exposure in as short as five seconds. Since microbubbles induce significant cytotoxicity even with short duration, low intensity ultrasound, the application of microbubbles in SDT shows promise in anti-tumor treatment.

  19. Cytoxicity and Apoptotic Mechanism of Ruthenium(II) Amino Acid Complexes in Sarcoma-180 Tumor Cells

    PubMed Central

    Lima, Aliny Pereira; Pereira, Flávia Castro; Almeida, Marcio Aurelio Pinheiro; Mello, Francyelli Mariana Santos; Pires, Wanessa Carvalho; Pinto, Thallita Monteiro; Delella, Flávia Karina; Felisbino, Sérgio Luis; Moreno, Virtudes; Batista, Alzir Azevedo; de Paula Silveira-Lacerda, Elisângela

    2014-01-01

    Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 µM to 50.18 µM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas. PMID:25329644

  20. Antitumor activity of Pleurotus ostreatus polysaccharide fractions on Ehrlich tumor and Sarcoma 180.

    PubMed

    Facchini, Jean Mary; Alves, Endi Pricila; Aguilera, Charlise; Gern, Regina Maria Miranda; Silveira, Marcia Luciane Lange; Wisbeck, Elisabeth; Furlan, Sandra Aparecida

    2014-07-01

    The medicinal properties of fungi of the genus Pleurotus have attracted great interest due to their therapeutic properties. Polysaccharides synthesized by Pleurotus, including the β-glucans are considered the main responsible for its therapeutic properties. This study aimed to evaluate the efficacy of polysaccharidic fractions extracted from mycelial biomass of Pleurotus ostreatus DSM 1833 in inhibiting the development of Ehrlich Tumor (ET) and Sarcoma 180 (S-180). FC, FI and FII fractions provided 60.6, 76.5 and 73.6% of ET inhibition, respectively (mean value of about 70%) while FS, FIII-1 and FIII-2 showed no inhibition against ET. FII and FIII-2 resulted in 85.6 and 93.6% (mean value of about 90%) while FIII-1, FC and FS resulted in 54.1 and 0%, respectively, of S-180 inhibition. The yields of the fractions FS, FI, FII, FIII-1 and FIII-2 obtained from P. ostreatus mycelial biomass were 11.6, 1.3, 0.4, 0.65 and 0.35%, respectively. FII fraction (30mg/kg) apparently had no toxic effect on healthy animals, since no difference between the body weights of animals in substance control (SC) and negative control (NC) groups was observed. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Cytoxicity and apoptotic mechanism of ruthenium(II) amino acid complexes in sarcoma-180 tumor cells.

    PubMed

    Lima, Aliny Pereira; Pereira, Flávia Castro; Almeida, Marcio Aurelio Pinheiro; Mello, Francyelli Mariana Santos; Pires, Wanessa Carvalho; Pinto, Thallita Monteiro; Delella, Flávia Karina; Felisbino, Sérgio Luis; Moreno, Virtudes; Batista, Alzir Azevedo; de Paula Silveira-Lacerda, Elisângela

    2014-01-01

    Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 µM to 50.18 µM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas.

  2. Antitumor and immunomodulatory effects of weikangfu granule compound in tumor-bearing mice

    PubMed Central

    Nie, Xiaohua; Shi, Baojun; Ding, Yuting; Tao, Wenyi

    2006-01-01

    Background: Weikangfu granule compound (WKC) is a drug preparation based on a clinical prescription drug, Weikangfu-tang, which has been found to have therapeutic effects on gastric cancer. WKC comprises 7 components, including polysaccharides, saponin, flavonoids, and essential oil. Objective: The purpose of this study was to assess the antitumor and immunomodulatory effects of WKC in a tumor-bearing rodent model. Methods: Male and female Kuming mice weighing ∼20 g were subcutaneously implanted with sarcoma 180 (S180) tumor cells and randomly assigned to 1 of 5 treatment groups: oral WKC 175, 350, or 525 mg/kg·d, isotonic saline (negative control), or intraperitoneal cyclophosphamide 25 mg/kg·d (positive control). All treatments were administered daily for 10 days. After euthanization on day 11, the mice, tumors, and spleens were weighed. Lymphocyte proliferation and cytotoxic T lymphocyte (CTL) activity were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cellular viability assay method. Macrophage phagocytosis was identified using a yeast test. Results: Fifty mice were included in the study (10 mice were assigned to each group). The tumors of the mice administered WKC 175, 350, and 525 mg/kg·d were significantly regressed, as determined using MICs, compared with those in the negative-control group (P<0.05, P<0.01, and P<0.01, respectively), and the inhibitory rates were 30.43%, 46.72%, and 54.35%, respectively. Compared with those in the negative-control group, CTL activities and lymphocyte proliferations in the presence of concanavalin A were significantly greater in the WKC-treated groups at all doses (CTL activities: P<0.05, P<0.01, and P<0.01, respectively; lymphocyte proliferations: P<0.05, P<0.01, and P<0.01, respectively). In the groups receiving WKC 175, 350, and 525 mg/kg·d, the phagocytic rates were 1.5- to 2.0-fold those in the negative-control group (P<0.05, P<0.01, and P<0.01, respectively). In the groups

  3. Comparison of therapeutic responses to an anticancer drug in three stocks of ICR mice derived from three different sources

    PubMed Central

    Sung, Ji Eun; Kim, Ji Eun; Lee, Hyun Ah; Yun, Woo Bin; Choi, Jun Young; Lee, Mi Rim; Park, Jin Ju; Kim, Hye Ryeong; Song, Bo Ram; Jung, Young Suk; Kim, Kil Soo

    2017-01-01

    Korl:ICR mice, established by the Korean National Institute of Food and Drug Safety Evaluation (NIFDS), are characterized based on their genetic variation, response to gastric injury, and response to constipation inducers. To compare the inhibitory responses of ICR stocks obtained from three different sources to the anticancer drug cisplatin (Cis), alterations in tumor volume, histopathological structure, and toxicity were examined in Sarcoma 180 tumor-bearing Korl:ICR, A:ICR (USA source), and B:ICR (Japan source) mice treated with low and high concentrations of Cis (L-Cis and H-Cis, respectively). Tumor size and volume were lower in H-Cis-treated mice than in L-Cis-treated mice in all three ICR stocks with no significant differences among stocks. There was a significant enhancement of the necrotizing areas in the histological structures in the L-Cis- and H-Cis-treated groups relative to that in the untreated group. The necrotizing area changes were similar in the Sarcoma 180 tumor-bearing Korl:ICR, A:ICR, and B:ICR mice. However, there were stock-bases differences in the serum biomarkers for liver and kidney toxic effects. In particular, the levels of AST, ALT and BUN increased differently in the three H-Cis-treated ICR stocks, whereas the levels of ALP and CRE were constant. Taken together, the results of the present study indicate that Korl:ICR, A:ICR, and B:ICR mice have similar overall inhibitory responses following Cis treatment of Sarcoma 180-derived solid tumors, although there were some differences in the magnitude of the toxic effects in the three ICR stocks. PMID:28747986

  4. Study on antitumor, antioxidant and immunoregulatory activities of the purified polyphenols from pinecone of Pinus koraiensis on tumor-bearing S180 mice in vivo.

    PubMed

    Yi, Juanjuan; Qu, Hang; Wu, Yunzhou; Wang, Zhenyu; Wang, Lu

    2017-01-01

    Pinecone polyphenols are bioactive dietary constituents that enhance health and help prevent and treat cancer through improving antioxidant and immunoregulatory activities. This study was designed to investigate the antitumor, antioxidant and immunoregulatory activities of the 40% ethanol eluent of polyphenols from pinecone of pinus koraiensis (PPP-40) in Sarcoma 180 (S180)-bearing mice models in vivo. The results of antitumor activity indicated that PPP-40 significantly inhibited S180 tumor growth and the dose of 150mg/kg exhibited the highest antitumor activity. Moreover, TdT-mediated dUTP nick end labeling (TUNEL) assay results further confirmed the apoptosis of S180 tumor cells. In addition, PPP-40 could obviously promote the expressions of Bax protein and inhibit the Bcl-2 protein, accordingly improve the expressions of activated Caspase-3 as well, which resulted in the activation of mitochondrial apoptotic pathway of tumor cells in S180 mice eventually. The results of antioxidant activity showed that the S180 mice treated with PPP-40 had the higher superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, the more glutathione (GSH) content, and the lower malondialdehyde (MDA) level in plasma comparing with non-treated control group. Moreover, the administration with PPP-40 (150mg/kg) significantly accelerated the proliferation of splenocytes (p<0.01) and increased the monocyte phagocytosis activity in vivo simultaneously. These results revealed that PPP-40 exerts an effective antitumor activity by activating the mitochondrial apoptotic pathway and improving the antioxidant and immunoregulatory activities. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Relationship between antitumor effect and metabolites of 5-fluorouracil in combination treatment with 5-fluorouracil and guanosine in ascites Sarcoma 180 tumor system

    SciTech Connect

    Iigo, M.; Kuretani, K.; Hoshi, A.

    1983-12-01

    The antitumor activity of (6-14C)5-fluorouracil ((6-14C)FUra) against ascites Sarcoma 180 was significantly enhanced by coadministration of guanosine, and slightly by adenosine, but not by cytidine or uridine. In advanced ascites Sarcoma 180, guanosine also enhanced the action of FUra, but adenosine, uridine, and cytidine did not. The potentiation of antitumor activity by guanosine was reversed by addition of cytidine. The antitumor activity of FUra was significantly potentiated when guanosine was administered either 0 to 15 min before or 5 min after FUra. Changes in metabolites of FUra after potentiation by guanosine were investigated. The potentiation of antitumor activity of FUra by guanosine was considered to be due to an increase in incorporation of FUra into FUra-nucleotides and RNA in the tumor cells.

  6. In vivo growth-inhibition of Sarcoma 180 by an alpha-(1-->4)-glucan-beta-(1-->6)-glucan-protein complex polysaccharide obtained from Agaricus blazei Murill.

    PubMed

    Gonzaga, Maria Leônia Costa; Bezerra, Daniel Pereira; Alves, Ana Paula Negreiros Nunes; de Alencar, Nylane Maria Nunes; Mesquita, Rodney de Oliveira; Lima, Michael Will; Soares, Sandra de Aguiar; Pessoa, Cláudia; de Moraes, Manoel Odorico; Costa-Lotufo, Letícia Veras

    2009-01-01

    Agaricus blazei Murrill, a native mushroom of Brazil, has been widely consumed in different parts of the world due to its anticancer potential. This effect is generally attributed to its polysaccharides; however, the precise structure of these has not been fully characterized. To better understand the relationship between polysaccharide structures and antitumor activity, we investigated the effect of the intraperitoneally (i.p.) or orally (p.o.) administered alpha-(1-->4)-glucan-beta-(1-->6)-glucan-protein complex polysaccharide from A. blazei alone or in association with 5-fluorouracil (5-FU) in tumor growth using Sarcoma 180 transplanted mice. Hematological, biochemical, and histopathological analyses were performed in order to evaluate the toxicological aspects of the polysaccharide treatment. The polysaccharide had no direct cytotoxic action on tumor cells in vitro. However, the polysaccharide showed strong in vivo antitumor effect. Thus, the tumor growth-inhibitory effect of the polysaccharide is apparently due to host-mediated mechanisms. The histopathological analysis suggests that the liver and the kidney were not affected by polysaccharide treatment. Neither enzymatic activity of transaminases (AST and ALT) nor urea levels were significantly altered. In hematological analysis, leucopeny was observed after 5-FU treatment, but this effect was prevented when the treatment was associated with the polysaccharide. In conclusion, this polysaccharide probably could explain the ethnopharmacological use of this mushroom in the treatment of cancer.

  7. Immunomodulatory and antitumour effects of abnormal Savda Munziq on S180 tumour-bearing mice

    PubMed Central

    2012-01-01

    Background Abnormal Savda Munziq (ASMq), a traditional uyghur medicine, has shown anti-tumour properties in vitro. This study attempts to confirm these effects in vivo and measure effects on the immune system. Methods Kunming mice transplanted with Sarcoma 180 cells were treated with ASMq (2–8 g/kg/day) by intra-gastric administration compared to model and cyclophosphamide (20 mg/kg/day). After the 14th day post tumour implant, thymus, liver, spleen and tumours were removed, weighed, and processed for histopathological analysis. Blood samples were also taken for haematological and biochemical analyses including TNF-α , IL-1 β and IL-2. Splenic lymphocyte function was measured with MTT; lymphocyte subpopulations were measured by flow cytometry. Results ASMq treated animals had reduced tumour volume compared to model and increased concentrations of TNF-α, IL-1β and IL-2 compared to untreated and to cyclophosphamide-treated animals. No histopathological alterations were observed. The absence of viable S180 cells and the presence of necrotic cells and granulation tissue were observed in tumour tissue of treated animals. The effect on T lymphocytes was unclear. Conclusions ASMq confirmed in vivo anti-tumour effects observed in vitro, which may be at least in part mediated by increased immune activity. PMID:22978453

  8. Photodynamic therapy and immune response in tumor-bearing mice

    NASA Astrophysics Data System (ADS)

    Canti, Gianfranco L.; Cubeddu, Rinaldo; Taroni, Paola; Valentini, Gianluca

    1999-06-01

    Since immune response of the host is important in the control of tumor growth and spreading, and the Photodynamic therapy (PDT) is able to increase the antitumor immunity, in our laboratory we examine the effect of PDT on immune compartment of tumor bearing mice. Lymphocytes and macrophages collected from tumor bearing mice pretreated with PDT are cytotoxic in vitro and in vivo against the parental tumor lines, in contrast the same immune cells population collected from tumor bearing mice pretreated only with laser light are unable to lyse the parental tumor cells. In adoptive immunotherapy experiments, treatment of mice bearing MS-2 tumor with adoptive transfer of immune lymphocytes collected from mice pretreated with PDT is able to significantly increase the survival time; in contrast the lymphocytes collected from mice pretreated only with laser light were not able to modify the survival time suggesting that the laser treatment alone did not increase the immune response of the host. In conclusion these results demonstrate that the PDT induce a strong immune response on the host and the stimulated lymphocytes generated could be used for an adoptive immunotherapy approach; moreover laser treatment alone (thermal effect) is unable to modulate the immune response of the host.

  9. Amino acid metabolism in tumour-bearing mice.

    PubMed Central

    Rivera, S; Azcón-Bieto, J; López-Soriano, F J; Miralpeix, M; Argilés, J M

    1988-01-01

    Mice bearing the Lewis lung carcinoma showed a high tumour glutaminase activity and significantly higher concentrations of most amino acids than in both the liver and the skeletal muscle of the host. Tumour tissue slices showed a marked preference for glutamine, especially for oxidation of its skeleton to CO2. It is proposed that the metabolism of this particular carcinoma is focused on amino acid degradation, glutamine being its preferred substrate. PMID:3342022

  10. Endotoxin contamination of Agaricus blazei Murrill extract enhances murine immunologic responses and inhibits the growth of sarcoma 180 implants in vivo.

    PubMed

    Kobayashi, Hitoshi; Masumoto, Junya

    2010-01-01

    Agaricus blazei Murrill, a native mushroom of Brazil, has been reported to be an immunoreactant with anti-tumor effect. There are many reports on the anti-tumor effect of Agaricus blazei Murrill; however, the precise mechanism of its effect is not fully understood. In this study, we tried to confirm the anti-tumor effect of Agaricus blazei Murrill against Sarcoma 180 cells in a mouse model and found that an inhibitory effect on tumor growth was induced by peritoneal injection of a freeze-dried, hot water extract of Agaricus blazei Murrill (FAG). We noted that there were differences among each sample in terms of anti-tumor activity. We hypothesized that this was because some contaminants of FAG were affecting the anti-tumor activity. We evaluated cytokine secretion from mouse peritoneal cells incubated with FAG. While high interleukin-6 and tumor necrosis factor-α secretions were observed in response to crude FAG, they were dramatically decreased by the removal of endotoxin from the FAG using an endotoxin-specific polymyxin B-conjugated affinity column. The reductions were synergistically recovered by adding an amount of lipopolysaccharide equivalent to the amount of contaminated endotoxin. Thus, these data suggest that the contaminated endotoxin of Agaricus blazei Murrill may act as an immunomodulator of anti-tumor activity.

  11. Chlorpromazine distribution in hamsters and mice bearing transplantable melanoma

    SciTech Connect

    Fairchild, R.G.; Greenberg, D.; Watts, K.P.; Packer, S.; Atkins, H.L.; Som, P.; Hannon, S.J.; Brill, A.B.; Fand, I.; McNally, W.P.

    1982-02-01

    Chlorpromazine (CPZ) distribution was measured in tissues of Syrian golden hamsters bearing Greene melanoma and in BALB/c mice bearing Harding-Passey melanoma. Distribution was evaluated as a function of time (0.5 to 14 days) and as a function of single and multiple doses (up to five) of from 5 to 50 mg CPZ per kg body weight. Routes of administration (i.p., i.v., p.o.) were compared. The physiological behavior of CPZ is of interest as it is used extensively as a tranquilizing drug (Thorazine). Further, since CPZ binds to the pigment melanin, the possibility exists of using CPZ to transport diagnostic or therapeutic agents to melanoma. It was found that, at 2 days postinjection, tumor/tissue concentration ratios exceeded 10 for metabolizing organs, such as liver, and 100 for background tissues, such as blood and muscle. Absolute concentrations of CPZ in tumor exceeding 100 ..mu..g CPZ per g tumor were obtained with both single and multiple doses. This selective high concentration in tumor would make CPZ an ideal vehicle for the transport of boron to tumor for use in neutron capture therapy via the /sup 10/B(n,..cap alpha..)/sup 7/Li reaction.

  12. Distribution of copper-64 in control mice and in mice bearing ascitic Krebs tumor cells

    SciTech Connect

    Apelgot, S.; Coppey, J.; Grisvard, J.; Guille, E.; Sissoeeff, I.

    1981-04-01

    Three to 20 hr after an i.p. injection of /sup 64/Cu (half-life, 12.8 hr) into mice bearing Krebs ascites cells, a high amount of the radioisotope was recovered in the ascites cells themselves. In the control group, the radioisotope was mainly present in the liver. Similar amounts of /sup 64/Cu were recovered in regenerating as well as in normal liver, whereas in the liver of mice bearing ascites cells, this amount was lower by 40 to 50% regardless of the ascitic volume. Thus, the copper metabolism seems to be disturbed at the hepatic level in mice bearing ascites cells. The distribution of /sup 64/Cu was 'analyzed in DNA, RNA, and proteins from cellular lysates fractionated by CsCl gradient. There was a uniform pattern of distribution in the macromolecules from ascites cells, while /sup 64/Cu' was preferentially associated with the protein fraction from liver. Further experiments indicated that, in vivo, /sup 64/Cu was bound to the DNA of ascites cells.

  13. Extracellular polysaccharide production by a strain of Pleurotus djamor isolated in the south of Brazil and antitumor activity on Sarcoma 180.

    PubMed

    Borges, Gisele Martini; De Barba, Fabiana Figueredo Molin; Schiebelbein, Ana Paula; Pereira, Bruna Parmezzani; Chaves, Mariane Bonatti; Silveira, Marcia Luciane Lange; Pinho, Mauro Souza Leite; Furlan, Sandra Aparecida; Wisbeck, Elisabeth

    2013-12-01

    Polysaccharides with medicinal properties can be obtained from fruiting bodies, mycelium and culture broth of several fungus species. This work was carried out in batch culture using a stirred tank reactor with two different initial glucose concentrations (40-50 g/L) and pH values (3.0-4.0) to enhance extracellular polysaccharides production by Pleurotus djamor UNIVILLE 001 and evaluate antitumor effect of intraperitonial administration of Pleurotus djamor extract on sarcoma 180 animal model. According to factorial design, the low pH value (pH 3.0) led to a gain of 1.6 g/L on the extracellular polysaccharide concentration, while glucose concentration in the tested range had no significant effect on the concentration of polysaccharide. With 40 g/L initial glucose concentration and pH 3.0, it was observed that yield factor of extracellular polysaccharide on substrate (YP/S = 0.072) and maximum extracellular polysaccharide productivity (Q(Pmax) = 11.26 mg/L.h) were about 188% and 321% respectively higher than those obtained in the experiment performed at pH 4.0. Under these conditions, the highest values of the yield factor of biomass on substrate (YX/S = 0.24) and maximal biomass productivity (Q(Xmax) = 32.2 mg/L.h) were also reached. In tumor response study, mean tumor volume on the 21th day was 35.3 cm(3) in untreated group and 1.6 cm(3) in treated group (p = 0.05) with a tumor inhibition rate of 94%. These impressive results suggests an inhibitory effect of P.djamor extract on cancer cells.

  14. Extracellular polysaccharide production by a strain of Pleurotus djamor isolated in the south of Brazil and antitumor activity on Sarcoma 180

    PubMed Central

    Borges, Gisele Martini; De Barba, Fabiana Figueredo Molin; Schiebelbein, Ana Paula; Pereira, Bruna Parmezzani; Chaves, Mariane Bonatti; Silveira, Marcia Luciane Lange; Pinho, Mauro Souza Leite; Furlan, Sandra Aparecida; Wisbeck, Elisabeth

    2013-01-01

    Polysaccharides with medicinal properties can be obtained from fruiting bodies, mycelium and culture broth of several fungus species. This work was carried out in batch culture using a stirred tank reactor with two different initial glucose concentrations (40–50 g/L) and pH values (3.0–4.0) to enhance extracellular polysaccharides production by Pleurotus djamor UNIVILLE 001 and evaluate antitumor effect of intraperitonial administration of Pleurotus djamor extract on sarcoma 180 animal model. According to factorial design, the low pH value (pH 3.0) led to a gain of 1.6 g/L on the extracellular polysaccharide concentration, while glucose concentration in the tested range had no significant effect on the concentration of polysaccharide. With 40 g/L initial glucose concentration and pH 3.0, it was observed that yield factor of extracellular polysaccharide on substrate (YP/S = 0.072) and maximum extracellular polysaccharide productivity (QPmax = 11.26 mg/L.h) were about 188% and 321% respectively higher than those obtained in the experiment performed at pH 4.0. Under these conditions, the highest values of the yield factor of biomass on substrate (YX/S = 0.24) and maximal biomass productivity (QXmax = 32.2 mg/L.h) were also reached. In tumor response study, mean tumor volume on the 21th day was 35.3 cm3 in untreated group and 1.6 cm3 in treated group (p = 0.05) with a tumor inhibition rate of 94%. These impressive results suggests an inhibitory effect of P.djamor extract on cancer cells. PMID:24688493

  15. Pharmaceutical production of anti-tumor and immune-potentiating Enterococcus faecalis-2001 β-glucans: enhanced activity of macrophage and lymphocytes in tumor-implanted mice.

    PubMed

    Gu, Yeun-Hwa; Choi, Hyunju; Yamashita, Takenori; Kang, Ki-Mun; Iwasa, Masahiro; Lee, Moon-Jo; Lee, Kyoung Hae; Kim, Cheorl-Ho

    2017-10-02

    Enterococcus faecalis 2001 is a probiotic lactic acid bacterium and has been used as a biological response modifier (BRM). From physiological limitation of bacterial preservation in storage and safety, the live E. faecalis 2001 has been heat-treated and the BRM components containing high level of β-glucan, named EF-2001, has been prepared. The heat-treated EF-2001 has been examined for the antioxidative potential for radical scavenging and anti-tumor activities as well as immune-enhancing response in mice. The lymphocyte versus polymorphonuclear leukocyte ratios was increased in mice upon treatment with EF-2001. The number of lymphocytes was increased in the EF-2001-treated group. In the mice bearing two different Ehrlich solid and Sarcoma-180 carcinomas, the treatment with EF-2001 resulted in anti-tumor action. Tumor-suppressive capacity upon treatment with EF-2001 was significantly increased compared to normal controls. During the time interval administration of 5 weeks between priming and secondary administration of EF-2001, the expression and production levels of TNF- were also observed in the EF-2001-administered mice. Additionally, anti-tumor activity examined with the intravenous administration of EF 2001 with a 34 time intervals was also observed, as the growth of Sarcoma180 cells was clearly inhibited by the EF-2001. From the results, it was suggested that the immune response is enhanced from the anti-oxidative provoked by the EF-2001 and anti-tumor activity is provoked through NK cells and TNF -. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Curcumin reduces trabecular and cortical bone in naive and Lewis lung carcinoma-bearing mice

    USDA-ARS?s Scientific Manuscript database

    The present study investigated the effects of dietary supplementation with curcumin on bone microstructural changes in female C57BL/6 mice in the presence or absence of Lewis lung carcinoma. Morphometric analysis showed that in tumor-bearing mice curcumin at 2% and 4% dietary levels (w/w) significa...

  17. Ibuprofen Ameliorates Fatigue- and Depressive-like Behavior in Tumor-bearing Mice

    PubMed Central

    Norden, Diana M.; McCarthy, Donna O.; Bicer, Sabahattin; Devine, Raymond; Reiser, Peter J.; Godbout, Jonathan P.; Wold, Loren E.

    2015-01-01

    Aims Cancer-related fatigue (CRF) is often accompanied by depressed mood, both of which reduce functional status and quality of life. Research suggests that increased expression of pro-inflammatory cytokines are associated with skeletal muscle wasting and depressive- and fatigue- like behaviors in rodents and cancer patients. We have previously shown that treatment with ibuprofen, a nonsteroidal anti-inflammatory drug, preserved muscle mass in tumor-bearing mice. Therefore, the purpose of the present study was to determine the behavioral effects of ibuprofen in a mouse model of CRF. Main Methods Mice were injected with colon-26 adenocarcinoma cells and treated with ibuprofen (10mg/kg) in the drinking water. Depressive-like behavior was determined using the forced swim test (FST). Fatigue-like behaviors were determined using voluntary wheel running activity (VWRA) and grip strength. The hippocampus, gastrocnemius muscle, and serum were collected for cytokine analysis. Key Findings Tumor-bearing mice showed depressive-like behavior in the FST, which was not observed in mice treated with ibuprofen. VWRA and grip strength declined in tumor-bearing mice, and ibuprofen attenuated this decline. Tumor-bearing mice had decreased gastrocnemius muscle mass and increased expression of IL-6, MAFBx and MuRF mRNA, biomarkers of protein degradation, in the muscle. Expression of IL-1β and IL-6 was also increased in the hippocampus. Treatment with ibuprofen improved muscle mass and reduced cytokine expression in both the muscle and hippocampus of tumor-bearing mice. Significance Ibuprofen treatment reduced skeletal muscle wasting, inflammation in the brain, and fatigue- and depressive-like behavior in tumor-bearing mice. Therefore, ibuprofen warrants evaluation as an adjuvant treatment for CRF. PMID:26498217

  18. Ibuprofen ameliorates fatigue- and depressive-like behavior in tumor-bearing mice.

    PubMed

    Norden, Diana M; McCarthy, Donna O; Bicer, Sabahattin; Devine, Raymond D; Reiser, Peter J; Godbout, Jonathan P; Wold, Loren E

    2015-12-15

    Cancer-related fatigue (CRF) is often accompanied by depressed mood, both of which reduce functional status and quality of life. Research suggests that increased expression of pro-inflammatory cytokines is associated with skeletal muscle wasting and depressive- and fatigue-like behaviors in rodents and cancer patients. We have previously shown that treatment with ibuprofen, a nonsteroidal anti-inflammatory drug, preserved muscle mass in tumor-bearing mice. Therefore, the purpose of the present study was to determine the behavioral effects of ibuprofen in a mouse model of CRF. Mice were injected with colon-26 adenocarcinoma cells and treated with ibuprofen (10mg/kg) in the drinking water. Depressive-like behavior was determined using the forced swim test (FST). Fatigue-like behaviors were determined using voluntary wheel running activity (VWRA) and grip strength. The hippocampus, gastrocnemius muscle, and serum were collected for cytokine analysis. Tumor-bearing mice showed depressive-like behavior in the FST, which was not observed in mice treated with ibuprofen. VWRA and grip strength declined in tumor-bearing mice, and ibuprofen attenuated this decline. Tumor-bearing mice had decreased gastrocnemius muscle mass and increased expression of IL-6, MAFBx and MuRF mRNA, biomarkers of protein degradation, in the muscle. Expression of IL-1β and IL-6 was also increased in the hippocampus. Treatment with ibuprofen improved muscle mass and reduced cytokine expression in both the muscle and hippocampus of tumor-bearing mice. Ibuprofen treatment reduced skeletal muscle wasting, inflammation in the brain, and fatigue- and depressive-like behavior in tumor-bearing mice. Therefore, ibuprofen warrants evaluation as an adjuvant treatment for CRF. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Synthesis and antitumor activity of duocarmycin derivatives: modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups.

    PubMed

    Amishiro, N; Nagamura, S; Murakata, C; Okamoto, A; Kobayashi, E; Asada, M; Gomi, K; Tamaoki, T; Okabe, M; Yamaguchi, N; Yamaguchi, K; Saito, H

    2000-02-01

    A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin bearing the simplified DNA-binding moieties such as cinnamoyl or heteroarylacryloyl groups were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted analogues in aqueous solution and the conversion to their active form (cyclopropane compound) from the 8-O-substituted analogues in mice or human serum were examined. The 8-O-substituted A-ring pyrrole derivatives bearing the simplified DNA-binding moieties showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment-B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreover, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result indicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW-2189.

  20. Effects of ghrelin on anorexia in tumor-bearing mice with eicosanoid-related cachexia.

    PubMed

    Wang, Wenhua; Andersson, Marianne; Iresjö, Britt-Marie; Lönnroth, Christina; Lundholm, Kent

    2006-06-01

    Ghrelin is a novel brain-gut peptide that stimulates food intake and may secondarily increase body weight via a growth hormone secretagogue receptor (GHS-R). Tumor-bearing mice (MCG101), characterized by anorexia, fat loss and muscle wasting due to increased concentration of PGE2 and proinflammatory cytokines (IL-1beta, IL-6, TNF-alpha), were provided ghrelin i.p. at a low (20 microg/day) and high dose (40 microg/day) to examine the ability of ghrelin to counteract tumor-induced anorexia. Immunohistochemical staining and Western blot analyses were used to identify GHS-R expression in the brain as well as its relationship to NPY expression in hypothalamic neurons. GHS-R mRNA in hypothalamus and ghrelin mRNA in gastric fundus were quantified by RT-PCR. Body composition was determined by carcass extractions. GHS-R expression in hypothalamus and plasma ghrelin levels were significantly increased in freely-fed tumor-bearing mice, while gastric fundus expression of ghrelin was unaltered compared to non-tumor-bearing mice (controls). Ghrelin treatment increased food intake, body weight and whole body fat at both low and high doses of ghrelin in normal controls, while tumor-bearing mice showed improved intake and body composition at the high dose of ghrelin only. Exogenous ghrelin normalized the GHS-R expression in hypothalamus from tumor-bearing mice without alterations in the gastric fundus expression of ghrelin. Tumor growth was not altered by exogenous ghrelin. Our results indicate that MCG 101-bearing mice became ghrelin resistant despite upregulation of hypothalamic GHS-R expression, which confirms similar indirect observations in cancer patients. Thus, other factors downstream of the ghrelin-GHS-R system appear to be more important than ghrelin to explain cancer-induced anorexia.

  1. Effect of hyperthemia induced by Nd:YAG laser and photodynamic therapy by Ar+ laser radiation in combination on the transplanted tumor in CM mice

    NASA Astrophysics Data System (ADS)

    Li, Xiaoyuan; Tan, Runchu; Li, Jishi; Shi, Hongmin

    1996-09-01

    The present paper reports the effect of hyperthermia (HT) induced by Nd:YAG laser and photodynamic therapy (PDT) by AR+ laser radiation in combination on the transplanted sarcoma 180 in CM mice. Tumor-bearing mice were divided into four groups: A) control group, B) HT group, C) PDT group and D) PDT followed by HT group. HT was induced by Nd:YAG laser radiation and the temperature at tumor edge was control at 43 degrees C for 30 minutes. Tumor-bearing mice of group C and D were given an i.p. injection of HpD 24 hours prior to AR+ laser radiation. The experiments show significant increases in inhibition rates against the S-180 in CM mice by the HT and PDT combination, compared to those by either HT or PDT alone. With that of Group D being the lowest, the DNA contents of tumor cells in the four groups are of statistical significance too. These results suggest the combination of HT induced by Nd:YAG and PDT by Ar+ laser radiation may become a new method of tumor treatment.

  2. Tannic acid raises survival rate of mice bearing syngeneic tumors.

    PubMed

    Koide, T; Kamei, H; Hashimoto, Y; Kojima, T; Hasegawa, M

    1999-06-01

    Tannic acid which was found earlier to have growth suppressive activity against cultured tumor cells, was given to Balb/c mice p.o. The mice had been inoculated with syngeneic tumor cells (Meth/A) i.p. When tannic acid was suspended in drinking water and given daily at doses of approximately 875 mg/kg/day and 1750 mg/kg/day, the respective survival rates were 59% and 48%, with that of the control mice being 29%. To study the cytotoxicity of tannic acid, we administered the tannic acid to mice at 875 and 1750 mg/kg/day for 35 days. The weight gain for each dose was lower than that of the control, although the difference was not significant. When tannic acid was given at 8750 mg/kg/day, the weight gain was significantly lower than the control. A histologic study did not show any pathological findings in the kidney, liver, or lungs in the mice given tannic acid at the above doses.

  3. Oyster (Crassostrea gigas) hydrolysates produced on a plant scale have antitumor activity and immunostimulating effects in BALB/c mice.

    PubMed

    Wang, Yu-Kai; He, Hai-Lun; Wang, Guo-Fan; Wu, Hao; Zhou, Bai-Cheng; Chen, Xiu-Lan; Zhang, Yu-Zhong

    2010-02-02

    Oyster extracts have been reported to have many bioactive peptides. But the function of oyster peptides produced by proteolysis is still unknown. In this study, the oligopeptide-enriched hydrolysates from oyster (Crassostrea gigas) were produced using the protease from Bacillus sp. SM98011 at laboratory level, and scaled up to pilot (100 L) and plant (1,000 L) levels with the same conditions. And the antitumor activity and immunostimulating effects of the oyster hydrolysates in BALB/c mice were investigated. The growth of transplantable sarcoma-S180 was obviously inhibited in a dose-dependent manner in BALB/c mice given the oyster hydrolysates. Mice receiving 0.25, 0.5 and 1 mg/g of body weight by oral gavage had 6.8%, 30.6% and 48% less tumor growth, respectively. Concurrently, the weight coefficients of the thymus and the spleen, the activity of natural killer (NK) cells, the spleen proliferation of lymphocytes and the phagocytic rate of macrophages in S180-bearing mice significantly increased after administration of the oyster hydrolysates. These results demonstrated that oyster hydrolysates produced strong immunostimulating effects in mice, which might result in its antitumor activity. The antitumor and immunostimulating effects of oyster hydrolysates prepared in this study reveal its potential for tumor therapy and as a dietary supplement with immunostimulatory activity.

  4. Antitumor Effect of Zhihuang Fuzheng Soft Capsules on Tumor-Bearing Mice.

    PubMed

    Bao, Yanyan; Pan, Xin; Jin, Yahong; Gao, Yingjie; Cui, Xiaolan

    2016-01-01

    Chinese medicines (CMs) have been shown to have some advantages in preventing and controlling tumors. In this study, we investigated the antitumor effect of ZFSC by establishing a mouse model of HT-1080, A-549, and HCT-8 tumors. The result showed that tumor volumes of HT-1080 tumor-bearing nude mice in ZFSC low, medium, and high dose groups were lower significantly compared to the model group, and the high dose ZFSC showed the best antitumor effect. Tumor volumes of A-549 tumor-bearing nude mice in ZFSC low, medium, and high dose groups were lower significantly compared to the model group and showed a good dose-response relationship. There was no significant effect on human colon cancer, although inhibition trends disappeared in the bar chart. In order to verify the immunomodulatory effect of ZFSC, ELISA was used to analyze serums IL-2, TNF-α, and IFN in spleens. The results showed that ZFSC could enhance the immune function of tumor-bearing mice. ZFSC reduced IFN-γ and TNF-α content in the serum of HT-1080 tumor-bearing mice and inhibit PD1 and PDL1 and suggested that the antitumor mechanism of ZFSC on human fibrosarcoma could be attributed to inhibition of the PDL1/PD1 pathway.

  5. Anergy-like immunosuppression in mice bearing pulmonary foreign-body granulomatous inflammation.

    PubMed Central

    Allred, D. C.; Kobayashi, K.; Yoshida, T.

    1985-01-01

    Pulmonary granulomas were induced in BALB/c mice by the intratracheal injection of insoluble polymerized dextran and latex microparticles. Very large granulomas developed around dextran beads, which reached peak intensity within 2-3 days and rapidly declined in size thereafter. Latex beads generated small stable lesions. The involvement of cell-mediated immunity could not be demonstrated in the inflammatory responses induced by either type of bead. Antigen-induced delayed type hypersensitivity (DTH) and mitogen-induced DTH-like footpad reactions were markedly suppressed in immunized mice bearing early dextran granulomas. Mitogen-induced DTH-like footpad reactions were suppressed in unimmunized animals bearing early dextran foreign-body granulomas. Antigen- and mitogen-induced footpad swelling recovered to normal levels as dextran granulomas diminished in size. No suppression of these footpad reactions was observed in mice bearing small latex foreign-body granulomas. The intraperitoneal injection of aqueous extracts prepared from the lungs of unimmunized donor animals bearing early dextran foreign-body granulomas could partially transfer suppression of mitogen DTH-like footpad responses to normal mice. These results suggest that cells within large, nonimmunologic lung granulomas produce a soluble factor which participates in the expression of anergy-like immunosuppression. Images Figure 2 PMID:3907366

  6. HemoHIM enhances the therapeutic efficacy of ionizing radiation treatment in tumor-bearing mice.

    PubMed

    Park, Hae-Ran; Ju, Eun-Jin; Jo, Sung-Kee; Jung, Uhee; Kim, Sung-Ho

    2010-02-01

    Although radiotherapy is commonly used for a variety of cancers, radiotherapy alone does not achieve a satisfactory therapeutic outcome. In this study, we examined the possibility that HemoHIM can enhance the anticancer effects of ionizing radiation (IR) in melanoma-bearing mice. The HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of three edible herbs-Angelica Radix, Cnidium Rhizoma, and Paeonia Radix. Anticancer effects of HemoHIM were evaluated in melanoma-bearing mice exposed to IR. IR treatment (5 Gy at 7 days after melanoma cell injection) reduced the weight of the solid tumors, and HemoHIM supplementation with IR enhanced the decreases in tumor weight (P < .03). In the melanoma-bearing mice treated with IR, HemoHIM administration also increased the activity of natural killer cells and cytotoxic T cells, although the proportions of these cells in spleen were not different. In addition, HemoHIM administration increased the interleukin-2 and tumor necrosis factor-alpha secretion from lymphocytes stimulated with concanavalin A, which seemed to contribute to the enhanced efficacy of HemoHIM in tumor-bearing mice treated with IR. In conclusion, HemoHIM may be a beneficial supplement during radiotherapy for enhancing the antitumor efficacy.

  7. The selective effect of cystathionine on doxorubicin hepatotoxicity in tumor-bearing mice.

    PubMed

    Kwiecień, Inga; Michalska, Magdalena; Włodek, Lidia

    2006-11-21

    The aim of the present study was to examine the protective effect of cystathionine as a cysteine precursor on doxorubicin toxicity in the liver of Ehrlich ascites tumor (EAT)-bearing mice and in the EAT cells. Both compounds were injected intraperitoneally alone or in combination at the following doses: cystathionine at 10 mg and doxorubicin at 5 mg per kg of body weight. In the liver of EAT-bearing mice, glutathione (GSH), cysteine and sulfane sulfur levels as well as the activities of: glutathione S-transferase, gamma-glutamyl transpeptidase, rhodanese and gamma-cystathionase significantly dropped in comparison with healthy animals. Administration of cystathionine elevated GSH and cysteine levels in the livers of EAT-bearing mice and reduced lipid peroxidation. Furthermore, cystathionine increased gamma-glutamyl transpeptidase activity, thereby activating gamma-glutamyl cycle, responsible for proper glutathione metabolism in the cells. Cystationine did not influence sulfane sulfur level and rhodanese and gamma-cystathionase activity in the livers of EAT-bearing mice. It was next shown that cystathionine administered in combination with doxorubicin protected against the drug toxicity since it elevated thiol level, lowering reactive oxygen species content and suppressing lipid peroxidation. This means that, cystathionine in the liver of EAT-bearing mice can both correct harmful effects of carcinogenesis, and protect the liver from doxorubicin cytotoxicity. In contrast, in EAT cells, cystathionine lowered GSH and cysteine levels and did not alter reactive oxygen species level, lipid peroxidation, and gamma-glutamyl transpeptidase activity. All these data indicate that cystathionine action is selectively beneficial for normal cells because it corrects harmful effects induced by EAT development and protects the organism against doxorubicin cytotoxicity without impairing cytotoxicity of this drug to tumor cells.

  8. Anticancer and immunoregulatory activity of Gynostemma pentaphyllum polysaccharides in H22 tumor-bearing mice.

    PubMed

    Liu, Jun; Zhang, Lihua; Ren, Yingang; Gao, Yanli; Kang, Li; Qiao, Qing

    2014-08-01

    A neutral polysaccharide fraction (CGPP) was extracted from Gynostemma pentaphyllum by water extraction and ethanol precipitation. Gas chromatography (GC) analysis showed that the CGPP was mainly composed of mannose, glucose, arabinose, rhamnose, galactose and glucuronic acid in molar ratios of 2.0:2.2:1.3:2.2:1.2:2.5. The present study aimed at evaluating the antitumor potentials of CGPP on the growth of H22 tumor transplanted in mice and the underlying mechanism. The results showed that CGPP (50 and 200mg/kg) could effectively inhibit the solid tumor growth of H22 hepatocarcinoma transplanted in ICR mice. Besides, the body weight, spleen/thymus indexes and splenocytes proliferation of H22 tumor bearing mice were also improved in CGPP-treated groups. Furthermore, the level of the cytokines, such as IL-2, TNF-α and IFN-γ, as well as the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) in tumor-bearing mice were markedly promoted by CGPP oral administration. In addition, CGPP treatment greatly prolonged the survival period in H22 ascites tumor-bearing mice. Taken together, these findings indicate that CGPP has antitumor activity in vivo at least partly via improving immune responses of host organism, and seems to be a safe and effective supplementary agent for the treatment of hepatocellular carcinoma (HCC).

  9. Enhanced photodynamic efficacy of PLGA-encapsulated 5-ALA nanoparticles in mice bearing Ehrlich ascites carcinoma

    NASA Astrophysics Data System (ADS)

    Shaker, Maryam N.; Ramadan, Heba S.; Mohamed, Moustafa M.; El khatib, Ahmed M.; Roston, Gamal D.

    2014-10-01

    Nanoparticles (NPs) fabricated from the biodegradable copolymer poly(lactic- co-glycolic acid) (PLGA) were investigated as a drug delivery system to enhance the photodynamic efficacy of 5-aminolevulinic acid (5-ALA) in mice bearing Ehrlich ascites carcinoma. The PLGA-encapsulated 5-ALA NPs were prepared using binary organic solvent diffusion method and characterized in terms of shape and particle size. The in vivo photodynamic efficiency in Ehrlich ascites-bearing mice was studied. The obtained particles were uniform in size with spherical shape of mean size of 249.5 nm as obtained by particle size analyzer and the in vitro release studies demonstrated a controlled release profile of 5-ALA. Tumor-bearing mice injected with PLGA-encapsulated 5-ALA NPs exhibited significantly smaller mean tumor volume, increased tumor growth delay compared with the control group and the group injected with free 5-ALA during the time course of the experiment. Histopathological examination of tumor from mice treated with PLGA-encapsulated 5-ALA NPs showed regression of tumor cells, in contrast to those obtained from mice treated with free 5-ALA. The results indicate that PLGA-encapsulated 5-ALA NPs are a successful delivery system for improving photodynamic activity in the target tissue.

  10. Effective adoptive transfer of haploidentical tumor-specific T cells in B16-melanoma bearing mice.

    PubMed

    Cui, Nai-peng; Xie, Shao-jian; Han, Jin-sheng; Ma, Zhen-feng; Chen, Bao-ping; Cai, Jian-hui

    2012-03-01

    Adoptive transfer of allogeneic tumor-specific T cells often results in severe graft-versus-host disease (GVHD). Here, we sought to maximize graft-versus-tumor and minimize GVHD by using haploidentical T cells in pre-irradiated B16-melanoma bearing mice. C57BL/6 mice bearing B16-melanoma tumors were irradiated with 0, 5, or 7 Gy total body irradiation (TBI), or 7 Gy TBI plus bone marrow transplantation. Tumor areas were measured every 3 days to assess the influence of irradiation treatment on tumor regression. B16-melanoma bearing mice were irradiated with 7 Gy TBI; sera and spleens were harvested at days 1, 3, 5, 7, 9, 11, and 13 after irradiation. White blood cell levels were measured and transforming growth factor β1 (TGF-b1) and interleukin 10 (IL-10) levels in serum were detected using enzyme-linked immunosorbent assay (ELISA) kits. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry were performed to test TGF-b1, IL-10 and Foxp3 mRNA levels and the proportion of CD4+CD25+Foxp3+ T-regulatory cells (Tregs) in spleens. B16-melanoma bearing C57BL/6 mice were irradiated with 7 Gy TBI followed by syngeneic (Syn1/Syn2) or haploidentical (Hap1/Hap2), dendritic cell-induced cytotoxic T lymphocytes (DC-CTLs) treatment, tumor areas and system GVHD were observed every 3 days. Mice were killed 21 days after the DC-CTLs adoptive transfer; histologic analyses of eyes, skin, liver, lungs, and intestine were then performed. Irradiation with 7 Gy TBI on the B16-melanoma-bearing mice did not influence tumor regression compared to the control group; however, it down-regulated the proportion of Tregs in spleens and the TGF-b1 and IL-10 levels in sera and spleens, suggesting inhibition of autoimmunity and intervention of tumor microenvironment. Adoptive transfer of haploidentical DC-CTLs significantly inhibited B16-melanoma growth. GVHD assessment and histology analysis showed no significant difference among the groups. Adoptive transfer of

  11. Enhanced antitumor efficacy of cisplatin in combination with HemoHIM in tumor-bearing mice

    PubMed Central

    2009-01-01

    Background Although cisplatin is one of the most effective chemotherapeutic agents, cisplatin alone does not achieve a satisfactory therapeutic outcome. Also cisplatin accumulation shows toxicity to normal tissues. In this study, we examined the possibility of HemoHIM both to enhance anticancer effect with cisplatin and to reduce the side effects of cisplatin in melanoma-bearing mice. Methods HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of 3 edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Anticancer effects of HemoHIM with cisplatin were evaluated in melanoma-bearing mice. We used a Cr51-release assay to measure the activity of NK/Tc cell and ELISA to evaluate the production of cytokines. Results In melanoma-bearing mice, cisplatin (4 mg/kg B.W.) reduced the size and weight of the solid tumors, and HemoHIM supplementation with cisplatin enhanced the decrease of both the tumor size (p < 0.1) and weight (p < 0.1). HemoHIM itself did not inhibit melanoma cell growth in vitro, and did not disturb the effects of cisplatin in vitro. However HemoHIM administration enhanced both NK cell and Tc cell activity in mice. Interestingly, HemoHIM increased the proportion of NK cells in the spleen. In melanoma-bearing mice treated with cisplatin, HemoHIM administration also increased the activity of NK cells and Tc cells and the IL-2 and IFN-γ secretion from splenocytes, which seemed to contribute to the enhanced efficacy of cisplatin by HemoHIM. Also, HemoHIM reduced nephrotoxicity as seen by tubular cell of kidney destruction. Conclusion HemoHIM may be a beneficial supplement during cisplatin chemotherapy for enhancing the anti-tumor efficacy and reducing the toxicity of cisplatin. PMID:19292900

  12. Enhanced antitumor efficacy of cisplatin in combination with HemoHIM in tumor-bearing mice.

    PubMed

    Park, Hae-Ran; Ju, Eun-Jin; Jo, Sung-Kee; Jung, Uhee; Kim, Sung-Ho; Yee, Sung-Tae

    2009-03-17

    Although cisplatin is one of the most effective chemotherapeutic agents, cisplatin alone does not achieve a satisfactory therapeutic outcome. Also cisplatin accumulation shows toxicity to normal tissues. In this study, we examined the possibility of HemoHIM both to enhance anticancer effect with cisplatin and to reduce the side effects of cisplatin in melanoma-bearing mice. HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of 3 edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Anticancer effects of HemoHIM with cisplatin were evaluated in melanoma-bearing mice. We used a Cr51-release assay to measure the activity of NK/Tc cell and ELISA to evaluate the production of cytokines. In melanoma-bearing mice, cisplatin (4 mg/kg B.W.) reduced the size and weight of the solid tumors, and HemoHIM supplementation with cisplatin enhanced the decrease of both the tumor size (p < 0.1) and weight (p < 0.1). HemoHIM itself did not inhibit melanoma cell growth in vitro, and did not disturb the effects of cisplatin in vitro. However HemoHIM administration enhanced both NK cell and Tc cell activity in mice. Interestingly, HemoHIM increased the proportion of NK cells in the spleen. In melanoma-bearing mice treated with cisplatin, HemoHIM administration also increased the activity of NK cells and Tc cells and the IL-2 and IFN-gamma secretion from splenocytes, which seemed to contribute to the enhanced efficacy of cisplatin by HemoHIM. Also, HemoHIM reduced nephrotoxicity as seen by tubular cell of kidney destruction. HemoHIM may be a beneficial supplement during cisplatin chemotherapy for enhancing the anti-tumor efficacy and reducing the toxicity of cisplatin.

  13. Pharmacokinetics of Polymersomes Composed of Poly(Butadiene-Ethylene Oxide); Healthy versus Tumor-Bearing Mice.

    PubMed

    Wang, G; de Kruijff, R M; Abou, D; Ramos, N; Mendes, E; Franken, L E; Wolterbeek, H T; Denkova, A G

    2016-02-01

    Vesicles composed of block copolymers (i.e., polymersomes) are one of the most versatile nano-carriers for medical purposes due to their tuneable physicochemical properties and the possibility to encapsulate simultaneously hydrophobic and hydrophilic substances, allowing, for instance, the combination of therapy and imaging. In cancer treatment, these vesicles need to remain long enough in the blood stream to be sufficiently taken up by tumors. Here, we have investigated the biodistribution and the pharmacokinetics of polymersomes, composed of poly(butadiene-b-ethylene oxide) having dimensions around 80 nm. The polymersomes have been radiolabeled with ¹¹¹In via the so-called active loading method achieving a loading efficiency of 92.9 ± 0.9% with radionuclide retention in mouse serum of more than 95% at 24 h. The optimized ¹¹¹In containing polymersomes have been intravenously administered in healthy and tumor bearing mice for pharmacokinetic determination using microSPECT (Single Photon Emission Computed Tomography). In healthy mice these polymersomes have been found to exhibit relatively long blood circulation (> 6 h), low liver uptake (6 ± 1.5%ID/g, 48 h p.i.) and elevated spleen uptake (188 ± 30%ID/g). The blood circulation in tumor bearing mice is dramatically reduced (< 1.5 h) most likely due to elevated splenic filtration, clearly indicating the importance of in vivo studies in diseased mice. Finally, the polymersomes have been injected subcutaneously in tumor bearing mice revealing retention of 77% in the mice, primarily accumulated at the site of injection, up to 48 hours after administration.

  14. Odor cues released by Ehrlich tumor-bearing mice are aversive and induce psychological stress.

    PubMed

    Alves, Glaucie Jussilane; Palermo-Neto, João

    2015-01-01

    This study aimed to verify if odor cues released by Ehrlich tumor-bearing mice are aversive and stressful. Female mice were divided into a control group and an experimental group. One animal of each experimental pair of mice was inoculated with 5 × 10(6) Ehrlich tumor cells intraperitoneally; the other animal was kept undisturbed and was referred to as a CSP (companion of sick partner). One mouse of each control pair was treated intraperitoneally with 0.9% NaCl (1 mg/kg); the other animal (CHP, companion of healthy partner) was kept undisturbed. It was shown that, in relation to CHP, CSP mice (1) spent less time within the companion zone in a T-maze place preference test, (2) had increased levels of social interaction, (3) had increased levels of plasmatic adrenaline and noradrenaline and (4) displayed no changes in serum corticosterone levels before and after an immobilization stress challenge. It was also shown that (5) cohabitation with 2 tumor-bearing mice was more effective in decreasing neutrophil oxidative burst than cohabitation with 1 sick partner and (6) the presence of a healthy conspecific within the cage of the tumor-injected/CSP pair abrogated the effects of cohabitation on neutrophil activity. These results show that odor cues released by Ehrlich tumor-injected mice are aversive and induce psychological stress. We postulate that the aversive response induced by the chemosignals released by Ehrlich tumor-injected animals activates the sympathetic nervous system and causes the neuroimmunal changes that occur in the mice cohabiting with the sick mice. © 2014 S. Karger AG, Basel.

  15. Inhibitory efficacy of the quantified prunellae spica extract on H22 tumor bearing mice

    NASA Astrophysics Data System (ADS)

    Wang, Zhi-ping; Chen, Tong-sheng

    2013-02-01

    Hepatocarcinoma, a malignant cancer, threaten human life badly. It is a current issue to seek the effective natural remedy from plant to treat cancer due to the resistence of the advanced hepatocarcinoma to chemotherapy. In this report, we assessed the antitumor activity of a prunellae spica aqueous extract (PSE) in vitro and in vivo. PSE was quantified by HPLC and UV. MTT assay showed that PSE did not effectively inhibit the growth of H22 cells. The in vivo anti-tumor activity was assessed by using the mice bearing H22 tumor. In vivo studies showed the higher antitumor efficacy of PSE without significant side effect assessed by the reduced tumor weight, and the extended survival time of the mice bearing H22 solid and ascites tumor. Collectively, PSE is a promising Chinese medicinal herb for treating hepatocarcinoma.

  16. Pharmacokinetics of Ro 03-8799 in mice bearing melanosarcoma: comparison with tumors without melanin

    SciTech Connect

    Laurent, F.; Canal, P.; Soula, G.

    1989-04-01

    The pharmacokinetics of Ro 03-8799 has been studied in melanic and non-melanic tumor bearing mice after iv administration of 150 mg/kg. The peak concentration in B16 melanosarcoma tumor reached 152 micrograms/g, that is 7.6-fold higher than the plasma concentration at the same time. This concentration is 3-times greater than that obtained in the tumor of mice bearing non-melanic sarcoma (DB16) or Lewis lung carcinoma (3LL). The exposure of B16 tumor (AUC) is respectively 15-times and 11-times higher than the 3LL and the DB16 ones. These experimental data confirm that this 2-nitro-imidazol compound has an important affinity for melanin and suggest that it might be used as a radiosensitizer for the treatment of malignant melanoma.

  17. Neutron capture autoradiographic study of the biodistribution of 10B in tumor-bearing mice.

    PubMed

    Ogura, K; Yanagie, H; Eriguchi, M; Lehmann, E H; Kühne, G; Bayon, G; Kobayashi, H

    2004-10-01

    For the study on boron neutron capture therapy, the whole-body sections of tumor-bearing mice infused with 10B attached to CR-39 plastic track detectors were exposed to thermal and cold neutron beams. Neutron capture autoradiographic images obtained by the cold neutron irradiation were extremely superior in quality to those of the thermal neutron beams. From the autoradiographic images, the 10B reaction dose of the neutron-induced particles was estimated using the differential LET distribution.

  18. Cytokine and cyclooxygenase-2 protein in brain areas of tumor-bearing mice with prostanoid-related anorexia.

    PubMed

    Wang, W; Lönnroth, C; Svanberg, E; Lundholm, K

    2001-06-15

    Evidence suggests that cytokines in the central nervous system are mediators behind anorexia in tumor-bearing hosts. We have therefore evaluated, by immunohistochemical image analyses, time course changes of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF) alpha, IL-6 receptor (gp130), IL-1 receptor I, and cyclooxygenase (Cox)-2 protein in brain cortex, hippocampus and the ventromedial hypothalamic nucleus (VMH) in tumor-bearing mice with prostanoid-related anorexia. Pair-fed non-tumor-bearing mice were used as controls. Prostaglandin E(2) was provided systemically to freely fed, non-tumor-bearing mice to confirm a role for prostanoids in modulation of brain cytokines and food intake. Time course changes of IL-1beta were significantly different between tumor-bearing mice and pair-fed controls in the hippocampus but not in the VMH. TNF-alpha in the hippocampus and VMH did not show any significant difference between tumor-bearing mice and pair-fed controls, whereas TNF-alpha showed a small increase over time in brain VMH. IL-6 content did not show any significant alterations among tumor-bearing and pair-fed mice but increased significantly over time in both the study and control group. Cox-2 in brain hippocampus and VMH showed a statistically significant rise in both tumor-bearing and pair-fed controls, with no difference between animal groups. Systemic provision of exogenous PGE(2) to non-tumor-bearing mice altered brain cytokines significantly in the hippocampus and VMH with associated changes in food intake. Our results demonstrate that some differences (IL-1beta) occurred in brain cytokines comparing tumor-bearing and pair-fed, non-tumor-bearing mice but within unexpected decreased levels in brain tissue from tumor-bearing mice. Surprisingly, many time course changes in brain cytokines were similarly altered in tumor-bearing and pair-fed mice. Our observations do not support that up-regulation of brain cytokines explains or promotes anorexia in cancer

  19. Sclerostin antibody inhibits skeletal deterioration in mice exposed to partial weight-bearing.

    PubMed

    Spatz, J M; Ellman, R; Cloutier, A M; Louis, L; van Vliet, M; Dwyer, D; Stolina, M; Ke, H Z; Bouxsein, M L

    2017-02-01

    Whereas much is known regarding the musculoskeletal responses to full unloading, little is known about the physiological effects and response to pharmacological agents in partial unloading (e.g. Moon and Mars) environments. To address this, we used a previously developed ground-based model of partial weight-bearing (PWB) that allows chronic exposure to reduced weight-bearing in mice to determine the effects of murine sclerostin antibody (SclAbII) on bone microstructure and strength across different levels of mechanical unloading. We hypothesize that treatment with SclAbII would improve bone mass, microarchitecture and strength in all loading conditions, but that there would be a greater skeletal response in the normally loaded mice than in partially unloaded mice suggesting the importance of combined countermeasures for exploration-class long duration spaceflight missions. Eleven-week-old female mice were assigned to one of four loading groups: normal weight-bearing controls (CON) or weight-bearing at 20% (PWB20), 40% (PWB40) or 70% (PWB70) of normal. Mice in each group received either SclAbII (25mg/kg) or vehicle (VEH) via twice weekly subcutaneous injection for 3 weeks. In partially-unloaded VEH-treated groups, leg BMD decreased -5 to -10% in a load-dependent manner. SclAbII treatment completely inhibited bone deterioration due to PWB, with bone properties in SclAbII-treated groups being equal to or greater than those of CON, VEH-treated mice. SclAbII treatment increased leg BMD from +14 to +18% in the PWB groups and 30 ± 3% in CON (p< 0.0001 for all). Trabecular bone volume, assessed by μCT at the distal femur, was lower in all partially unloaded VEH-treated groups vs. CON-VEH (p< 0.05), and was 2-3 fold higher in SclAbII-treated groups (p< 0.001). Midshaft femoral strength was also significantly higher in SclAbII vs. VEH-groups in all-loading conditions. These results suggest that greater weight bearing leads to greater benefits of SclAbII on bone

  20. Sclerostin antibody inhibits skeletal deterioration in mice exposed to partial weight-bearing

    NASA Astrophysics Data System (ADS)

    Spatz, J. M.; Ellman, R.; Cloutier, A. M.; Louis, L.; van Vliet, M.; Dwyer, D.; Stolina, M.; Ke, H. Z.; Bouxsein, M. L.

    2017-02-01

    Whereas much is known regarding the musculoskeletal responses to full unloading, little is known about the physiological effects and response to pharmacological agents in partial unloading (e.g. Moon and Mars) environments. To address this, we used a previously developed ground-based model of partial weight-bearing (PWB) that allows chronic exposure to reduced weight-bearing in mice to determine the effects of murine sclerostin antibody (SclAbII) on bone microstructure and strength across different levels of mechanical unloading. We hypothesize that treatment with SclAbII would improve bone mass, microarchitecture and strength in all loading conditions, but that there would be a greater skeletal response in the normally loaded mice than in partially unloaded mice suggesting the importance of combined countermeasures for exploration-class long duration spaceflight missions. Eleven-week-old female mice were assigned to one of four loading groups: normal weight-bearing controls (CON) or weight-bearing at 20% (PWB20), 40% (PWB40) or 70% (PWB70) of normal. Mice in each group received either SclAbII (25 mg/kg) or vehicle (VEH) via twice weekly subcutaneous injection for 3 weeks. In partially-unloaded VEH-treated groups, leg BMD decreased -5 to -10% in a load-dependent manner. SclAbII treatment completely inhibited bone deterioration due to PWB, with bone properties in SclAbII-treated groups being equal to or greater than those of CON, VEH-treated mice. SclAbII treatment increased leg BMD from +14 to +18% in the PWB groups and 30 ± 3% in CON (p < 0.0001 for all). Trabecular bone volume, assessed by μCT at the distal femur, was lower in all partially unloaded VEH-treated groups vs. CON-VEH (p < 0.05), and was 2-3 fold higher in SclAbII-treated groups (p < 0.001). Midshaft femoral strength was also significantly higher in SclAbII vs. VEH-groups in all-loading conditions. These results suggest that greater weight bearing leads to greater benefits of SclAbII on bone mass

  1. Radioprotection of normal tissues in tumor-bearing mice by troxerutin.

    PubMed

    Maurya, Dharmendra Kumar; Salvi, Veena Prakash; Krishnan Nair, Cherupally Krishnan

    2004-06-01

    The flavanoid derivative troxerutin, used clinically for treating venous disorders, protected biomembranes and cellular DNA against the deleterious effects of gamma-radiation. The peroxidation of lipids (measured as thiobarbituric acid-reacting substances, or TBARS) in rat liver microsomal and mitochondrial membranes resulting from gamma-irradiation up to doses of 500 Gy in vitro was prevented by 0.2 mM troxerutin. The administration of troxerutin (175 mg/kg body weight) to tumor-bearing mice by ip one hour prior to 4 Gy whole-body gamma-irradiation significantly decreased the radiation-induced peroxidation of lipids in tissues such as liver and spleen, but there was no reduction of lipid peroxidation in tumor. The effect of troxerutin in gamma-radiation-induced DNA strand breaks in different tissues of tumor-bearing mice was studied by comet assay. The administration of troxerutin to tumor-bearing animals protected cellular DNA against radiation-induced strand breaks. This was evidenced from decreases in comet tail length, tail moment, and percent of DNA in the tails in cells of normal tissues such as blood leukocytes and bone marrow, and these parameters were not altered in cells of fibrosarcoma tumor. The results revealed that troxerutin could preferentially protect normal tissues against radiation-induced damages in tumor-bearing animals.

  2. Administration of polysaccharide from Panax notoginseng prolonged the survival of H22 tumor-bearing mice

    PubMed Central

    Li, Huaiyu; Gu, Longlong; Zhong, Yuanyuan; Chen, Yajuan; Zhang, Lei; Zhang, Annie R; Sobol, Robert W; Chen, Tong; Li, Jianfeng

    2016-01-01

    Background Polysaccharides from various sources are being considered potential sources for the treatment of liver cancer. The aim of this study was to investigate the impact of polysaccharide isolated from Panax notoginseng (PPN) on the proliferation of H22 liver cancer cells and the survival of the tumor-bearing mice transplanted with H22 cells. Materials and methods Polysaccharide from PPN was added to the culture medium of mouse hepatoma H22 cells at different doses. Cell proliferation was assayed with a standard MTT assay. Survival rates of tumor-bearing mice were recorded. Peripheral blood lymphocytes were assayed by flow cytometry. Serum interleukin-2 levels in peripheral blood were measured by enzyme-linked immunosorbent assay. Results Polysaccharide from PPN inhibited the growth of H22 cells and significantly prolonged the survival of tumor-bearing mice. The increase in activated CD4+ T-cells and the elevation of serum interleukin-2 may contribute to the antitumor activity of PPN. Conclusion PPN has potential antitumor activity for the treatment of liver cancer. PMID:27354815

  3. The effect of hypobaric hypoxia on misonidazole binding in normal and tumour-bearing mice.

    PubMed Central

    MacManus, M. P.; Maxwell, A. P.; Abram, W. P.; Bridges, J. M.

    1989-01-01

    The effect of hypobaric hypoxia on the in vivo binding of misonidazole was investigated in normal mice and mice bearing T50/80 or CA NT mammary carcinomas. After the intraperitoneal injection of radiolabelled misonidazole, mice were randomised to breathe either room air or air at 0.5 atmospheres. The distribution of misonidazole in liver, kidney, heart, spleen and tumour tissue, 24 h later, was studied by scintillation counting and by autoradiography. Significantly higher misonidazole binding occurred in the livers (x2.5), kidneys (x2.4), spleens (x2.9) and hearts (x1.8) of hypoxic mice compared to controls. Hypobaric hypoxia was associated with a greater than four-fold increase in misonidazole binding within T50/80 tumours. However, significantly higher binding was not demonstrated within CA NT tumours after exposure of tumour-bearing animals to hypoxic conditions. In autoradiographs of hypoxic liver, labelling was intense in regions near to hepatic veins but sparse in areas surrounding portal tracts. This pattern was striking and consistent. In hypoxic kidney, labelling was most intense over tubular cells, less intense over glomeruli and sparse in the renal medulla. It is likely that the hepatic and renal cortical distributions of misonidazole binding reflect local oxygen gradients. Images Figure 4 Figure 5 PMID:2930698

  4. Antitumor activity of polysaccharide from Laminaria japonica on mice bearing H22 liver cancer.

    PubMed

    Zhu, Qingwen; Chen, Jianghua; Li, Qiong; Wang, Ting; Li, Haibo

    2016-11-01

    Water-soluble polysaccharide was extracted from Laminaria japonica, and its antitumor effect on mice bearing H22 liver cancer was investigated. The mice were inoculated with H22 hepatoma cells and randomly divided into four groups: three treatment groups that received 50, 100 and 150mg/kg L. japonica polysaccharide (LJP) intraperitoneal injection and one control group that received equal volume of physiological saline. Intraperitoneal injection of LJP increased serum interleukin-2 and tumour necrosis factor-α levels, as well as tumour inhibition rate of mice, but decreased serum vascular endothelial growth factor level. Therefore, LJP exerts antitumor effect and can be used as a therapeutic agent for cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Lipid metabolism in tumour bearing mice treated withAeromonas L-asparaginase.

    PubMed

    Benny, P J; Kurup, G M; Sreejith, K

    1997-07-01

    The anticancerous drug isolated in our laboratory from estuarineAeromonas was characterised and is found to be an enzyme, L-asparaginase. The antileukaemic effect of this drug was studied in mice by inducing leukaemia with Ehrlich ascites cell lines. It was compared with commercially available drug, Leunase, isolated fromE. coli. The lipid profiles in mice during leukaemia and under treatment was studied. The decreased levels of cholesterol and increased levels of triglycerides and phospholipids in serum, liver and kidney were observed in tumour bearing mice. Significant changes in the above values were observed with enzyme therapy. It could bring some of the values to near normal level. L-asparaginase fromAeromonas was found to be more effective.

  6. Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD-1 antibodies.

    PubMed

    Levingston, Corinne A; Young, M Rita I

    2017-04-01

    A carcinogen-induced premalignant oral lesion model that progresses to oral cancer was used to examine the impact of blocking PD-1 on cytokine expression and on progression of lesions to cancer. The results of this study show increased production of IL-2 and the inflammatory cytokines IL-6, IL-17 and TNF-α by spleen cells of lesion-bearing mice that were treated with PD-1 antibody for 1 week compared to cytokine production by spleen cells of lesion-bearing mice treated with control antibody. Production of IFN-γ increased at 3 weeks of PD-1 antibody treatment, although production of the other Th1 and inflammatory mediators declined. By 5 weeks, levels of these cytokines declined for both control and PD-1 antibody-treated mice. Flow cytometric analysis for IFN-γ-expressing cells showed shifts in CD4(+) cells expressing IFN-γ consistent with the changes in cytokine secretion. Whether or not treatment generated reactivity to lesions or HNSCC was determined. Spleen cells from PD-1 antibody-treated mice were stimulated by lysates of premalignant lesion and HNSCC tongue tissues to produce increased levels of Th1 and select inflammatory cytokines early in the course of PD-1 antibody treatment. However, with continued treatment, reactivity to lesion and HNSCC lysates declined. Analysis of clinical response to treatment suggested an early delay in lesion progression but, with continued treatment, lesions in PD-1 antibody-treated mice progressed to the same degree as in control antibody-treated mice. Overall, these results show an early beneficial response to PD-1 antibody treatment, which then fails with continued treatment and lesion progression.

  7. Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

    PubMed Central

    Levingston, Corinne A.

    2017-01-01

    A carcinogen‐induced premalignant oral lesion model that progresses to oral cancer was used to examine the impact of blocking PD‐1 on cytokine expression and on progression of lesions to cancer. The results of this study show increased production of IL‐2 and the inflammatory cytokines IL‐6, IL‐17 and TNF‐α by spleen cells of lesion‐bearing mice that were treated with PD‐1 antibody for 1 week compared to cytokine production by spleen cells of lesion‐bearing mice treated with control antibody. Production of IFN‐γ increased at 3 weeks of PD‐1 antibody treatment, although production of the other Th1 and inflammatory mediators declined. By 5 weeks, levels of these cytokines declined for both control and PD‐1 antibody‐treated mice. Flow cytometric analysis for IFN‐γ‐expressing cells showed shifts in CD4+ cells expressing IFN‐γ consistent with the changes in cytokine secretion. Whether or not treatment generated reactivity to lesions or HNSCC was determined. Spleen cells from PD‐1 antibody‐treated mice were stimulated by lysates of premalignant lesion and HNSCC tongue tissues to produce increased levels of Th1 and select inflammatory cytokines early in the course of PD‐1 antibody treatment. However, with continued treatment, reactivity to lesion and HNSCC lysates declined. Analysis of clinical response to treatment suggested an early delay in lesion progression but, with continued treatment, lesions in PD‐1 antibody‐treated mice progressed to the same degree as in control antibody‐treated mice. Overall, these results show an early beneficial response to PD‐1 antibody treatment, which then fails with continued treatment and lesion progression. PMID:27914100

  8. Antioxidant supplementation accelerates cachexia development by promoting tumor growth in C26 tumor-bearing mice.

    PubMed

    Assi, Mohamad; Derbré, Frédéric; Lefeuvre-Orfila, Luz; Rébillard, Amélie

    2016-02-01

    More than 50% of patients with advanced stages of colon cancer suffer from progressive loss of skeletal muscle, called cachexia, resulting in reduced quality of life and shortened survival. It is becoming evident that reactive oxygen species (ROS) regulate pathways controlling skeletal muscle atrophy. Herein we tested the hypothesis that antioxidant supplementation could prevent skeletal muscle atrophy in a model of cachectic Colon 26 (C26) tumor-bearing mice. Seven-week-old BALB/c mice were subcutaneously inoculated with colon 26 (C26) cancer cells or PBS. Then C26-mice were daily gavaged during 22 days either with PBS (vehicle) or an antioxidant cocktail whose composition is close to that of commercial dietary antioxidant supplements (rich in catechins, quercetin and vitamin C). We found that antioxidants enhanced weight loss and caused premature death of mice. Antioxidants supplementation failed to prevent (i) the increase in plasma TNF-α levels and systemic oxidative damage, (ii) skeletal muscle atrophy and (iii) activation of the ubiquitin-proteasome system (MuRF-1, MAFbx and polyubiquitinated proteins). Accordingly, immunohistological staining for Ki-67 and the expression of cell cycle inhibitors demonstrated that tumor of supplemented mice developed faster with a concomitant decrease in oxidative damage. Previous studies have shown that the use of catechins and quercetin separately can improve the musculoskeletal function in cachectic animals. However, our results indicate that the combination of these antioxidants reduced survival and enhanced cachexia in C26-mice. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1.

    PubMed

    Ruud, Johan; Nilsson, Anna; Engström Ruud, Linda; Wang, Wenhua; Nilsberth, Camilla; Iresjö, Britt-Marie; Lundholm, Kent; Engblom, David; Blomqvist, Anders

    2013-03-01

    It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia-cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia-cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE(2) levels in plasma - a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE(2)-levels in the cerebrospinal fluid. Neutralization of plasma PGE(2) with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP(4) receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE(2) and neuronal EP(4) signaling. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Distribution of radiolabeled alloantibodies in mice bearing 3-methylcholanthrene-induced sarcoma.

    PubMed

    Buchsbaum, D J; Walker, P C; Johnson, E A

    1979-09-01

    The distribution of purified 125I-labeled alloantibodies, prepared from the serum of DBA/2J mice obtained after immunization with C3H/HeJ spleen cells, was studied in immunosuppressed DBA/2J mice bearing either allogeneic C3H/HeJ 3-methylcholanthrene sarcomas growing s.c. or syngeneic SaD2 3-methylcholanthrene sarcomas. Once purified radiolabeled antibody was isolated from 125I-labeled immune gamma-globulin by a single adsorption onto C3H/HeJ RBC and elution from stroma prepared from these cells, by using 0.1 M glycine buffer (pH 3.0). Twice-purified alloantibody was then produced by Bio-Gel P-200 or Sephadex G-200 gel filtration chromatography or DEAE A-50 ion-exchange chromatography. In vitro, such purified antibodies bound specifically to C3H/HeJ RBC. In vivo, they localized to a significant extent following i.p. injection, preferentially in C3H/HeJ 3-methylcholanthrene sarcomas (4.4 to 8.9% of the injected dose per g of tumor equal to 1% of mouse weight), with mean tumor/blood ratios of 4.0 to 7.8, at 24 or 48 hr after injection. The percentage of injected dose localized in tumor and the tumor/blood ratio did not show significant differences with respect to time or method of antibody purification. Normal tissue/blood ratios in C3H/HeJ or SaD2 sarcoma-bearing mice were less than 0.9. The tumor/blood ratios in SaD2 sarcomas were approximately 0.6. Injection of 131I-labeled normal DBA/2J gamma-globulin resulted in normal tissue/blood and tumor/blood ratios of less than 0.9 in C3H/HeJ tumor-bearing mice.

  11. Toxicity Profiles In Vivo in Mice and Antitumour Activity in Tumour-Bearing Mice of Di- and Triorganotin Compounds

    PubMed Central

    Willem, R.; Dalil, H.; de Vos, D.; Kuiper, C. M.; Peters, G. J.

    1998-01-01

    The in vivo toxicity profiles in mice and the antitumour activity in tumour bearing mice were screened for four di-n-butyltin and five triorganotin carboxylates, di-n-butyltin diterebate (5), bis(phenylacetate) (6), bis(deoxycholate) (7), bis(lithocholate) (8), tri-n-butyltin terebate (9), cinnamate (10), and triphenyltin terebate (11). At their maximum tolerated dosis (MTD), no antitumour effect (T/C ~1) was observed for the compounds 5, 7, 9, 10 and 11. The compounds 6 (T/C = 0.51) and 8 (T/C = 0.42) showed clear antitumour activity after single dose administration and might therefore be of interest for further antitumour activity studies. PMID:18475827

  12. Radioprotection by Macerated Extract of Nigella sativa in Normal Tissues of Fibrosarcoma Bearing Mice

    PubMed Central

    Velho-Pereira, Reelma; Kumar, A.; Pandey, B. N.; Mishra, K. P.; Jagtap, Aarti G.

    2012-01-01

    The current study was undertaken to study the effect of a macerated extract of Nigella sativa seeds in normal as well as in tumour bearing mice against gamma radiation-induced cellular damage to normal tissues. This was done to mimic the clinical setting where in, normal tissues of cancer patients undergoing radiotherapy are exposed to the deleterious effects of radiation. The protection of cellular DNA was analysed in peripheral blood leucocytes of whole body irradiated mice following pretreatment with macerated extract of Nigella sativa seeds (100 mg/kg), using alkaline comet assay, and also estimating biochemical and blood parameters such as levels of antioxidant enzymes superoxide dismutase and catalase, thiobarbituric acid reactive substances and protein oxidation in organs such as spleen, liver, brain and intestine haemoglobin and total leucocyte count, respectively. The results showed that the macerated extract of Nigella sativa seeds protected the liver, spleen, brain and intestines both in normal as well as tumour bearing mice. This study concludes that macerated extract of Nigella sativa seeds has protective effects against radiation-induced damage and biochemical alterations which could be attributed to the ability to scavenge free radicals and its antioxidant properties. Hence macerated extract of Nigella sativa seeds, could be used in combination with radiation to protect against oxidative stress in normal tissues and improving the quality of life of cancer patients by mitigating unwanted side effects of radiation in normal tissues. PMID:23716868

  13. Anticancer effect and immunologic response to xenogeneic embryonic proteins in mice bearing Ehrlich solid carcinoma.

    PubMed

    Symchych, T V; Fedosova, N I; Karaman, О М; Yevstratieva, L M; Potebnia, H P

    2017-03-01

    To investigate anticancer and immunologic effects of chicken embryonic proteins (CEP) in mice bearing Ehrlich solid carcinoma. The study was carried out on male Balb/c mice bearing Ehrlich solid carcinoma. The immunizations were performed after the tumor transplantation. The immune status was assessed on days 7, 14, 21 and 28 after the tumor challenge. Cytotoxic activity (CAT) of macrophages (Mph), natural killer cells (NK), cytotoxic T-lymphocytes (CTL) and blood serum, as well as the influence of the blood serum on immune cells activity was checked in MTT-assay; Mph's cytochemical activity was tested in NBT-assay; Ehrlich antigen-specific or CEP-specific antibodies were detected in ELISA-assay; medium size circulating immune complexes (CIC) were detected in reaction of 4.5% polyethylene glycol precipitation. The immunization resulted in tumor growth suppression and significant 25.64% prolongation of the survival time. In both control and immunized mice with transplanted tumors antibodies specific to Ehrlich carcinoma antigens and to CEP were detected, but antibody response was more balanced in the treatment group. In the treatment group both cytochemical and CAT of Mph was moderately activated and well preserved until late stages of tumor development; CAT of NK and CTL remained in the range of the intact mice until day 28 after the tumor transplantation. The immunized mice were well protected from accumulation of CIC and suppressive activity of autologous blood serum. Collectively, our data indicate that CEP can elicit immunomodulating and immunoprotecting effects sufficient to provide tumor growth inhibition. The further elaboration of a xenogeneic anticancer vaccine based on CEP is warranted.

  14. [Pulsed electric fields inhibit tumor growth but induce myocardial injury of melanoma-bearing mice].

    PubMed

    Pan, Fengying; Wu, Sha; Wang, Xiaoxu; Zhang, Xiaogang

    2016-07-01

    Objective To investigate the tumor inhibiting effect of pulsed electric fields (PEFs) on melanoma-bearing mice, and understand its influence on myocardial cells and cardial electrical activity. Methods The melanoma models of the BALB/c mice were established by subcutaneously injecting B16 melanoma cells. These mice were randomly divided into four groups. The treated groups received pulsed electric stimulation at pulse width of 1, 3, 5 ms, with field strength of 100 V/cm and frequency of 10 Hz for 10 minutes daily in 15 consecutive days. ECG of mice was recorded. Tumor volume was measured with vernier caliper. Morphological changes of tumors were observed by HE staining. The expression of proliferating cell nuclear antigen (PCNA) mRNA was tested by real-time quantitative PCR, and the expression of PCNA protein was detected by immunofluorescence histochemistry. The ultrastructural changes of the cardiac tissues were observed by transmission electron microscopy (TEM). The serum levels of cardial troponin T (cTnT) and creatine kinase isoenzyme MB (CK-MB) were detected by ELISA. Results Compared with the control group, tumor volumes in all treated groups were reduced 7 days after PEFs treatment; more melanin granules in tumor cells were found in the treated groups; the expressions of PCNA mRNA and protein were down-regulated in all treated groups, and there were greater changes in the groups receiving the bigger pulse width. Myocardial injury was found in 3 ms group and 5 ms group, and the expressions of cTnT and CK-MB were significantly higher than those in the control group. Conclusion PEFs can inhibit tumor growth in melanoma-bearing mice. Increase of pulse width will aggravate myocardial injury.

  15. Specific antitumour immunity of HIFU-activated cytotoxic T lymphocytes after adoptive transfusion in tumour-bearing mice.

    PubMed

    Ran, Li-Feng; Xie, Xun-Peng; Xia, Ji-Zhu; Xie, Fang-Lin; Fan, Yan-Min; Wu, Feng

    2016-01-01

    The aim of this study was to investigate the specific anti-tumour immunity of cytotoxic T lymphocytes (CTL) activated by high-intensity focused ultrasound (HIFU) after adoptive transfer in a murine tumour model. H22 tumour-bearing mice were treated by either HIFU or sham-HIFU, while naïve syngeneic mice were used as controls. They were sacrificed and the spleens were harvested 14 days after HIFU. T lymphocytes were obtained from the spleens, and then adoptively transferred into 40 mice each bearing a 3-day implanted H22 tumour. On day 14 after adoptive transfer, 10 mice were sacrificed in each group for assessment of the number of tumour-infiltrating T lymphocytes and interferon-gamma (IFN-γ) secreting cells. The remaining 30 mice were continuously observed for 60 days, and tumour growth, progression and survival were recorded. HIFU significantly increased peripheral blood CD3(+), CD4(+) levels and CD4(+)/CD8(+) ratio (P < 0.05), CTL cytotoxicity (P < 0.01) and IFN-γ and TNF-α secretion (P < 0.01) in H22 tumour-bearing mice. Adoptive transfer of HIFU-activated T lymphocytes into the autologous tumour-bearing mice induced a significant increase of tumour-infiltrating T lymphocytes and IFN-γ-secreting cells (P < 0.001). Compared to the control and sham-HIFU groups, HIFU-activated lymphocytes elicited significant inhibition of in vivo tumour growth (P < 0.01) and progression (P < 0.0001), and longer survival time in the tumour-bearing mice (P < 0.001). HIFU could enhance CTL's specific antitumour immunity. Adoptive transfer of HIFU-activated T lymphocytes could increase local antitumour immunity, and elicit stronger inhibition on tumour growth and progression, with more survival benefit in the autologous tumour-bearing mice.

  16. Enhanced thermal stability of lysosomal beta-D-galactosidase in parenchymal cells of tumour bearing mice.

    PubMed Central

    Lenti, L.; Lipari, M.; Lombardi, D.; Zicari, A.; Dotta, A.; Pontieri, G. M.

    1986-01-01

    The thermal stability of the enzyme beta-D-galactosidase varies among different organs in normal C57Bl/6 mice, and increases in the same organs in mice with Lewis Lung carcinoma. Thermal stability of this enzyme is also increased by treatment of the mice with cell-free extracts of tumour cells or with inflammatory compounds such as carrageenan or orosomucoid. After desialylation, orosomucoid more effectively increases the heat stability of the enzyme. By contrast talc, which has no galactosyl groups, is without effect on the stability of the enzyme in vivo. Macrophages of tumour bearing mice release into the culture medium a more heat resistant enzyme than macrophages from control mice. In both cases the heat resistance of the secreted enzyme is higher when fetal calf serum is present in the culture medium. Bovine serum does not modify the thermal stability of beta-D-galactosidase in this system. Incubation of lysosomal fractions of various organs with the synthetic beta-D-galactosidase substrate, p-nitrophenyl-galactopyranoside, also strongly increases the heat resistance of the enzyme. The results suggest that one factor influencing the heat resistance of this enzyme may be complex formation between the enzyme and its substrates, an example of substrate protection of the enzyme. This may not be the only factor involved in enzyme stabilization in vivo. PMID:3099822

  17. Generation of Immunodeficient Mice Bearing Human Immune Systems by the Engraftment of Hematopoietic Stem Cells.

    PubMed

    Hasgur, Suheyla; Aryee, Ken Edwin; Shultz, Leonard D; Greiner, Dale L; Brehm, Michael A

    2016-01-01

    Immunodeficient mice are being used as recipients of human hematopoietic stem cells (HSC) for in vivo analyses of human immune system development and function. The development of several stocks of immunodeficient Prkdc (scid) (scid), or recombination activating 1 or 2 gene (Rag1 or Rag2) knockout mice bearing a targeted mutation in the gene encoding the IL2 receptor gamma chain (IL2rγ), has greatly facilitated the engraftment of human HSC and enhanced the development of functional human immune systems. These "humanized" mice are being used to study human hematopoiesis, human-specific immune therapies, human-specific pathogens, and human immune system homeostasis and function. The establishment of these model systems is technically challenging, and levels of human immune system development reported in the literature are variable between laboratories. The use of standard protocols for optimal engraftment of HSC and for monitoring the development of the human immune systems would enable more direct comparisons between humanized mice generated in different laboratories. Here we describe a standard protocol for the engraftment of human HSC into 21-day-old NOD-scid IL2rγ (NSG) mice using an intravenous injection approach. The multiparameter flow cytometry used to monitor human immune system development and the kinetics of development are described.

  18. Saccharomyces cerevisiae, the Baker's Yeast, suppresses the growth of Ehrlich carcinoma-bearing mice.

    PubMed

    Ghoneum, Mamdooh; Badr El-Din, Nariman K; Noaman, Eman; Tolentino, Lucilene

    2008-04-01

    This study was undertaken to evaluate the effectiveness and mechanisms of anti-tumor activity of Baker's yeast, Saccharomyces cerevisiae, in immunocompetent mice. Swiss albino mice were inoculated intramuscularly in the right thigh with Ehrlich Ascites Carcinoma (EAC) cells. At day 8, mice bearing Solid Ehrlich Carcinoma tumor (SEC) were intratumorally (IT) injected with killed S. cerevisiae (10 x 10(6) and 20 x 10(6) cells) for 35 days. Histopathology of yeast-treated mice showed extensive tumor degeneration, apoptosis, and ischemic (coagulative) and liquefactive necrosis. These changes are associated with a tumor growth curve that demonstrates a significant antitumor response that peaked at 35 days. Yeast treatment (20 x 10(6) cells) three times a week resulted in a significant decrease in tumor volume (TV) (67.1%, P < 0.01) as compared to PBS-treated mice. The effect was determined to be dependent on dose and frequency. Yeast administered three and two times per week induced significant decrease in TV as early as 9 and 25 days post-treatment, respectively. Administration of yeast significantly enhanced the recruitment of leukocytes, including macrophages, into the tumors and triggered apoptosis in SEC cells as determined by flow cytometry (78.6%, P < 0.01) at 20 x 10(6) cells, as compared to PBS-treated mice (42.6%). In addition, yeast treatment elevated TNF-alpha and IFN-gamma plasma levels and lowered the elevated IL-10 levels. No adverse side effects from the yeast treatment were observed, including feeding/drinking cycle and life activity patterns. Indeed, yeast-treated mice showed significant final body weight gain (+21.5%, P < 0.01) at day 35. These data may have clinical implications for the treatment of solid cancer with yeast, which is known to be safe for human consumption.

  19. Antitumor Activity of Prosopis glandulosa Torr. on Ehrlich Ascites Carcinoma (EAC) Tumor Bearing Mice

    PubMed Central

    Senthil Kumar, Raju; Rajkapoor, Balasubramanian; Perumal, Perumal; Dhanasekaran, Thangavel; Alvin Jose, Manonmani; Jothimanivannan, Chennakesavalu

    2011-01-01

    The antitumor activity of ethanol extract of Prosopis glandulosa Torr. (EPG) was evaluated against Ehrlich ascites carcinoma (EAC) tumor model in Swiss albino mice on dose dependent manner. The activity was assessed using survival time, average increase in body weight, hematological parameters and solid tumor volume. Oral administration of EPG at the dose of 100, 200 and 400 mg/Kg, significantly (p < 0.001) increased the survival time and decreased the average body weight of the tumor bearing mice. After 14 days of inoculation, EPG was able to reverse the changes in the hematological parameters, protein and PCV consequent to tumor inoculation. Oral administration of EPG was effective in reducing solid tumor mass development induced by EAC cells. The results indicate that EPG possess significant antitumor activity on dose dependent manner. PMID:24250382

  20. Radiosynthesis and pharmacokinetics of [18F]fluoroethyl bufalin in hepatocellular carcinoma-bearing mice

    PubMed Central

    Yang, Zhaoshuo; Liu, Jianhua; Huang, Qingqing; Zhang, Zhouji; Zhang, Jiawei; Pan, Yanjia; Yang, Yunke; Cheng, Dengfeng

    2017-01-01

    Purpose Bufalin, the main component of a Chinese traditional medicine chansu, shows convincing anticancer effects in a lot of tumor cell lines. However, its in vivo behavior is still unclear. This research aimed to evaluate how bufalin was dynamically absorbed after intravenous injection in animal models. We developed a radiosynthesis method of [18F]fluoroethyl bufalin to noninvasively evaluate the tissue biodistribution and pharmacokinetics in hepatocellular carcinoma-bearing mice. Methods [18F]fluoroethyl bufalin was synthesized with conjugation of 18F-CH2CH2OTs and bufalin. The radiochemical purity was proved by the radio-high-performance liquid chromatography (HPLC). The pharmacokinetic studies of [18F]fluoroethyl bufalin were then performed in Institute of Cancer Research (ICR) mice. Furthermore, the biodistribution and metabolism of [18F]fluoroethyl bufalin in HepG2 and SMMC-7721 tumor-bearing nude mice were studied in vivo by micro-positron emission tomography (micro-PET). Results The radiochemical purity (RCP) of [18F]fluoroethyl bufalin confirmed by radio-HPLC was 99%±0.18%, and [18F]fluoroethyl bufalin showed good in vitro and in vivo stabilities. Blood dynamics of [18F]fluoroethyl bufalin conformed to the two compartments in the ICR mice model. The pharmacokinetic parameters of [18F]fluoroethyl bufalin were calculated by DAS 2.0 software. The area under concentration–time curve (AUC0–t) and the values of clearance (CL) were 540.137 μg/L·min and 0.001 L/min/kg, respectively. The half-life of distribution (t1/2α) and half-life of elimination (t1/2β) were 0.693 and 510.223 min, respectively. Micro-PET imaging showed that [18F]fluoroethyl bufalin was quickly distributed via the blood circulation; the major tissue biodistribution of [18F]fluoroethyl bufalin in HepG2 and SMMC-7721 tumor-bearing mice was liver and bladder. Conclusion [18F]fluoroethyl bufalin was accumulated rapidly in the liver at an early time point (5 min) post injection (pi) and

  1. [Simulated weightlessness inhibits antitumor immunity of T lymphocytes in melanoma-bearing mice].

    PubMed

    Si, Shaoyan; Song, Shujun; Shi, Liang; Liu, Junli; Xu, Bingxin; Yi, Yong; Tan, Xiaoqing; Zhang, Jianzhong

    2013-02-01

    To investigate the effects of simulated weightlessness on antitumor immunity of T lymphocytes in mice. The malignant melanoma was xenografted by subcutaneous injection of B16 cells into the right hind limb of every mouse. The mice suspended by tail at a -15 degree to 20 degree head-down tilt were used as simulated weightlessness models. The effects of simulated weightlessness on tumor volume and survival time were observed. T the numbers of leucocytes, lymphocytes and T lymphocyte subsets in peripheral blood of tumor-bearing mice under simulated weightlessness were monitored by an automatic hemacytometer and a flow cytometer. The effects of simulated weightlessness on the production of IL-2, TNF-α and IFN-γ in T lymphocytes and the cytotoxicities of tumor-specific CTLs to tumor cells were analyzed by ELISA and LDH release. Compared with control group, the tumors grew faster, the survival times were shorter, the number of lymphocytes, the ratio of lymphocytes, CD3(+);, CD4(+);/CD3(+); and CD8(+);/CD3(+); T lymphocytes in peripheral blood dropped, and the proliferation of splenic T lymphocytes induced by mitogen was reduced (P<0.05 or P<0.01) in the simulated weightlessness group. The production of IL-2, TNF-α and IFN-γ induced by tumor cells and cytotoxicities of tumor-specific CTLs to tumor cells were inhibited in mice under simulated weightlessness (P<0.05 or P<0.01). Simulated weightlessness inhibits antitumor immunity of T lymphocytes.

  2. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice.

    PubMed

    Le, Hanh K; Graham, Laura; Cha, Esther; Morales, Johanna K; Manjili, Masoud H; Bear, Harry D

    2009-07-01

    Myeloid derived suppressor cells (MDSCs) accumulate in 4T1 mammary carcinoma bearing mice and present a barrier to the success of adoptive immunotherapy (AIT) by suppressing T cell immunity. In this study, we investigated the inhibition of MDSCs by gemcitabine (GEM), a chemotherapy agent that may have favorable immunologic effects. BALB/c mice were inoculated with 4T1 mammary carcinoma cells and treated with GEM either once a week starting 5 days after tumor inoculation (EARLY GEM) or as a single dose at days 20-25 (LATE GEM). Splenic mononuclear cells were isolated, activated in vitro, expanded, and stimulated with tumor antigen. T cells were then used for AIT to treat tumor-bearing mice. EARLY GEM treatment of 4T1 tumor-bearing mice significantly inhibited tumor growth, reduced splenomegaly, and significantly decreased MDSC proportion in the spleen. Support for a direct effect was demonstrated through suppression of MDSCs in spleens, bone marrow, and blood harvested 24 and 48 h after LATE GEM treatment, despite no significant decrease in tumor burden. Interestingly, treatment of tumor-bearing mice with GEM augmented in vitro expansion of splenic T cells and boosted IFN-gamma secretion in response to stimulation by tumor antigen. However, despite GEM-mediated inhibition of MDSC suppression, splenic T cells from mice with advanced tumors were ineffective in vivo against established tumors. This study provides support for direct inhibition of MDSCs and direct reduction of tumor burden by GEM in 4T1 tumor-bearing mice. GEM treatment of mice with advanced tumors improves T cell function and growth in vitro.

  3. Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts.

    PubMed

    Zhu, Yin; Cheng, Ming; Yang, Zhen; Zeng, Chun-Yan; Chen, Jiang; Xie, Yong; Luo, Shi-Wen; Zhang, Kun-He; Zhou, Shu-Feng; Lu, Nong-Hua

    2014-01-01

    Mesenchymal stem cells (MSCs) have been recognized as promising delivery vehicles for gene therapy of tumors. Gastric cancer is the third leading cause of worldwide cancer mortality, and novel treatment modalities are urgently needed. NK4 is an antagonist of hepatocyte growth factor receptors (Met) which are often aberrantly activated in gastric cancer and thus represent a useful candidate for targeted therapies. This study investigated MSC-delivered NK4 gene therapy in nude mice bearing gastric cancer xenografts. MSCs were transduced with lentiviral vectors carrying NK4 complementary DNA or enhanced green fluorescent protein (GFP). Such transduction did not change the phenotype of MSCs. Gastric cancer xenografts were established in BALB/C nude mice, and the mice were treated with phosphate-buffered saline (PBS), MSCs-GFP, Lenti-NK4, or MSCs-NK4. The tropism of MSCs toward gastric cancer cells was determined by an in vitro migration assay using MKN45 cells, GES-1 cells and human fibroblasts and their presence in tumor xenografts. Tumor growth, tumor cell apoptosis and intratumoral microvessel density of tumor tissue were measured in nude mice bearing gastric cancer xenografts treated with PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4 via tail vein injection. The results showed that MSCs migrated preferably to gastric cancer cells in vitro. Systemic MSCs-NK4 injection significantly suppressed the growth of gastric cancer xenografts. MSCs-NK4 migrated and accumulated in tumor tissues after systemic injection. The microvessel density of tumor xenografts was decreased, and tumor cellular apoptosis was significantly induced in the mice treated with MSCs-NK4 compared to control mice. These findings demonstrate that MSC-based NK4 gene therapy can obviously inhibit the growth of gastric cancer xenografts, and MSCs are a better vehicle for NK4 gene therapy than lentiviral vectors. Further studies are warranted to explore the efficacy and safety of the MSC-based NK4 gene therapy in

  4. Identification of tissue sites for increased albumin degradation in sarcoma-bearing mice

    SciTech Connect

    Andersson, C.; Iresjoe, B.M.L.; Lundholm, K. )

    1991-02-01

    Plasma albumin concentration declines in both experimental and clinical cancer. Previous investigations have demonstrated that this is partly explained by increased breakdown of albumin. The present study has identified the tissue sites for increased albumin degradation in a nonmetastasizing sarcoma mouse (C57/BL6J) model. Results have been compared to nontumor-bearing animals either freely fed or food restricted (pair-weighed) so that their body composition was similar to tumor-bearing animals. Tumor-bearing mice had increased albumin degradation (0.13 +/- 0.02 mg/hr/g bw) compared to both freely fed (0.09 +/- 0.007) and pair-weighed control animals (0.05 +/- 0.008). Radioactivity from circulating (3H)raffine aldehyde labeled albumin appeared with maximum peak values in lysosomes isolated from both tumor and nontumor tissues at 48 hr following iv injection. The intralysosomal accumulation of radioactivity was two- to threefold higher in tumor tissue compared to liver tissue, although the specific activity of protease(s) for albumin degradation measured in vitro was not higher in tumor tissue (30.4 +/- 3.6 mg/hr/g tissue) compared to normal liver tissue (36.9 +/- 1.7). Accounting for the entire tumor the proteolytic capacity for albumin breakdown was however much larger in the tumor (161.6 +/- 32.6 mg/organ) compared to both normal liver (37.5 +/- 2.3) and tumor-host liver (56.4 +/- 2.8). Pepstatin inhibited 78 +/- 6% of the proteolytic activity in the tumor measured by 125I-labeled undenatured mouse albumin as the substrate. Leupeptin inhibited 49 +/- 6%. There was a significantly decreased breakdown of albumin in both skeletal muscles and the gastrointestinal tract from tumor-bearing animals.

  5. Primary tumorectomy promotes angiogenesis and pulmonary metastasis in osteosarcoma-bearing nude mice.

    PubMed

    Wang, Zhi-Yuan; Mei, Jiong; Gao, You-Shui; Ni, Ming; Yao, Bin

    2013-03-01

    To investigate the effect of primary tumorectomy on angiogenesis and pulmonary metastasis in osteosarcoma-bearing nude mice. Osteosarcoma was introduced to nude mice via subcutaneous injection of MG-63 cells. One hundred and eighty osteosarcoma-bearing mice were used equally in 3 parallel experiments. The effect of tumorectomy (TR) on the expression of vascular endothelial growth factor (VEGF) and endostatin was investigated by ELISA. Meanwhile, the effect on angiogenesis was evaluated by Matrigel plug assay, and pulmonary metastasis assessed by calculating the metastatic foci. Sham-operation (SO) and untreated (UT) groups served as controls. The VEGF (TR: 79.55 ± 7.82 pg/mL vs. SO: 110.01 ± 5.69 pg/mL, UT: 123.50 ± 10.41 pg/mL; p < 0.01) and endostatin (TR: 47.09 ± 6.22 ng/mL vs. SO: 117.64 ± 7.39 ng/mL, UT: 126.73 ± 6.55 ng/mL; p<0.01) were down-regulated significantly after tumorectomy, and angiogenesis was significantly promoted simultaneously. The incidence of pulmonary metastatic foci was 80.0% in the TR group, 40.0% in the SO group and 35.0% in the UT group. Primary tumorectomy can down-regulate the expression of VEGF and endostatin and promote angiogenesis which leads to the acceleration of pulmonary metastasis. These findings imply that anti-angiogenic treatment can be considered after primary tumorectomy.

  6. Protective effect of genistein on radiation-induced intestinal injury in tumor bearing mice

    PubMed Central

    2013-01-01

    Background Radiation therapy is the most widely used treatment for cancer, but it causes the side effect of mucositis due to intestinal damage. We examined the protective effect of genistein in tumor-bearing mice after abdominal irradiation by evaluation of apoptosis and intestinal morphological changes. Methods Mouse colon cancer CT26 cells were subcutaneously injected at the flank of BALB/c mice to generate tumors. The tumor-bearing mice were treated with abdominal radiation at 5 and 10 Gy, and with genistein at 200 mg/kg body weight per day for 1 d before radiation. The changes in intestinal histology were evaluated 12 h and 3.5 d after irradiation. To assess the effect of the combination treatment on the cancer growth, the tumor volume was determined at sacrifice before tumor overgrowth occurred. Results Genistein significantly decreased the number of apoptotic nuclei compared with that in the irradiation group 12 h after 5 Gy irradiation. Evaluation of histological changes showed that genistein ameliorated intestinal morphological changes such as decreased crypt survival, villus shortening, and increased length of the basal lamina 3.5 d after 10 Gy irradiation. Moreover, the genistein-treated group exhibited more Ki-67-positive proliferating cells in the jejunum than the irradiated control group, and crypt depths were greater in the genistein-treated group than in the irradiated control group. The mean weight of the CT26 tumors was reduced in the group treated with genistein and radiation compared with the control group. Conclusion Genistein had a protective effect on intestinal damage induced by irradiation and delayed tumor growth. These results suggest that genistein is a useful candidate for preventing radiotherapy-induced intestinal damage in cancer patients. PMID:23672582

  7. [Targeting therapy of magnetic doxorubicin liposome in nude mice bearing colon cancer].

    PubMed

    Zhou, Ping-hong; Yao, Li-qing; Qin, Xin-yu; Shen, Xi-zhong; Liu, Yi-shu; Lu, Wei-yue; Yao, Ming

    2003-12-10

    To investigate the effect of magnetic doxorubicin liposome (MDL) in the targeting treatment of nude mice bearing colon cancer. Human colon cancer line LoVo cells were implanted hypodermically into nude mouse. Two weeks after the mouse was killed and the tumor was taken out and cut into small pieces to be retransplanted into nude mice so as to establish an experimental model. MDL was prepared by reverse-phase evaporation method. The particle size and structure of MDL were evaluated. Eighteen nude mice with colon cancer were divided into 3 groups of 3 mice: free DOX group, MDL (-) group (no magnetic field was added to the tumor surface), and MDL (+) group (magnetic field with the strength of 4,500 G was added). DOX of the dosage of 5 mg/kg was injected through the caudal vein in these 3 groups. Then the mice were killed 30 minutes after. Fluorescence spectrophotometry was used to examine the concentrations of DOX in the tissues and plasma. Another 36 nude mice with colon cancer were divided into 6 groups of 6 mice: normal saline group (as controls), DOX group, blank liposome group, magnetic liposome group, MDL (-) group (non-magnetic alloy was implanted into the tumor), and MDL (+) group (rare earth magnet was implanted into the tumor). The body weight, longest diameter of tumor, and short diameter vertical to the longest diameter were calculated regularly. The mice were killed 11 days after. The tumors were taken out to undergo staining and light microscopy. Flow cytometry was used to examine the apoptosis of tumor cells. The particle size of MDL was 230 nm and the magnetic particles (Fe(3)O(4)) were evenly distributed within the liposome. The DOX concentration in tumor tissue of the MDL (+) group was remarkably higher than those of the DOX and MDL (-) groups (both P < 0.05). The DOX concentration in heart and kidney of the DOX group were higher than those of the other 2 groups, and the plasma DOX concentrations of the DOX group was significantly lower than those of

  8. Garlic oil suppressed the hematological disorders induced by chemotherapy and radiotherapy in tumor-bearing mice.

    PubMed

    Zeng, Tao; Li, Yang; Zhang, Cui-Li; Yu, Li-Hua; Zhu, Zhen-Ping; Zhao, Xiu-Lan; Xie, Ke-Qin

    2013-06-01

    Although the anticancer effects of garlic and its products have been demonstrated by a variety of studies; however, few studies were conducted to investigate the effects of garlic on the adverse effects of chemo/radiotherapy. In order to clarify the above question and make a more comprehensive understanding of the anticancer effects of garlic, tumor xenograft mice model was established by subcutaneous injection of H22 tumor cells, and was used for the investigation of effects of garlic oil (GO) on the chemo/radiotherapy. In the chemotherapy test, tumor-bearing mice were treated with cyclophosphamide (CTX) or CTX plus GO (25 or 50 mg/kg bw) for 14 d, while the mice received a single 5 Gy total body radiation or radiation plus GO (25 or 50 mg/kg bw) in radiotherapy test. The results showed that GO did not increase the tumor inhibitory rate of CTX/radiation, which indicated that GO could not enhance the chemo/radiosensitivity of cancer cells. However, the decrease of the peripheral total white blood cells (WBCs) count induced by CTX/radiation was significantly suppressed by GO cotreatment. Furthermore, GO cotreatment significantly inhibited the decrease of the DNA contents and the micronuclei ratio of the bone marrow. Lastly, the reduction of the endogenous spleen colonies induced by CTX/radiation was significantly suppressed by GO cotreatment. These findings support the idea that GO consumption may benefit for the cancer patients receiving chemotherapy or radiotherapy. © 2013 Institute of Food Technologists®

  9. Metabolic shifts induced by human H460 cells in tumor-bearing mice.

    PubMed

    Liu, Linsheng; Wang, Yaqiong; Zheng, Tian; Cao, Bei; Li, Mengjie; Shi, Jian; Aa, Nan; Wang, Xinwen; Zhao, Chunyan; Aa, Jiye; Wang, Guangji

    2016-03-01

    Tumor markers are most popularly used in diagnosis of various cancers clinically. However, the confounding factors of individual background diversities, such as genetics, food preferences, living styles, physical exercises, etc., greatly challenge the identification of tumor markers. Study of the metabolic impact of inoculated tumors on model animals can facilitate the identification of metabolomic markers relevant to tumor insult. In this study, serum metabolites from nude mice (n = 14) inoculated with human H460 cells (human nonsmall cell lung carcinoma) were profiled using gas chromatography time-of-flight mass spectrometry. The mice with inoculated tumors showed an obviously different metabolic pattern from the control; identification of the discriminatory metabolites suggested the metabolic perturbation of free fatty acids, amino acids, glycolysis and tricarboxylic acid (TCA) cycle turnover. The significantly decreased TCA intermediates, free fatty acids, 3-hydroxybutyric acid and fluctuating amino acids (t-test, p < 0.05) in serum of tumor-bearing mice characterized the metabolic impact of local inoculated H460 tumor cells on the whole system. This indicates that they are candidate metabolomic markers for translational study of lung cancer, clinically.

  10. Solanum Nigrum polysaccharide (SNL) extract effects in transplanted tumor-bearing mice--erythrocyte membrane fluidity and blocking of functions.

    PubMed

    Yuan, Hong-Liang; Liu, Xiao-Lei; Liu, Ying-Jie

    2014-01-01

    Solanum nigrum L. has been used in traditional Chinese medicine because of its diuretic and antipyretic effects. The present research concerned effects of crude polysaccharides isolated from Solanum nigrum L. on erythrocyte membranes of tumor-bearing S180 and H22 in mice. Fluorescence- labeled red blood cell membranes were used with DPH fluorescence spectrophotometry to examine erythrocyte membrane fluidity, and colorimetry to determine degree of erythrocyte surface membrane blocking. Extent of reaction by tumor-bearing mice with the enzyme erythrocyte membrane bubble shadow detection of red cell membrane variation in the degree of closure before and after administration. Solanum nigrum polysaccharide could significantly improve the S180 and H22 tumor-bearing mice erythrocyte membrane fluidity, compared with the control group, the difference was significant (p<0.01), SNL can significantly improve the red blood cell membrane and then S180 tumor-bearing mice sealing ability, compared with the negative control group, the difference was significant(p<0.05, p<0.01). H22 tumor-bearing mice can increase red cell membrane and then sealing ability, the difference was significant (p<0.05). Solanum nigrum polysaccharide degree of fluidity and blocking two transplanted tumors in mice restored the ability to raise the red cell membrane has a significant effect. Solanum nigrum L.-type mice transplanted tumor can affect the red blood cell membrane fluidity and re-closed, through the red cell membrane of red blood cells to enhance the immune function of the possibility of erythrocyte immunity against tumor formation garland provide experimental basis.

  11. Differences in food intake of tumour-bearing cachectic mice are associated with hypothalamic serotonin signalling

    PubMed Central

    Dwarkasing, Jvalini T; Boekschoten, Mark V; Argilès, Joseph M; van Dijk, Miriam; Busquets, Silvia; Penna, Fabio; Toledo, Miriam; Laviano, Alessandro; Witkamp, R F; van Norren, Klaske

    2015-01-01

    Background Anorexia is a common symptom among cancer patients and contributes to malnutrition and strongly impinges on quality of life. Cancer-induced anorexia is thought to be caused by an inability of food intake-regulating systems in the hypothalamus to respond adequately to negative energy balance during tumour growth. Here, we show that this impaired response of food-intake control is likely to be mediated by altered serotonin signalling and by failure in post-transcriptional neuropeptide Y (NPY) regulation. Methods Two tumour cachectic mouse models with different food intake behaviours were used: a C26-colon adenocarcinoma model with increased food intake and a Lewis lung carcinoma model with decreased food intake. This contrast in food intake behaviour between tumour-bearing (TB) mice in response to growth of the two different tumours was used to distinguish between processes involved in cachexia and mechanisms that might be important in food intake regulation. The hypothalamus was used for transcriptomics (affymetrix chips). Results In both models, hypothalamic expression of orexigenic NPY was significantly higher compared with controls, suggesting that this change does not directly reflect food intake status but might be linked to negative energy balance in cachexia. Expression of genes involved in serotonin signalling showed to be different between C26-TB mice and Lewis lung carcinoma-TB mice and was inversely associated with food intake. In vitro, using hypothalamic cell lines, serotonin repressed neuronal hypothalamic NPY secretion while not affecting messenger NPY expression, suggesting that serotonin signalling can interfere with NPY synthesis, transport, or secretion. Conclusions Altered serotonin signalling is associated with changes in food intake behaviour in cachectic TB mice. Serotonins' inhibitory effect on food intake under cancer cachectic conditions is probably via affecting the NPY system. Therefore, serotonin regulation might be a

  12. Chronopharmacodynamics and mechanisms of antitumor effect induced by erlotinib in xenograft-bearing nude mice.

    PubMed

    Lin, Pingping; An, Fengmei; Xu, Xia; Zhao, Liyan; Liu, Liang; Liu, Ning; Wang, Peipei; Liu, Jiao; Wang, Le; Li, Mingchun

    2015-05-01

    Receptor tyrosine kinases, mediators of a variety of critical cellular functions, contribute to tumor progression and metastasis. The epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase family, is ubiquitously expressed on the surface of mammalian cells. Erlotinib hydrochloride (Tarceva) can inhibit the intracellular phosphorylation of tyrosine kinases. To investigate the influence of dosing time on the ability of erlotinib to inhibit tumor growth and the underlying molecular mechanisms via the PI3K/AKT and ERK/MAPK pathway, we established nude mice HCC827 tumor xenografts models. The tumor-bearing mice were housed 3-4 per cage under standardized light/dark cycle conditions (lights on at 07:00 h, off at 19:00 h) with food and water ad libitum. The mice were randomly divided into erlotinib treated groups and control groups, gavaged with erlotinib and vehicle respectively at 6 different time points for 21 days. To draw tumor growth curves, the tumor volume was measured every three days. After the mice were sacrificed, the tumor masses of each group were removed and weighed. The relative protein expression levels of p-EGFR, p-AKT and p-MAPK were assayed at 4 h after erlotinib or vehicle gavage by Western blot analysis. The antitumor effect of erlotinib presented diurnal rhythmicity. The growth of HCC827 xenograft was more potently inhibited by erlotinib in the early light phase than in the early dark phase (p < 0.05). The inhibitory effect of erlotinib on phosphorylation of EGFR, AKT and MAPK varied with its administration time. The results indicate that the antitumor effect of erlotinib is more potent when the drug was administered when the activities of EGFR and its downstream factors increased. Our findings may provide a clue to optimize the dosing schedule of erlotinib. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Antitumor effect of vitamin D-binding protein-derived macrophage activating factor on Ehrlich ascites tumor-bearing mice.

    PubMed

    Koga, Y; Naraparaju, V R; Yamamoto, N

    1999-01-01

    Cancerous cells secrete alpha-N-acetylgalactosaminidase (NaGalase) into the blood stream, resulting in deglycosylation of serum vitamin D3-binding protein (known as Gc protein), which is a precursor for macrophage activating factor (MAF). Incubation of Gc protein with immobilized beta-galactosidase and sialidase generates the most potent macrophage activating factor (designated GcMAF). Administration of GcMAF to cancer-bearing hosts can bypass the inactivated MAF precursor and act directly on macrophages for efficient activation. Therapeutic effects of GcMAF on Ehrlich ascites tumor-bearing mice were assessed by survival time and serum NaGalase activity, because serum NaGalase activity was proportional to tumor burden. A single administration of GcMAF (100 pg/mouse) to eight mice on the same day after transplantation of the tumor (5 x 10(5) cells) showed a mean survival time of 21 +/- 3 days for seven mice, with one mouse surviving more than 60 days, whereas tumor-bearing controls had a mean survival time of 13 +/- 2 days. Six of the eight mice that received two GcMAF administrations, at Day 0 and Day 4 after transplantation, survived up to 31 +/- 4 days whereas, the remaining two mice survived for more than 60 days. Further, six of the eight mice that received three GcMAF administrations with 4-day intervals showed an extended survival of at least 60 days, and serum NaGalase levels were as low as those of control mice throughout the survival period. The cure with subthreshold GcMAF-treatments (administered once or twice) of tumor-bearing mice appeared to be a consequence of sustained macrophage activation by inflammation resulting from the macrophage-mediated tumoricidal process. Therefore, a protracted macrophage activation induced by a few administrations of minute amounts of GcMAF eradicated the murine ascites tumor.

  14. Muscarinic receptors participation in angiogenic response induced by macrophages from mammary adenocarcinoma-bearing mice

    PubMed Central

    de la Torre, Eulalia; Davel, Lilia; Jasnis, María A; Gotoh, Tomomi; de Lustig, Eugenia Sacerdote; Sales, María E

    2005-01-01

    Introduction The role of macrophages in tumor progression has generated contradictory evidence. We had previously demonstrated the ability of peritoneal macrophages from LMM3 murine mammary adenocarcinoma-bearing mice (TMps) to increase the angiogenicity of LMM3 tumor cells, mainly through polyamine synthesis. Here we investigate the ability of the parasympathetic nervous system to modulate angiogenesis induced by TMps through the activation of the muscarinic acetylcholine receptor (mAchR). Methods Peritoneal macrophages from female BALB/c mice bearing a 7-day LMM3 tumor were inoculated intradermally (3 × 105 cells per site) into syngeneic mice. Before inoculation, TMps were stimulated with the muscarinic agonist carbachol in the absence or presence of different muscarinic antagonists or enzyme inhibitors. Angiogenesis was evaluated by counting vessels per square millimeter of skin. The expression of mAchR, arginase and cyclo-oxygenase (COX) isoforms was analyzed by Western blotting. Arginase and COX activities were evaluated by urea and prostaglandin E2 (PGE2) production, respectively. Results TMps, which stimulate neovascularization, express functional mAchR, because carbachol-treated TMps potently increased new blood vessels formation. This response was completely blocked by preincubating TMps with pirenzepine and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), M1 and M3 receptor antagonists, and partly by the M2 receptor antagonist methoctramine. M1 receptor activation by carbachol in TMps triggers neovascularization through arginase products because Nω-hydroxy-L-arginine reversed the agonist action. Preincubation of TMps with methoctramine partly prevented carbachol-stimulated urea formation. In addition, COX-derived liberation of PGE2 is responsible for the promotion of TMps angiogenic activity by M3 receptor. We also detected a higher expression of vascular endothelial growth factor (VEGF) in TMps than in macrophages from normal mice. Carbachol

  15. Muscarinic receptors participation in angiogenic response induced by macrophages from mammary adenocarcinoma-bearing mice.

    PubMed

    de la Torre, Eulalia; Davel, Lilia; Jasnis, María A; Gotoh, Tomomi; de Lustig, Eugenia Sacerdote; Sales, María E

    2005-01-01

    The role of macrophages in tumor progression has generated contradictory evidence. We had previously demonstrated the ability of peritoneal macrophages from LMM3 murine mammary adenocarcinoma-bearing mice (TMps) to increase the angiogenicity of LMM3 tumor cells, mainly through polyamine synthesis. Here we investigate the ability of the parasympathetic nervous system to modulate angiogenesis induced by TMps through the activation of the muscarinic acetylcholine receptor (mAchR). Peritoneal macrophages from female BALB/c mice bearing a 7-day LMM3 tumor were inoculated intradermally (3 x 10(5) cells per site) into syngeneic mice. Before inoculation, TMps were stimulated with the muscarinic agonist carbachol in the absence or presence of different muscarinic antagonists or enzyme inhibitors. Angiogenesis was evaluated by counting vessels per square millimeter of skin. The expression of mAchR, arginase and cyclo-oxygenase (COX) isoforms was analyzed by Western blotting. Arginase and COX activities were evaluated by urea and prostaglandin E2 (PGE2) production, respectively. TMps, which stimulate neovascularization, express functional mAchR, because carbachol-treated TMps potently increased new blood vessels formation. This response was completely blocked by preincubating TMps with pirenzepine and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), M1 and M3 receptor antagonists, and partly by the M2 receptor antagonist methoctramine. M1 receptor activation by carbachol in TMps triggers neovascularization through arginase products because Nomega-hydroxy-L-arginine reversed the agonist action. Preincubation of TMps with methoctramine partly prevented carbachol-stimulated urea formation. In addition, COX-derived liberation of PGE2 is responsible for the promotion of TMps angiogenic activity by M3 receptor. We also detected a higher expression of vascular endothelial growth factor (VEGF) in TMps than in macrophages from normal mice. Carbachol significantly increased VEGF

  16. The therapeutic potency of HSP65-GTL in GL261 glioma-bearing mice.

    PubMed

    Yan, Youyou; Fang, Mingli; Xuan, Wei; Wu, Xiuli; Meng, Xiuping; Wang, Liying; Yu, Yongli

    2015-01-01

    Gliomas are the most common type of brain tumor with poor prognosis. Even after combination treatments including surgery, radiation, and chemotherapy, the median survival is around 15 months, calling for novel approaches such as immunotherapy. To develop novel therapeutic approaches, we tried to prepare a candidate vaccine by mixing the recombinant mycobacterial heat-shock protein 65 (HSP65) with GL261 glioma tissue lysate (GTL). Our data showed that HSP65-GTL induced potent cytotoxic T lymphocyte and prolonged the survival of mice bearing GL261 gliomas. Furthermore, HSP65 or HSP65-GTL upregulated mRNA expressions of RORγt and interleukin-17A in spleen cells or draining lymph node cells, respectively, and enhanced the ratios of brain-infiltrating Th17 cells and inflammatory cells, indicating that the antitumor effect of HSP65-GTL was associated with Th17-type immunity.

  17. Controlled targeting of different subcellular sites by porphyrins in tumour-bearing mice.

    PubMed

    Jori, G; Reddi, E; Cozzani, I; Tomio, L

    1986-05-01

    Unilamellar liposomes of dipalmitoyl-phosphatidylcholine can incorporate various porphyrins in either the phospholipid bilayer or the internal aqueous compartment depending on the water-/lipo-solubility of the drug. Intraperitoneal injection of the liposome-bound porphyrins to mice bearing a MS-2 fibrosarcoma results in remarkably more efficient tumour targeting than that obtained by administration of the same porphyrins dissolved in homogeneous aqueous solution. Moreover, also water-insoluble porphyrins can be transported to the tumour via liposomes. Fractionation of liver and neoplastic cells indicates that the subcellular distribution of liposome-delivered porphyrins is also dependent on their solubility properties: thus, relatively polar porphyrins, such as tetra(4-sulfonatophenyl)porphine and uroporphyrin, are mainly recovered from the soluble fraction, whereas hydrophobic porphyrins, such as haematoporphyrin or porphyrin esters, preferentially partition in the cytoplasmic membrane. As a consequence, different subcellular sites can be targeted by porphyrins and possibly photodamaged through a suitable choice of the drug-carrier system.

  18. Immunomodulatory activity of 3beta,6beta-dihydroxyolean-12-en-27-oic acid in tumor-bearing mice.

    PubMed

    Deng, Wen; Sun, Hong-Xiang; Chen, Feng-Yang; Yao, Min-Li

    2009-08-01

    3beta,6beta-dihydroxyolean-12-en-27-oic acid (1) is a pentacyclic triterpenoid isolated from the rhizomes of Astilbe chinensis. To evaluate the in vivo antitumor potential and to elucidate its immunological mechanisms, effect of 1 on the growth of mouse-transplantable tumors, and the immune response in naive and tumor-bearing mice were investigated. The mice inoculated with mouse tumor cell lines were orally treated with 1 at the doses of 40, 60, and 80 mg/kg for 10 days. The effects of 1 on the growth of mouse-transplantable S180 sarcoma and H22 hepatoma, splenocyte proliferation, cytotoxic T lymphocyte (CTL) activity, natural killer (NK) cell activity, and production of interleukin-2 (IL-2) from splenocytes in S180-bearing mice were measured. Furthermore, the effect of 1 on 2,4-dinitrofluorobenzene (DNFB)-induced delayed-type hypersensitivity (DTH) reactions and the sheep red blood cell (SRBC)-induced antibody response in naive mice were also studied. Compound 1 could not only significantly inhibit the growth of mouse transplantable S180 sarcoma and H22 hepatoma, increase splenocytes proliferation, CTL and NK cell activity, and the level of IL-2 secreted by splenocytes in tumor-bearing mice, but also remarkably promote the DTH reaction and enhance anti-SRBC antibody titers in naive mice. These results suggested that 1 could improve both cellular and humoral immune response, and could act as antitumor agent with immunomodulatory activity.

  19. 1H-NMR METABONOMICS ANALYSIS OF SERA DIFFERENTIATES BETWEEN MAMMARY TUMOR-BEARING MICE AND HEALTHY CONTROLS

    EPA Science Inventory

    Global analysis of 1H-NMR spectra of serum is an appealing approach for the rapid detection of cancer. To evaluate the usefulness of this method in distinguishing between mammary tumor-bearing mice and healthy controls, we conducted 1H-NMR metabonomic analyses on serum samples ob...

  20. Sister chromatid exchanges and chromosome aberrations induced by radiosensitizing agents in bone marrow cells of treated tumor-bearing mice

    SciTech Connect

    Banerjee, R.; Goldfeder, A.; Mitra, J.

    1983-03-01

    The frequency of sister chromatid exchanges (SCE) in vivo and chromosome aberrations and/or alterations were analyzed from the bone marrow cells of the treated dbrB tumor-bearing DBA/1J inbred mouse host. The results were compared with analogous data obtained from the bone marrow cells of untreated tumor-bearing mice for evaluation of the ''indirect,'' i.e., somatic stress, effect on the normal host cells following triple-agent therapy intended for a mammary adenocarcinoma. Misonidazole (MIS), which is a known radiosensitizing drug, microwave hyperthermia (delta), and X-radiation (X) were used as therapeutic agents. Significant (P less than 0.05) numbers of SCE were induced in the bone marrow cells of the mice whose tumors received these triple-agent treatments (MIS + delta + X) simultaneously as compared with values of SCE per cell noted in bone marrow cells of untreated tumor-bearing control mice. The highest number of chromosome aberrations and alterations, including an increase in heteroploidy, was also noticed in the bone marrow cells of the mice whose tumors were treated simultaneously with MIS + delta + X. The triple-agent therapy on dbrB tumor also resulted in an unusually high polyploid metaphase plate in the bone marrow cell consisting of 320 chromosomes, indicating that this mode of therapy may act directly on the genetic material of the tumor-bearing host cells, inducing cytogenetic abnormalities as a side effect.

  1. 1H-NMR METABONOMICS ANALYSIS OF SERA DIFFERENTIATES BETWEEN MAMMARY TUMOR-BEARING MICE AND HEALTHY CONTROLS

    EPA Science Inventory

    Global analysis of 1H-NMR spectra of serum is an appealing approach for the rapid detection of cancer. To evaluate the usefulness of this method in distinguishing between mammary tumor-bearing mice and healthy controls, we conducted 1H-NMR metabonomic analyses on serum samples ob...

  2. Proliferative actions of muscarinic receptors expressed in macrophages derived from normal and tumor bearing mice.

    PubMed

    de la Torre, Eulalia; Genaro, Ana M; Ribeiro, María L; Pagotto, Romina; Pignataro, Omar P; Sales, María E

    2008-02-01

    Macrophages (Mps) are essential cellular components of the innate immune system. They are released from the bone marrow as immature monocytes and after circulating in the blood stream, migrate into tissues to undergo final differentiation into resident Mps. In general terms Mps behavior in breast tumors, was described as being either for or against tumor growth. Under certain well defined circumstances Mps are able to kill cells in two ways: direct tumor cytotoxicity or antibody dependent cytotoxicity. We had previously demonstrated that peritoneal Mps from LMM3 mammary tumor bearing mice (TMps) enhanced in vivo the LMM3 induced angiogenesis, promoting tumor growth while Mps from normal BALB/c mice (NMps) did not. In this work, we demonstrate that Mps, expressing functional muscarinic acetylcholine receptors, are able to proliferate in vitro in response to the muscarinic agonist carbachol. These peritoneal cells use two distinct metabolic pathways: TMps are primed by tumor presence and they proliferate mainly by activating arginase pathway and by producing high levels of prostaglandin E(2) via M(1)-M(3) receptors activation. In NMps, carbachol stimulates M(2) receptors function, triggering protein kinase C activity and induces moderate prostaglandin E(2) liberation via M(1) receptor.

  3. Pharmacokinetics and therapeutics of sterically stabilized liposomes in mice bearing C-26 colon carcinoma.

    PubMed

    Huang, S K; Mayhew, E; Gilani, S; Lasic, D D; Martin, F J; Papahadjopoulos, D

    1992-12-15

    Three different liposome types were compared for blood clearance and tissue uptake in mice bearing C-26 colon carcinoma growing either s.c. or in liver. Therapeutic experiments were performed with the liposome preparation showing the highest tumor uptake. Liposomes were composed of solid-phase phosphatidylcholine, either distearoyl phosphatidylcholine or hydrogenated soy phosphatidylcholine, and cholesterol at a 2:1 molar ratio. These liposomes were compared with similar but sterically stabilized liposomes (SL) which, in addition, contained either GM1 ganglioside or phosphatidylethanolamine derivatized with poly(ethylene glycol). Pharmacokinetic analysis of drug disposition was based on the areas under the curve for liposome-entrapped 67Ga uptake per gram of tissue up to 96 h following i.v. injection. The highest tissue area under the curve values with both liposome types were obtained in spleen, liver, and tumor. However, the sterically stabilized liposomes gave an area under the curve value 2-3-fold higher in the s.c. tumor and about 2-fold lower in liver and spleen. The therapeutic efficacy of doxorubicin (DOX) and epirubicin (EPI) encapsulated in poly(ethylene glycol)-derivatized phosphatidylethanolamine-containing liposomes was compared with that of free drug at two doses, 6 and 9 (or 10) mg/kg animal weight. Liposomes containing drug were injected either as a single dose, at different times following tumor implantation, or as three weekly doses starting 10 days after implantation. When injected as a single dose, liposome-encapsulated DOX had the maximal effect on tumor growth when injected 6 to 9 days after tumor implantation. When injected as three weekly doses, with treatment starting with a delay of 10 days, tumors which had grown to a size of approximately 0.05-0.1 cm3 regressed in groups of animals treated with either liposome-encapsulated drug (SL-DOX or SL-EPI) but continued to grow unabated in untreated mice and in mice receiving either of the free

  4. Anticancer activity of cationic porphyrins in melanoma tumour-bearing mice and mechanistic in vitro studies

    PubMed Central

    2014-01-01

    Background Porphyrin TMPyP4 (P4) and its C14H28-alkyl derivative (C14) are G-quadruplex binders and singlet oxygen (1O2) generators. In contrast, TMPyP2 (P2) produces 1O2 but it is not a G-quadruplex binder. As their photosensitizing activity is currently undefined, we report in this study their efficacy against a melanoma skin tumour and describe an in vitro mechanistic study which gives insights into their anticancer activity. Methods Uptake and antiproliferative activity of photoactivated P2, P4 and C14 have been investigated in murine melanoma B78-H1 cells by FACS, clonogenic and migration assays. Apoptosis was investigated by PARP-1 cleavage and annexin-propidium iodide assays. Biodistribution and in vivo anticancer activity were tested in melanoma tumour-bearing mice. Porphyrin binding and photocleavage of G-rich mRNA regions were investigated by electrophoresis and RT-PCR. Porphyrin effect on ERK pathway was explored by Western blots. Results Thanks to its higher lipophylicity C14 was taken up by murine melanoma B78-H1 cells up to 30-fold more efficiently than P4. When photoactivated (7.2 J/cm2) in B78-H1 melanoma cells, P4 and C14, but not control P2, caused a strong inhibition of metabolic activity, clonogenic growth and cell migration. Biodistribution studies on melanoma tumour-bearing mice showed that P4 and C14 localize in the tumour. Upon irradiation (660 nm, 193 J/cm2), P4 and C14 retarded tumour growth and increased the median survival time of the treated mice by ~50% (P <0.01 by ANOVA), whereas porphyrin P2 did not. The light-dependent mechanism mediated by P4 and C14 is likely due to the binding to and photocleavage of G-rich quadruplex-forming sequences within the 5′-untranslated regions of the mitogenic ras genes. This causes a decrease of RAS protein and inhibition of downstream ERK pathway, which stimulates proliferation. Annexin V/propidium iodide and PARP-1 cleavage assays showed that the porphyrins arrested tumour growth by apoptosis

  5. [Study on biodistribution and imaging of radioiodinated antisense oligonucleotides in nude mice bearing human lymphoma].

    PubMed

    Shen, Jing; Wang, Rong-fu; Zhang, Chun-li; Liu, Meng; Guo, Feng-qin

    2004-12-01

    To investigate the possibility of using radioiodine labeled framework region (FR) antisense oligonucleotides (ASONs) as an imaging agent or antisense therapeutic radiopharmaceutical in lymphoma. A 18-mer partial phosphorothioate oligonucleotide sequence was synthesized and grafted in 5' with a tyramine group which was further radioiodinated. Radioiodination of the tyramine derivatized oligonucleotides was performed using the chloramine T method. (1) Normal CD-1 mice were injected via a tail vein with 148 kBq (125)I-FR-ASON (2-3 microg). Animals were sacrificed at the end of 1, 2, 4 and 24 h, and tissue samples were studied.(2) Liposome-mediated 3.33 MBq (131)I-FR-ASON (7-9 microg) were injected intratumorally into tumor-bearing BALB/c mice (6 weeks after inoculation of 107 Namalwa cells) meanwhile liposome-mediated (131)I labeled sense oligonucleotides served as controls. Biodistribution was monitored by sequential scintigraphy and organ radioactivity measurement 24 h after injection. Percentage of the injected dose per gram of tumor and tumor/non-tumor tissue ratios (T/NT) were calculated for each group of mice and the difference between two groups was assessed. The 5' tyramine group allowed specific and stable radiolabeling of the ASON with radioiodine. The radioactivity reached its peak 1 h after injection, and then decreased rapidly in normal mice after intravenous administration of (125)I-FR-ASON. The liver, stomach and intestine played an important role in biodistribution and radioactivity counts were low in bone, brain and blood. When (131)I-FR-ASON was injected intratumorally into mice grafted with Namalwa cell line, images showed the tracer accumulated in the tumor. Immediately after intratumoral administration, only the tumor was visible. Scintiscans performed at the end of 1 and 2 h showed elimination of the tracer from the tumor to the abdomen and at the end of 24 h the tumor was clearly seen. Percentage of the injected dose per gram of tumor and T

  6. A study on the antitumour effect of total flavonoids from Pteris multifida Poir in H22 tumour-bearing mice.

    PubMed

    Yu, Canqiu; Chen, Jinwei; Huang, Li

    2013-01-01

    The objective of this paper was to investigate the inhibitory effect of total flavonoids from Pteris multifida Poir on growth of transplanted H22 tumour in mice. H22 tumour-bearing mice model was established; the experimental animals were divide/d into the model group, Pteris multifida Poir total flavonoids high-, low-dose groups, and CTX group. Pteris multifida Poir groups were administered continuously for 10d, and CTX group was administered every other day. Tumour inhibition rate, thymus index and spleen index were calculated. Serum levels of TNF-α and IL-2 were determined, as well as total antioxidant capacity (T-AOC) and malondialdehyde (MDA) levels in serum. Compared with the model group, the total flavonoids of Pteris multifida Poir can significantly inhibit tumour growth, with tumour inhibition rates of high-and low-dose groups 49.36% and 33.97%, respectively. They can also evidently increase the spleen and thymus indices of tumour-bearing mice, elevate serum TNF-α and IL-2 levels increase serum T-AOC level and reduce serum MDA level in tumour-bearing mice. The study concluded that total flavonoids from Pteris multifida Poir has an obvious inhibitory effect on transplanted H22 tumours; its mechanism of action may be associated with the improvement of immune function and enhancement of antioxidant capacity in mice.

  7. MicroRNA-2 suppresses Lewis lung cancer cells proliferation, invasion, and migration in tumor-bearing mice.

    PubMed

    Wang, Xu; Wang, Ping-fan; Yuan, Wu-ying

    2014-12-01

    We sought to find the biological effects of MicroRNA-2 in suppressing Lewis lung cancer cells proliferation, invasion, and migration in tumor-bearing mice. MicroRNA-2 was transfected into Lewis lung cancer cells of tumor-bearing mice by gene transient transfection technique and these Lewis-microRNA-2 cells were taken as MicroRNA transfection group. At the same time, Lewis cells were taken as control group and Lewis-EGFP cells as empty plasmid group. The growth curves of cells in the three groups were drawn by manual counting method, while the invasiveness of cells in the three groups was compared by transmembrane cell invasion assay. The three kinds of cells were seeded into BALB/Nude SPF level nude mice to detect the formation of tumors and the number of metastases by Xenograft experiments. The result showed that the MicroRNA transfection group has the lowest vitality of cells proliferation, fewest cells passed through matrigel matrix protein layer, and lowest cells invasive rate. Mice with Lewis-microRNA-2 cells apparently had a longer time of tumor formation. The average tumor mass and the number of metastases were significantly lower than the other two groups. MicroRNA-2 significantly inhibited Lewis lung cancer cell proliferation, invasion and migration in tumor-bearing mice, which may be associated with the regulation of target genes PLK1 and TGF-β.

  8. Food intake, tumor growth, and weight loss in EP2 receptor subtype knockout mice bearing PGE2-producing tumors

    PubMed Central

    Iresjö, Britt-Marie; Wang, Wenhua; Nilsberth, Camilla; Andersson, Marianne; Lönnroth, Christina; Smedh, Ulrika

    2015-01-01

    Previous studies in our laboratory have demonstrated that prostaglandin (PG) E2 is involved in anorexia/cachexia development in MCG 101 tumor-bearing mice. In the present study, we investigate the role of PGE receptor subtype EP2 in the development of anorexia after MCG 101 implantation in wild-type (EP2+/+) or EP2-receptor knockout (EP2−/−) mice. Our results showed that host absence of EP2 receptors attenuated tumor growth and development of anorexia in tumor-bearing EP2 knockout mice compared to tumor-bearing wild-type animals. Microarray profiling of the hypothalamus revealed a relative twofold change in expression of around 35 genes including mRNA transcripts coding for Phospholipase A2 and Prostaglandin D2 synthase (Ptgds) in EP2 receptor knockout mice compared to wild-type mice. Prostaglandin D2 synthase levels were increased significantly in EP2 receptor knockouts, suggesting that improved food intake may depend on altered balance of prostaglandin production in hypothalamus since PGE2 and PGD2 display opposing effects in feeding control. PMID:26197930

  9. Avidin chase reduces side effects of radioimmunotherapy in nude mice bearing human colon carcinoma

    PubMed Central

    Li, Gui-Ping; Wang, Yong-Xian; Huang, Kai; Zhang, Hui; Zhang, Chun-Fu

    2005-01-01

    AIM: To evaluate the influence of avidin chase on the side effects of radioimmunotherapy (RIT) in nude mice bearing human colon carcinoma and therapeutic outcome. METHODS: Purified anti-CEA monoclonal antibody (McAb) was biotinylated with NHS-biotin, and then radiolabeled with 188Re by the direct method. 188Re-labeled biotinylated anti-CEA McAb (188Re-CEA McAb-Bt) was intravenously injected followed by intravenous injection of avidin after 24 h. SPECT imaging and biodistribution study were performed at 28-48 h after the injection of 188Re-CEA McAb-Bt. Three groups of nude mice subcutaneously grafted with human colon carcinoma were treated 7 d after the graft. Mice in the avidin chase group received intravenous injection of 188Re-CEA McAb-Bt (11.1 MBq/20 μg) followed by intravenous injection of cold avidin (80 μg) after 24 h. Mice in the control group (treated group without avidin chase) only received the injection of 188Re-CEA McAb-Bt (11.1 MBq/20 μg), another control group (non-treated group) only received 0.1 mL normal saline solution. Toxicity was evaluated on the basis of change of body weight and peripheral WBC counts, and therapy effects were determined by variation in tumor volume. Histological analysis of tumors was also performed. RESULTS: Avidin chase markedly accelerated the clearance of 188Re-CEA McAb-Bt from the blood and normal tissues. The tumor uptakes of 188Re-CEA McAb-Bt at 28 h were 5.90 and 6.42% ID/g, respectively, in chase group and in non-chase group, while the tumor-to-background (T/NT) ratios were 3.19 and 0.56, respectively. The tumor uptake was slightly decreased by avidin chase, but the T/NT ratios were increased. In treated groups the growth rate of body weight and the number of WBC decreased after injection of 188Re-CEA McAb-Bt, and the WBC counts recovered earlier in the group with avidin chase than in the group without avidin chase. Compared to the non-treated group, treated groups with and without avidin chase showed significant

  10. Five Stabilized 111In-labeled neurotensin analogs in nude mice bearing HT29 tumors.

    PubMed

    Janssen, Paul J J M; de Visser, Moniaue; Verwijnen, Suzanne M; Bernard, Bert F; Srinivasan, Ananth; Erion, Jack L; Breeman, Wouter A P; Vulto, Arnold G; Krenning, Eric P; de Jong, Marion

    2007-06-01

    Neurotensin (NT) receptors are overexpressed in different human tumors, such as human ductal pancreatic adenocarcinoma. New stable neurotensin analogs with high receptor affinity have been synthesized by replacing arginine residues with lysine and arginine derivatives. The aim of this study was to explore the biodistribution, tumor uptake, kidney localization, and stability characteristics of these new analogs in order to develop new diagnostic tools for exocrine pancreatic cancer. Four (111)In-labeled DTPA-chelated NT analogs and one (111)In-labeled DOTA-chelated NT analog were evaluated in NMRI nude mice bearing NT receptor-positive HT29 tumors. Experiments with a coinjection of unlabeled NT or lysine were performed to investigate receptor-mediated uptake and kidney protection, respectively. In addition, the in vivo serum stability of the most promising analog was analyzed. In the biodistribution study in mice, at 4 hours postinjection, a low percentage of the injected dose per gram (%ID/g) of tissue for all compounds was found in NT receptor-negative organs, such as the blood, spleen, pancreas, liver, muscle, and femur. A high uptake was found in the colon, intestine, kidneys, and in implanted HT29 tumors. The coinjection of excess unlabeled neurotensin significantly reduced tumor uptake, showing tumor uptake to be receptor-mediated. To a lesser extent, this was also observed for the colon, but not for other tissues. We concluded that DTPA-(Pip)Gly-Pro-(PipAm)Gly-Arg-Pro-Tyr-tBuGly-Leu-OH and the DOTA-linked counterpart have the most favorable biodistribution properties regarding tumor uptake.

  11. Delivery of methoxymorpholinyl doxorubicin by interleukin 2-activated NK cells: effect in mice bearing hepatic metastases

    PubMed Central

    Quintieri, L; Rosato, A; Amboldi, N; Vizler, C; Ballinari, D; Zanovello, P; Collavo, D

    1999-01-01

    The possibility of using interleukin 2 (IL-2)-activated natural killer cells (A-NK) to carry methoxymorpholinyl doxorubicin (MMDX; PNU 152243) to liver-infiltrating tumours was explored in mice bearing 2-day established M5076 reticulum cell sarcoma hepatic metastases. In vitro, MMDX was 5.5-fold more potent than doxorubicin against M5076 tumour cells. MMDX uptake by A-NK cells correlated linearly with drug concentration in the incubation medium [correlation coefficient (r) = 0.999]; furthermore, as MMDX incorporation was readily reproducible in different experiments, the amount of drug delivered by A-NK cells could be modulated. In vivo experiments showed that intravenous (i.v.) injection of MMDX-loaded A-NK cells exerted a greater therapeutic effect than equivalent or even higher doses of free drug. The increase in lifespan (ILS) following A-NK cell delivery of 53 μg kg−1 MMDX, a dosage that is ineffective when administered in free form, was similar to that observed in response to 92 μg kg−1 free drug, a dosage close to the 10% lethal dose (ILS 42% vs. 38% respectively). These results correlated with pharmacokinetic studies showing that MMDX encapsulation in A-NK cells strongly modifies its organ distribution and targets it to tissues in which IL-2 activated lymphocytes are preferentially entrapped after i.v. injection. © 1999 Cancer Research Campaign PMID:10098738

  12. Citrus unshiu peel extract alleviates cancer-induced weight loss in mice bearing CT-26 adenocarcinoma

    PubMed Central

    Kim, Aeyung; Im, Minju; Gu, Min Jung; Ma, Jin Yeul

    2016-01-01

    Skeletal muscle atrophy is a critical feature of cancer-induced cachexia, caused by pro-cachectic factors secreted by host cells and tumor cells. Therefore, blockade of these factors has considered a reasonable target for pharmacological and nutritional interventions to prevent skeletal muscle loss under cancer-induced cachexia. Citrus unshiu peel (CUP) has been used for treating the common cold, dyspepsia, and bronchial discomfort and reported to have pharmacological activities against inflammation, allergy, diabetes, and viral infection. In the present study, we observed that daily oral administration of water extract of CUP (WCUP) to male BALB/c mice bearing CT-26 adenocarcinoma remarkably reduced the losses in final body weight, carcass weight, gastrocnemius muscle, epididymal adipose tissue, and hemoglobin (Hb), compared with saline treatment. The levels of serum IL-6 and muscle-specific E3 ligases elevated by tumor burden were also considerably reduced by WCUP administration. In an in vitro experiment, WCUP efficiently suppressed the production of pro-cachectic cytokines in immune cells as well as cancer cells. In addition, WCUP treatment attenuated C2C12 skeletal muscle cell atrophy caused by cancer cells. These findings collectively suggest that WCUP is beneficial as a nutritional supplement for the management of cancer patients with severe weight loss. PMID:27064118

  13. Citrus unshiu peel extract alleviates cancer-induced weight loss in mice bearing CT-26 adenocarcinoma.

    PubMed

    Kim, Aeyung; Im, Minju; Gu, Min Jung; Ma, Jin Yeul

    2016-04-11

    Skeletal muscle atrophy is a critical feature of cancer-induced cachexia, caused by pro-cachectic factors secreted by host cells and tumor cells. Therefore, blockade of these factors has considered a reasonable target for pharmacological and nutritional interventions to prevent skeletal muscle loss under cancer-induced cachexia. Citrus unshiu peel (CUP) has been used for treating the common cold, dyspepsia, and bronchial discomfort and reported to have pharmacological activities against inflammation, allergy, diabetes, and viral infection. In the present study, we observed that daily oral administration of water extract of CUP (WCUP) to male BALB/c mice bearing CT-26 adenocarcinoma remarkably reduced the losses in final body weight, carcass weight, gastrocnemius muscle, epididymal adipose tissue, and hemoglobin (Hb), compared with saline treatment. The levels of serum IL-6 and muscle-specific E3 ligases elevated by tumor burden were also considerably reduced by WCUP administration. In an in vitro experiment, WCUP efficiently suppressed the production of pro-cachectic cytokines in immune cells as well as cancer cells. In addition, WCUP treatment attenuated C2C12 skeletal muscle cell atrophy caused by cancer cells. These findings collectively suggest that WCUP is beneficial as a nutritional supplement for the management of cancer patients with severe weight loss.

  14. Hexamethylmelamine and pentamethylmelamine tissue distribution in M5076/73A ovarian cancer-bearing mice.

    PubMed

    Broggini, M; Rossi, C; Colombo, T; D'Incalci, M

    1982-01-01

    The distribution of hexamethylmelamine (HMM), pentamethylmelamine (PMM), and their metabolites N2,N2,N4,N6-tetramethylmelamine (TMM) and N2,N4,N6-trimethylmelamine (TriMM) was investigated in different tissues of M5076/73A ovarian cancer-bearing mice given 100 mg/kg ip of either drug. The area-under-the-curve (AUC) values of HMM and PMM, expressed in microgram/g x min after these drug treatments, were 2432 and 1296 in tumor, 6290 and 8141 in liver, 9779 and 21,294 in spleen, 6840 and 10,800 in kidney, 4003 and 4295 in heart, 1569 and 1327 in brain, 163,689 and 50,809 in adipose tissue, 88,725 and 45,070 in lymph nodes, 15,033 and 18,992 in small intestine, and 393 and 351 in plasma, respectively. The elimination rate of HMM for the different organs was similar, with a half-life of 37-48 mins; PMM disappeared with more variability, the half-life being 19-46 mins. While TMM concentrations were not very different from those of HMM or PMM, TriMM was much higher in all organs evaluated, particularly the brain, where AUC values were 21-24 times those of the administered drug.

  15. Therapeutic Effect of Astragalus Polysaccharides on Hepatocellular Carcinoma H22-Bearing Mice

    PubMed Central

    Lai, Xiaoyu; Xia, Weibiao; Wei, Jing

    2017-01-01

    The purpose of this study was to investigate the effect of astragalus polysaccharides (APSs), active constituents of astragalus, in the treatment of hepatocellular carcinoma (HCC) and their potential as a promising candidate for future anticancer drug development. Astragalus polysaccharide was administered at different doses to HCC H22-bearing mice to investigate their antitumor effects. Results revealed that APS inhibited the growth of H22 cells with a tumor inhibition rate in the APS 400 mg·kg−1 group of 59.01%. Astragalus polysaccharides significantly increased the spleen and thymus indexes, and also the interleukin (IL) 2, IL-6, and tumor necrosis factor α cytokine concentration in serum, indicating that APS influences immune-regulating properties involved in antitumor activity. In addition, APS increased Bax protein expression and decreased Bcl-2 protein expression; these proteins are apoptosis-regulating factors responsible for cell death or survival. Further development and exploration of APS may enable it to become an effective clinical agent for liver cancer therapy. PMID:28210201

  16. Biodegradable three-dimension micro-device delivering 5-fluorouracil in tumor bearing mice.

    PubMed

    Ren, Xiaojiao; Zheng, Na; Gao, Yang; Chen, Tianning; Lu, Wen

    2012-01-01

    A novel three-dimension micro-device was formulated to control delivery of 5-fluorouracil (5-FU) for the treatment of solid tumors. The poly-(lactic-co-glycolic) acid (PLGA), which is both biocompatible and biodegradable, was used as carrier material. The characteristics of drug release in vitro and in vivo and the performance of the micro-device after implantation in tumor bearing mice were evaluated. A constant release profile from in vitro test was obtained for a period of 7 days, and it correlated well with the in vivo release profile. In the distribution experiment of 5-FU micro-device, it was demonstrated that 5-FU remained in the tumor tissues for more than 7 days after implantation. Likewise, we found that the 5-FU concentration in tumor correlated well with the in vivo release. Tumors treated with 5-FU loaded micro-device of three different dosages showed significant tumor reduction (P < 0.05) compared with empty control micro-device 7 days after administration. Moreover, the implantation treatment showed enhanced efficacy compared with the intraperitoneal administration with the same dosage. These results suggested that the three-dimensional micro-device may provide a promising local and controlled release drug delivery system, which may enable delivery of multiple drugs for post-surgical chemotherapy against solid tumor.

  17. Excess iron undermined bone load-bearing capacity through tumor necrosis factor-α-dependent osteoclastic activation in mice.

    PubMed

    Li, Junping; Hou, Yanli; Zhang, Shuping; Ji, Hong; Rong, Haiqin; Qu, Guangbo; Liu, Sijin

    2013-01-01

    Iron overload has been associated with bone mass loss. To elucidate the effects of excess iron on bone metabolism, an iron-overloading mouse model was established by administering iron-dextran at 250 mg/kg to female BALB/c mice. After 4 weeks, the mice were sacrificed and the biomechanical properties of the femurs were examined. The results suggested a notable decrease of the maximal bending stress and the modulus of bending elasticity in the femurs obtained from the excess iron-treated mice compared to the control mice. The levels of the serum osteocalcin, C-telopeptide of type I collagen (CTX-1) and tumor necrosis factor-α (TNF-α) were measured in order to investigate the underlying mechanism responsible for the excess iron-induced bone strength reduction. Overall, the results suggested that iron overload resulted in a marked reduction of bone load-bearing capacity through a TNF-triggered osteoclast differentiation and resorption mechanism.

  18. Trichosanthes dioica root extract induces tumor proliferation and attenuation of antioxidant system in albino mice bearing Ehrlich ascites carcinoma

    PubMed Central

    Bhattacharya, Sanjib; Haldar, Pallab Kanti

    2011-01-01

    Trichosanthes dioica Roxb. (Cucurbitaceae), called pointed gourd in English, is a dioecious climber grown widely in the Indian subcontinent. The present study assessed the influence of treatment of hydroalcoholic extract of Trichosanthes dioica root (TDA) on Ehrlich ascites carcinoma (EAC) in Swiss albino mice with effects on antioxidant systems. Twenty-four hours after intraperitoneal inoculation of tumor (EAC) cells in mice, TDA was administered at 25 and 50 mg/kg for 8 consecutive days. On the 9th day, half of the mice were sacrificed for estimation of tumor proliferation, hematological, and hepatic antioxidative parameters. The rest were kept for assessment of survival parameters. TDA exhibited dose dependent and significant increase in tumor weight, tumor volume, packed cell volume and viable cells and reduced non-viable cells and life span of EAC bearing animals. Hematological parameters were significantly worsened in TDA-treated mice. TDA treatment significantly aggravated the hepatic antioxidative parameters. The present study demonstrated that T. dioica root possessed tumor promoting activity in EAC bearing albino mice, plausibly mediated by attenuation of endogenous antioxidant systems. PMID:22319252

  19. Anti-carcinogenic action of ellagic acid mediated via modulation of oxidative stress regulated genes in Dalton lymphoma bearing mice.

    PubMed

    Mishra, Sudha; Vinayak, Manjula

    2011-11-01

    An elevated level of reactive oxygen species (ROS) in a cancerous condition causes oxidative stress which in turn activates a number of genes, and therefore an interruption in the oxidative microenvironment should be able to inactivate these genes, contributing to cancer prevention. The present work was designed to evaluate the role of ellagic acid in the modulation of protein kinase Cα (PKCα) activity and expression and its correlation with the oncogene, c-Myc, and tumor suppressor gene, transforming growth factor-β (TGF-β1), in lymphoma bearing mice. We also evaluated its implication for cell viability. Our results show that ellagic acid leads to down-regulation of the expression and activity of PKCα via decreasing the oxidative stress, measured in terms of lipid peroxidation and protein carbonylation. It also reduces c-Myc expression and improves TGF-β1 expression besides decreasing cell viability in Dalton lymphoma bearing mice, which supports its anti-carcinogenic action.

  20. Role of macrophage migration inhibitory factor in the regulatory T cell response of tumor-bearing mice

    PubMed Central

    Choi, Susanna; Kim, Hang-Rae; Leng, Lin; Kang, Insoo; Jorgensen, William L.; Cho, Chul-Soo; Bucala, Richard; Kim, Wan-Uk

    2012-01-01

    Macrophage migration inhibitory factor (MIF) is involved in tumorigenesis by facilitating tumor proliferation and evasion of apoptosis; however, its role in tumor immunity is unclear. In this study, we investigated the effect of MIF on the progression of the syngenic, CT26 colon carcinoma and the generation of tumor regulatory T cells (Tregs). The results showed that the tumor growth rate was significantly lower in MIF knockout (MIF−/−) mice than in wild type (MIF+/+) mice. Flow cytometric analysis of both spleen and tumor cells revealed that MIF−/− mice had significantly lower levels of tumor-associated CD4+Tregs than MIF+/+ mice. The splenic cells of MIF−/− mice also showed a decrease in CD8+Tregs, which was accompanied by an increase in CD8-induced tumor cytotoxicity. Interestingly, the inducible Treg response in spleen cells to anti-CD3/CD28+IL-2+TGF-β was greater in MIF−/− mice than in MIF+/+ mice. Spleen cells of MIF−/− mice, stimulated with anti-CD3/CD28, produced lower levels of IL-2, but not TGF-β, than those of MIF+/+ mice, which was recovered by the addition of recombinant MIF. Conversely, a neutralizing anti-MIF Ab blocked anti-CD3-induced IL-2 production by splenocytes of MIF+/+ mice and suppressed the inducible Treg generation. Moreover, the administration of IL-2 into tumor-bearing MIF−/− mice restored the generation of Tregs and tumor growth. Taken together, our data suggest that MIF promotes tumor growth by increasing Tregs generation through the modulation of IL-2 production. Thus, anti-MIF treatment might be useful in enhancing the adaptive immune response to colon cancers. PMID:22972922

  1. Antitumor activity of a polysaccharide fraction from Laminaria japonica on U14 cervical carcinoma-bearing mice.

    PubMed

    Zhai, Qingzhi; Li, Xiuli; Yang, Yizhuo; Yu, Ling; Yao, Yuanqing

    2014-01-01

    In the present study, we investigated the in vitro and in vivo antitumor effects of a sulfated polysaccharide fraction from the brown alga Laminaria japonica (LJSP) on cervical carcinoma. In vitro, the results showed that LJSP exhibited the highest cell growth inhibitory effect on cervical carcinoma U14 cells among five tumor cell lines. In vivo, the results showed that LJSP could not only inhibit the growth of the tumor but also enhance the spleen and thymus indexes, as well as the body weight of U14 tumor-bearing mice. Moreover, the white blood cell count of H22 tumor-bearing mice showed no change in the LJSP-treated groups and little toxicological effects were observed on hepatic function and renal function in LJSP-treated mice bearing U14 tumor cells. Besides, LJSP induced apoptosis of transplanted tumor tissues by increasing the ratio of Bax/Bcl-2. These data showed that LJSP exhibited prominent antitumor activities and low toxic effects; thus, it could be developed to a safe and effective anticancer agent.

  2. Chemoprotective and chemosensitizing properties of selenium nanoparticle (Nano-Se) during adjuvant therapy with cyclophosphamide in tumor-bearing mice.

    PubMed

    Bhattacharjee, Arin; Basu, Abhishek; Biswas, Jaydip; Sen, Tuhinadri; Bhattacharya, Sudin

    2017-01-01

    Cyclophosphamide (CP) is one of the widely used anticancer agents; however, it has serious deleterious effects on normal host cells due to its nonspecific action. The essential trace element Selenium (Se) is suggested to have chemopreventive and chemotherapeutic efficacy and currently used in pharmaceutical formulations. Previous report had shown Nano-Se could protect CP-induced hepatotoxicity and genotoxicity in normal Swiss albino mice; however, its role in cancer management is still not clear. The aim of present study is to investigate the chemoprotective efficacy of Nano-Se against CP-induced toxicity as well as its chemoenhancing capability when used along with CP in Swiss albino mice against Ehrlich's ascites carcinoma (EAC) cells. CP was administered (25 mg/kg b.w., i.p.) and Nano-Se was given (2 mg Se/kg b.w., p.o.) in concomitant and pretreatment schedule. Increase levels of serum hepatic marker, hepatic lipid peroxidation, DNA damage, and chromosomal aberration in CP-treated mice were significantly (P < 0.05) reversed by Nano-Se. The lowered status of various antioxidant enzymes in tumor-bearing mice after CP treatment was also effectively increased by Nano-Se. Administration of Nano-Se along with CP caused a significant reduction in tumor volume, packed cell volume, viable tumor cell count, and increased the survivability of the tumor-bearing hosts. The results suggest that Nano-Se exhibits significant antitumor and antioxidant effects in EAC-bearing mice. The potential for Nano-Se to ameliorate the CP-evoked toxicity as well as to improve the chemotherapeutic effect could have beneficial implications for patients undergoing chemotherapy with CP.

  3. Antitumor activity in mice of orally administered polysaccharide from Kefir grain.

    PubMed

    Shiomi, M; Sasaki, K; Murofushi, M; Aibara, K

    1982-04-01

    The antitumor activity of a water-soluble polysaccharide (KGF-C), isolated from the Kefir grain, was studied in the mice subcutaneously inoculated with Ehrlich carcinoma (EC) or Sarcoma 180 (S-180). The growth of EC and S-180 solid tumor was inhibited by 40-59% and 21-81%, respectively, by oral administration of KGF-C as compared with the unadministered mice. The tumor growth was similarly inhibited by intraperitoneal administration. The mechanism of the antitumor activity of KGF-C was considered to be host-mediated because of the lack of direct in vitro effect on tumor cells.

  4. [Effects of primary tumor excision on angiogenesis and pulmonary metastasis in osteosarcoma-bearing nude mice].

    PubMed

    Mei, Jiong; Ni, Ming; Chen, Yan-xi; Yao, Bin; Gao, You-shui; Yu, Xiu-mao; Wang, Zhi-yuan

    2009-04-01

    To investigate the effects of primary tumor excision on osteosarcoma angiogenesis and pulmonary metastasis, and explore its possible mechanism and clinical significance. The tumor-bearing nude mice were constructed by injection of human osteosarcoma cell suspension, and divided into primary tumor resection, amputation and normal groups. The level of VEGF and endostatin was examined by ELISA assay. The hemoglobin content in Matrigel pellets was measured with HiCN method. Pulmonary metastasis was detected with dilated-squash technique and immunohistochemical staining. The serum VEGF and endostatin level was significantly decreased in the primary tumor excision group compared with that in the normal and control groups after operation, but endostatin decreased more prominently [VEGF: (71.43 +/- 9.15) pg/ml vs. (115.81 +/- 4.38) pg/ml, (111.68 +/- 12.26) pg/ml, P < 0.01; ES: (40.77 +/- 5.41) ng/ml vs. (123.18 +/- 5.94) ng/ml, (128.06 +/- 4.52) ng/ml, P < 0.01]. The HB contents in Matrigel pellets increased in the primary tumor excision group compared with that in normal and control groups [(36.55 +/- 2.35) g/L vs. (16.84 +/- 1.15) g/L, (16.29 +/- 1.10) g/L, P < 0.01]. The rate of pulmonary metastasis in tumor excision group was much higher than that in the un-excised groups (80.0% vs. 40.0% and 35.0%, P < 0.05). The excision of primary tumor can promote osteosarcoma angiogenesis and pulmonary metastasis, so anti-angiogenic treatment after operation has instructive clinical significance in preventing tumor metastasis.

  5. Antitumor activity of PEGylated nanoliposomes containing crocin in mice bearing C26 colon carcinoma.

    PubMed

    Rastgoo, Marziyeh; Hosseinzadeh, Hossein; Alavizadeh, Hoda; Abbasi, Azam; Ayati, Zahra; Jaafari, Mahmoud R

    2013-04-01

    Crocin is a pharmacologically active component of Crocus sativus. It is an unusual water-soluble carotenoid responsible for the red color of saffron. In various studies, the anticancer effect of saffron and its constituents has been established. Polyethylene glycolated nanoliposomes with a size range up to 200 nm are suitable for encapsulation of cytotoxic drugs and can target tumors passively through the enhanced permeation and retention effect. The aim of this study was to develop a nanoliposomal formulation containing crocin with a higher therapeutic index for the treatment of cancer. Four formulations of polyethylene glycolated nanoliposomes containing 25 mg/ml crocin were prepared with hydrogenated soy phosphatidylcholine, cholesterol, and methoxy-polyethylene glycol (MW 2000)-distearoylphosphatidylcholine at different molar ratios by a solvent evaporation method plus extrusion. Then the liposomes were characterized for their size, zeta potential, crocin encapsulation, release properties, and in vitro cytotoxicity against C26 colon carcinoma cells. Based on in vitro results, the best formulation was selected for an in vivo study, and its antitumor activity was evaluated in BALB/c mice bearing C26 colon carcinoma. The IC50 of crocin itself against C26 colon carcinoma was 0.73 mM. The characterization of the best formulation was as follow: Z-average size: 127.6 ± 1.5 nm; polydispersity index: 0.087 ± 0.018; zeta potential: - 21.7 mV ± 6.7; % encapsulation: 84.62 ± 0.59; % release after 168 hours in RPMI 1640 containing 30 % FBS: 16.26 ± 0.01 %. Liposomal crocin at doses of 50 and 100 mg/kg significantly decreased tumor size and increased survival rate compared with PBS and crocin in buffer (100 mg/kg) groups. The results of this study indicated that liposomal encapsulation of crocin could increase its antitumorigenic activity. Thus, to obtain an optimal dose for use in humans, the formulation merits further investigation.

  6. Compact whole-body fluorescent imaging of nude mice bearing EGFP expressing tumor

    NASA Astrophysics Data System (ADS)

    Chen, Yanping; Xiong, Tao; Chu, Jun; Yu, Li; Zeng, Shaoqun; Luo, Qingming

    2005-01-01

    Issue of tumor has been a hotspot of current medicine. It is important for tumor research to detect tumors bearing in animal models easily, fast, repetitively and noninvasivly. Many researchers have paid their increasing interests on the detecting. Some contrast agents, such as green fluorescent protein (GFP) and Discosoma red fluorescent protein (Dsred) were applied to enhance image quality. Three main kinds of imaging scheme were adopted to visualize fluorescent protein expressing tumors in vivo. These schemes based on fluorescence stereo microscope, cooled charge-coupled-device (CCD) or camera as imaging set, and laser or mercury lamp as excitation light source. Fluorescence stereo microscope, laser and cooled CCD are expensive to many institutes. The authors set up an inexpensive compact whole-body fluorescent imaging tool, which consisted of a Kodak digital camera (model DC290), fluorescence filters(B and G2;HB Optical, Shenyang, Liaoning, P.R. China) and a mercury 50-W lamp power supply (U-LH50HG;Olympus Optical, Japan) as excitation light source. The EGFP was excited directly by mercury lamp with D455/70 nm band-pass filter and fluorescence was recorded by digital camera with 520nm long-pass filter. By this easy operation tool, the authors imaged, in real time, fluorescent tumors growing in live mice. The imaging system is external and noninvasive. For half a year our experiments suggested the imaging scheme was feasible. Whole-body fluorescence optical imaging for fluorescent expressing tumors in nude mouse is an ideal tool for antitumor, antimetastatic, and antiangiogenesis drug screening.

  7. [Studies on the absorption, excretion and distribution of aclacinomycin A: absorption, excretion and distribution of 14C- or 3H-aclacinomycin A in mice, rats and rabbits (author's transl)].

    PubMed

    Iguchi, H; Seryu, Y; Kiyosaki, T; Hori, S; Tone, H; Oki, T

    1980-02-01

    A new anthracycline antitumor antibiotic, aclacinomycin A, was labeled with 3H uniformly or with 14C simultaneously at the anthracycline nucleus and L-rhodosamine. These labeled drugs were administered intravenously to normal dd mice, solid type Sarcoma 180 tumor-bearing ICR mice, normal or pregnant Wistar rats and normal rabbits, respectively. 14C-Aclacinomycin A given to rabbits (5 mg/kg) was rapidly cleared from the blood and transferred to tissues. But low level of radioactivity (equivalent to about 0.5 mcg/ml) was remained in the blood even 8 approximately 10 hours after administration. About 45% of the radioactivity were recovered from the urine and 20% from the feces by 72 hours after administration. Tissue levels of 3H-14C-aclacinomycin A given to normal and tumor-bearing mice were highest in the lungs and spleen. Higher distribution was observed also in the liver and kidneys 2 hours after administration. Bioassay revealed that the drug was present in the lungs and spleen in biologically active form and in the liver and kidneys in inactive form, respectively. In the tumor tissue the radioactivity was low but it persisted for 48 hours. Autoradiography with 14C-aclacinomycin A in rats demonstrated that radioactivity due to the drug distributed in the lungs, spleen, kidneys, thymus, intestine, lymph nodes, bone marrow, salivary gland, hypophysis and pineal body but it was rapidly cleared. About 0.2% of radioactivity given to a pregnant rat were transferred to a fetus when 14C-aclacinomycin A was administered intravenously on the 18 approximately 19th day of pregnancy.

  8. Evaluation of the biochemical effects of CHIP in normal and tumour-bearing C3H mice.

    PubMed Central

    Laverick, M.; Gordon, M.; Kind, P. R.; Slavin, B. M.; Nias, A. H.

    1986-01-01

    The biochemical effects of CHIP have been studied in C3H mice with and without transplanted mammary tumour. The maximum tolerated dose of CHIP was first determined by lethality and intestinal crypt assays to be 40 mg kg-1 and this dose was used to assay the time course of gastric distension and the pattern of drug distribution. A high level of CHIP uptake was found in liver as well as kidney. For this reason, tests for both kidney and liver damage were undertaken up to 60 days post-treatment using a dose of 10 mg kg-1 Neoplatin for comparison. Despite the high level of platinum drug uptake in liver, there was no biochemical evidence of hepatocellular or cholestatic damage. From the renal point of view, there was the expected rise in serum urea after Neoplatin but not after CHIP and there was also a rise in urinary NAG after Neoplatin in tumour bearing mice. There was, however, evidence of suppression of protein levels including enzymes, following treatment with both drugs. Tumour-bearing mice respond differently from normal mice following treatment with platinum drugs. The study confirms that CHIP is less toxic than Neoplatin. PMID:3718829

  9. Disposition of 1,4,6,8-tetramethyl-furoquinolinone in normal and ascitic tumor bearing mice.

    PubMed

    Bevilacqua, Rita; Baccichetti, Francarosa; Gaion, Rosa Maria; Guiotto, Adriano

    2006-01-01

    1,4,6,8-Tetramethyl-2H-furo[2,3h]quinolin-2-one (FQ) belongs to a series of furocoumarin isosters, designed to obtain new drugs for photochemotherapy. The objective of this study was to characterize the disposition of orally administered 3H-FQ in normal and ascitic tumor bearing mice and to evaluate the influence of UVA irradiation in control mice. This compound was rapidly absorbed and its decay in serum was biphasic. Binding to serum proteins, which was maximum at 30 min (74 %), time-dependently declined. FQ was distributed to all the studied tissues, primarily to the liver and kidneys. The administered radioactivity was excreted mostly in the urine (43 %) and was associated with polar metabolites. The unchanged compound was not present to any detectable extent in the urine. Elimination in the faeces, that may include FQ not absorbed, was low (14 % of administered radioactivity), emphasizing the quantitatively efficient gastrointestinal absorption of the drug. UVA irradiation of FQ-treated mice for 2 h caused a significant increase in radioactivity measured in serum as well as in the liver. In mice bearing Ehrlich ascitic tumor, serum and tissue concentrations were lower than in control animals, possibly due to the larger volume of body fluids (10+/-4 ml of ascitic fluid) available for drug distribution.

  10. Effect of interleukin-2 treatment combined with magnetic fluid hyperthermia on Lewis lung cancer-bearing mice.

    PubMed

    Hu, Runlei; Ma, Shenglin; Ke, Xianfu; Jiang, Hong; Wei, Dongshan; Wang, Wei

    2016-01-01

    The present study aimed to investigate the therapeutic effect of interleukin-2 (IL-2) treatment combined with magnetic fluid hyperthermia (MFH) on Lewis lung cancer-bearing mice. Magnetic fluids were prepared in vitro and directly injected into the tumors in the mice, which were subjected to an alternating magnetic field. The temperature in the tumor reached 43°C and was maintained by controlling the strength of magnetic field for 30 min. Twenty-four hours later, IL-2 was injected directly into the tumors. Mice were divided into four groups: Group I (control), II (MFH), III (IL-2) and IV (IL-2+MFH). The tumor grew gradually in groups II and IV (both P<0.05) compared to the control group. Histological analysis showed that the tumor cells underwent apoptosis and necrosis. Immunohistochemistry results demonstrated that heat-shock protein 70 and cluster of differentiation (CD) 8-positive and CD4-positive T cells were strongly expressed following hypothermia. Therefore, the present study provided evidence that IL-2 treatment combined with MFH improves the therapeutic effect on lung cancer-bearing mice.

  11. Boron neutron capture therapy demonstrated in mice bearing EMT6 tumors following selective delivery of boron by rationally designed liposomes

    PubMed Central

    Kueffer, Peter J.; Maitz, Charles A.; Khan, Aslam A.; Schuster, Seth A.; Shlyakhtina, Natalia I.; Jalisatgi, Satish S.; Brockman, John D.; Nigg, David W.; Hawthorne, M. Frederick

    2013-01-01

    The application of boron neutron capture therapy (BNCT) following liposomal delivery of a 10B-enriched polyhedral borane and a carborane against mouse mammary adenocarcinoma solid tumors was investigated. Unilamellar liposomes with a mean diameter of 134 nm or less, composed of an equimolar mixture of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine and incorporating Na3[1-(2′-B10H9)-2-NH3B10H8] in the aqueous interior and K[nido-7-CH3(CH2)15-7,8-C2B9H11] in the bilayer, were injected into the tail veins of female BALB/c mice bearing right flank EMT6 tumors. Biodistribution studies indicated that two identical injections given 24 h apart resulted in tumor boron levels exceeding 67 µg/g tumor at 54 h—with tumor/blood boron ratios being greatest at 96 h (5.68:1; 43 µg boron/g tumor)—following the initial injection. For BNCT experiments, tumor-bearing mice were irradiated 54 h after the initial injection for 30 min with thermal neutrons, resulting in a total fluence of 1.6 × 1012 neutrons per cm2 (±7%). Significant suppression of tumor growth was observed in mice given BNCT vs. control mice (only 424% increase in tumor volume at 14 d post irradiation vs. 1551% in untreated controls). In a separate experiment in which mice were given a second injection/irradiation treatment 7 d after the first, the tumor growth was vastly diminished (186% tumor volume increase at 14 d). A similar response was obtained for mice irradiated for 60 min (169% increase at 14 d), suggesting that neutron fluence was the limiting factor controlling BNCT efficacy in this study. PMID:23536304

  12. Boron neutron capture therapy demonstrated in mice bearing EMT6 tumors following selective delivery of boron by rationally designed liposomes.

    PubMed

    Kueffer, Peter J; Maitz, Charles A; Khan, Aslam A; Schuster, Seth A; Shlyakhtina, Natalia I; Jalisatgi, Satish S; Brockman, John D; Nigg, David W; Hawthorne, M Frederick

    2013-04-16

    The application of boron neutron capture therapy (BNCT) following liposomal delivery of a (10)B-enriched polyhedral borane and a carborane against mouse mammary adenocarcinoma solid tumors was investigated. Unilamellar liposomes with a mean diameter of 134 nm or less, composed of an equimolar mixture of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine and incorporating Na3[1-(2'-B10H9)-2-NH3B10H8] in the aqueous interior and K[nido-7-CH3(CH2)15-7,8-C2B9H11] in the bilayer, were injected into the tail veins of female BALB/c mice bearing right flank EMT6 tumors. Biodistribution studies indicated that two identical injections given 24 h apart resulted in tumor boron levels exceeding 67 µg/g tumor at 54 h--with tumor/blood boron ratios being greatest at 96 h (5.68:1; 43 µg boron/g tumor)--following the initial injection. For BNCT experiments, tumor-bearing mice were irradiated 54 h after the initial injection for 30 min with thermal neutrons, resulting in a total fluence of 1.6 × 10(12) neutrons per cm(2) (±7%). Significant suppression of tumor growth was observed in mice given BNCT vs. control mice (only 424% increase in tumor volume at 14 d post irradiation vs. 1551% in untreated controls). In a separate experiment in which mice were given a second injection/irradiation treatment 7 d after the first, the tumor growth was vastly diminished (186% tumor volume increase at 14 d). A similar response was obtained for mice irradiated for 60 min (169% increase at 14 d), suggesting that neutron fluence was the limiting factor controlling BNCT efficacy in this study.

  13. Boswellic acids synergize antitumor activity and protect against the cardiotoxicity of doxorubicin in mice bearing Ehrlich's carcinoma.

    PubMed

    Ali, Shimaa A; Zaitone, Sawsan A; Moustafa, Yasser M

    2015-08-01

    This study aimed to test whether boswellic acids add to the antitumor effects of doxorubicin against solid tumors of Ehrlich's ascites carcinoma (EAC) grown in mice, and to investigate the protective effects of boswellic acids against doxorubicin-induced cardiotoxicity. Sixty-four female Swiss albino mice bearing EAC solid tumors were distributed among 8 groups as follows: group 1, EAC control group; group 2, doxorubicin treatment group [mice were injected with doxorubicin (6 mg·(kg body mass)(-1)·week(-1)) for 3 weeks]; groups 3-5, these mice were treated with boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively; groups 6-8, these mice were treated with a combination of doxorubicin and boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively, for 3 weeks. The results indicated that boswellic acids synergized the antitumor activity of doxorubicin. Doxorubicin-treated mice showed elevated serum activities of lactate dehydrogenase and creatine kinase isoenzyme MB as well as cardiac malondialdehyde. Further, decreases in cardiac levels of reduced glutathione, superoxide dismutase, and catalase activities were observed. These effects were accompanied by an increase in cardiac expression of caspase 3. Thus, treatment with boswellic acids attenuated doxorubicin-evoked disturbances in the above-mentioned parameters, highlighting antioxidant and antiapoptotic activities. Therefore, boswellic acids could be potential candidates for ameliorating the cardiotoxicity of doxorubicin.

  14. Immunologic abnormalities of mice bearing the gld mutation suggest a common pathway for murine nonmalignant lymphoproliferative disorders with autoimmunity.

    PubMed

    Davidson, W F; Holmes, K L; Roths, J B; Morse, H C

    1985-02-01

    Mice bearing the autosomal recessive mutation gld have been shown to develop massive lymphadenopathy, hypergammaglobulinemia, and autoantibodies and to die prematurely with interstitial pneumonitis. In this study, lymphocytes from C3H gld and C3H +/+ mice were examined for a variety of phenotypic and functional characteristics. Spleens and lymph nodes of mutant mice were expanded by an aberrant population of Ly-5(B220)+ surface immunoglobulin negative cells that were Thy-1+Ly-1+ or Thy-1-Ly-1+. Cells from both tissues of mutant mice older than 8 wk were impaired in their ability to proliferate in response to allogeneic stimuli, and supernatants of cells stimulated with concanavalin A contained significantly reduced levels of interleukin 2. Cytotoxic T-lymphocyte responses of spleen and lymph node cells from C3H gld mice were normal at all ages tested. These results are strikingly similar to those obtained with C3H mice homozygous for the nonallelic autosomal recessive mutation lpr. We suggest that the similarities between the syndromes induced by these two mutations may reflect alterations in different enzymes that act in a common metabolic pathway of major importance to the differentiation and function of T cells.

  15. MicroRNA expression profiles of granulocytic myeloid‑derived suppressor cells from mice bearing Lewis lung carcinoma.

    PubMed

    Jiang, Jingwei; Gao, Qingmin; Wang, Tian; Lin, Hao; Zhan, Qiong; Chu, Zhaohui; Huang, Ruofan; Zhou, Xinli; Liang, Xiaohua; Guo, Weijian

    2016-11-01

    Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous myeloid cells that can suppress antitumor immunity. MDSCs are divided into granulocytic (G‑MDSCs) and monocytic subsets. In the present study, the microRNA profiles of the G‑MDSCs were determined and the differential expression of microRNAs between G‑MDSCs from tumor‑bearing mice and tumor‑free mice was examined. The number of G‑MDSCs in spleens of Lewis lung carcinoma (LLC)‑bearing mice was ~6‑fold higher than in spleens of normal mice (13.54±1.74% vs. 2.14±1.44%; P<0.01) and G‑MDSCs account for about 72.9% of all MDSCs. The microRNA (miRNA) profiles of the G‑MDSCs from spleen of LLC‑bearing mice were obtained using a microRNA microarray and compared with their counterparts from spleens of tumor‑free mice. A total of 43 miRNAs with >1.3‑fold increased or decreased change were differentially expressed between the experimental and control group mice. The levels of nine of these differentially expressed miRNAs, miRNA‑468 (miR‑486), miR‑192, miR‑128, miR‑125a, miR‑149, miR‑27a, miR‑125b, miR‑350 and miR‑328, were also analyzed by RT‑qPCR to validate the microarray data. The concordance rate between the results tested by the two methods was 88.9%. Bioinformatics analyses revealed that these miRNAs may act on various target genes, including Adar, Pik3r1, Rybp and Rabgap1, to regulate the survival, differentiation and the function of tumor‑induced granulocytic MDSCs. The results revealed microRNAs and potential targets that may be vital for regulating survival, differentiation and function of G‑MDSCs induced by LLC. Further investigation should be performed to clarify the roles of these microRNAs in regulating LLC‑induced granulocytic MDSCs and the target genes that mediate their functions.

  16. MicroRNA expression profiles of granulocytic myeloid-derived suppressor cells from mice bearing Lewis lung carcinoma

    PubMed Central

    Jiang, Jingwei; Gao, Qingmin; Wang, Tian; Lin, Hao; Zhan, Qiong; Chu, Zhaohui; Huang, Ruofan; Zhou, Xinli; Liang, Xiaohua; Guo, Weijian

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous myeloid cells that can suppress antitumor immunity. MDSCs are divided into granulocytic (G-MDSCs) and monocytic subsets. In the present study, the microRNA profiles of the G-MDSCs were determined and the differential expression of microRNAs between G-MDSCs from tumor-bearing mice and tumor-free mice was examined. The number of G-MDSCs in spleens of Lewis lung carcinoma (LLC)-bearing mice was ~6-fold higher than in spleens of normal mice (13.54±1.74% vs. 2.14±1.44%; P<0.01) and G-MDSCs account for about 72.9% of all MDSCs. The microRNA (miRNA) profiles of the G-MDSCs from spleen of LLC-bearing mice were obtained using a microRNA microarray and compared with their counterparts from spleens of tumor-free mice. A total of 43 miRNAs with >1.3-fold increased or decreased change were differentially expressed between the experimental and control group mice. The levels of nine of these differentially expressed miRNAs, miRNA-468 (miR-486), miR-192, miR-128, miR-125a, miR-149, miR-27a, miR-125b, miR-350 and miR-328, were also analyzed by RT-qPCR to validate the microarray data. The concordance rate between the results tested by the two methods was 88.9%. Bioinformatics analyses revealed that these miRNAs may act on various target genes, including Adar, Pik3r1, Rybp and Rabgap1, to regulate the survival, differentiation and the function of tumor-induced granulocytic MDSCs. The results revealed microRNAs and potential targets that may be vital for regulating survival, differentiation and function of G-MDSCs induced by LLC. Further investigation should be performed to clarify the roles of these microRNAs in regulating LLC-induced granulocytic MDSCs and the target genes that mediate their functions. PMID:27748875

  17. Pharmacokinetics and tissue distribution of parenterally administered human alpha-lymphotoxin in normal and meth-A tumor-bearing BALB/c mice

    SciTech Connect

    Averbook, B.J.; Jeffes, E.B.; Yamamoto, R.S.; Masunaka, I.; Kobayashi, M.; Granger, G.A. )

    1989-08-01

    These in vivo studies examine the pharmacokinetics of parenterally administered purified, native human alpha-lymphotoxin (LT) in normal and Meth-A bearing BALB/c mice. We found that the lytic activity of alpha-LT was inactivated within 5 h in the blood of both normal and tumor-bearing mice in vivo. However, LT bioactivity in vitro was not affected by incubation with fresh serum. Radioiodinated LT was rapidly sequestered in the kidneys of both normal and tumor-bearing animals. Systemically administered, radioiodinated LT did not selectively localize in tumor tissues.

  18. Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

    PubMed Central

    Kretzer, Iara F; Maria, Durvanei A; Guido, Maria C; Contente, Thaís C; Maranhão, Raul C

    2016-01-01

    Purpose Lipid nanoemulsions (LDEs) that bind to low-density lipoprotein (LDL) receptors used as carriers of paclitaxel (PTX) can decrease toxicity and increase PTX antitumoral action. The administration of simvastatin (Simva), which lowers LDL-cholesterol, was tested as an adjuvant to commercial PTX and to PTX associated with LDE (LDE-PTX). Materials and methods B16F10 melanoma-bearing mice were treated with saline solution or LDE (controls), Simva, PTX, PTX and Simva, LDE-PTX, and LDE-PTX and Simva: PTX dose 17.5 μmol/kg (three intraperitoneal injections, 3 alternate days): Simva 50 mg/kg/day by gavage, 9 consecutive days. Results Compared with saline controls, 95% tumor-growth inhibition was achieved by LDE-PTX and Simva, 61% by LDE-PTX, 44% by PTX and Simva, and 43% by PTX. Simva alone had no effect. Metastasis developed in only 37% of the LDE-PTX and Simva, 60% in LDE-PTX, and 90% in PTX and Simva groups. Survival rates were higher in LDE-PTX and Simva and in LDE-PTX groups. The LDE-PTX and Simva group presented tumors with reduced cellular density and increased collagen fibers I and III. Tumors from all groups showed reduction in immunohistochemical expression of ICAM, MCP-1, and MMP-9; LDE-PTX and Simva presented the lowest MMP-9 expression. Expression of p21 was increased in the Simva, LDE-PTX, and LDE-PTX and Simva groups. In the Simva and LDE-PTX and Simva groups, expression of cyclin D1, a proliferation and survival promoter of tumor cells, was decreased. Therapy with LDE-PTX and Simva showed negligible toxicity compared with PTX and Simva, which resulted in weight loss and myelosuppression. Conclusion Simva increased the antitumor activity of PTX carried in LDE but not of PTX commercial presentation, possibly because statins increase the expression of LDL receptors that internalize LDE-PTX. PMID:27022257

  19. Stressful presentations: mild cold stress in laboratory mice influences phenotype of dendritic cells in naïve and tumor-bearing mice.

    PubMed

    Kokolus, Kathleen M; Spangler, Haley M; Povinelli, Benjamin J; Farren, Matthew R; Lee, Kelvin P; Repasky, Elizabeth A

    2014-01-01

    The ability of dendritic cells (DCs) to stimulate and regulate T cells is critical to effective anti-tumor immunity. Therefore, it is important to fully recognize any inherent factors which may influence DC function under experimental conditions, especially in laboratory mice since they are used so heavily to model immune responses. The goals of this report are to 1) briefly summarize previous work revealing how DCs respond to various forms of physiological stress and 2) to present new data highlighting the potential for chronic mild cold stress inherent to mice housed at the required standard ambient temperatures to influence baseline DCs properties in naïve and tumor-bearing mice. As recent data from our group shows that CD8(+) T cell function is significantly altered by chronic mild cold stress and since DC function is crucial for CD8(+) T cell activation, we wondered whether housing temperature may also be influencing DC function. Here we report that there are several significant phenotypical and functional differences among DC subsets in naïve and tumor-bearing mice housed at either standard housing temperature or at a thermoneutral ambient temperature, which significantly reduces the extent of cold stress. The new data presented here strongly suggests that, by itself, the housing temperature of mice can affect fundamental properties and functions of DCs. Therefore differences in basal levels of stress due to housing should be taken into consideration when interpreting experiments designed to evaluate the impact of additional variables, including other stressors on DC function.

  20. Stressful Presentations: Mild Cold Stress in Laboratory Mice Influences Phenotype of Dendritic Cells in Naïve and Tumor-Bearing Mice

    PubMed Central

    Kokolus, Kathleen M.; Spangler, Haley M.; Povinelli, Benjamin J.; Farren, Matthew R.; Lee, Kelvin P.; Repasky, Elizabeth A.

    2013-01-01

    The ability of dendritic cells (DCs) to stimulate and regulate T cells is critical to effective anti-tumor immunity. Therefore, it is important to fully recognize any inherent factors which may influence DC function under experimental conditions, especially in laboratory mice since they are used so heavily to model immune responses. The goals of this report are to 1) briefly summarize previous work revealing how DCs respond to various forms of physiological stress and 2) to present new data highlighting the potential for chronic mild cold stress inherent to mice housed at the required standard ambient temperatures to influence baseline DCs properties in naïve and tumor-bearing mice. As recent data from our group shows that CD8+ T cell function is significantly altered by chronic mild cold stress and since DC function is crucial for CD8+ T cell activation, we wondered whether housing temperature may also be influencing DC function. Here we report that there are several significant phenotypical and functional differences among DC subsets in naïve and tumor-bearing mice housed at either standard housing temperature or at a thermoneutral ambient temperature, which significantly reduces the extent of cold stress. The new data presented here strongly suggests that, by itself, the housing temperature of mice can affect fundamental properties and functions of DCs. Therefore differences in basal levels of stress due to housing should be taken into consideration when interpreting experiments designed to evaluate the impact of additional variables, including other stressors on DC function. PMID:24575090

  1. Cohabitation with an Ehrlich tumor-bearing cagemate induces immune but not behavioral changes in male mice.

    PubMed

    Machado, Thalita R M; Alves, Glaucie J; Quinteiro-Filho, Wanderley M; Palermo-Neto, João

    2017-02-01

    Cohabitation with Ehrlich ascitic tumor-injected conspecifics induces behavioral, neurochemical, endocrine and immune changes indicative of stress and immune impairment in female mice. The present work analyzed the effects of similar cohabitation in Swiss and Balb/C male mice. At least 12 pairs of male mice were divided into a control group and an experimental group. On experimental day 1 (ED1), one animal within each experimental pair was inoculated with 5×10(6) Ehrlich tumor cells intraperitoneally (i.p.); the other animal was kept undisturbed and was referred to as the CSP (companion of a sick partner). One male mouse of each control pair was treated i.p. with 0.9% NaCl (1mL/kg); the other animal (the CHP, companion of a healthy partner) was kept undisturbed. Cohabitation with a sick partner for 11days did not induce any behavioral, hypothalamic noradrenergic, corticosterone or adrenal weight changes in the Swiss CSP male mice compared to those of the Swiss CHP group. However, impairments in neutrophil phagocytosis and oxidative burst as well as increased levels of catecholamines were observed in Swiss and Balb/C CSP mice relative to CHP male animals of the same strains on ED11 and ED14, respectively. Moreover, after a challenge with 5×10(6) Ehrlich tumor cells on ED11 of cohabitation, the number and concentration of tumor cells found in the ascitic fluid were higher in the Swiss CSP male mice than in the CHP mice. These data suggest that the immune changes observed in Swiss and Balb/C male CSP mice after cohabitation with a sick cagemate might, ultimately, depend on the changes induced by catecholamines, as previously reported for CSP female mice. However, contrary to that reported in Swiss CSP female mice, changes in behavioral and hypothalamic noradrenaline activity were not found in the Swiss CSP male mice analyzed in this work. This fact suggests that male and female CSP mice might use similar immune but different CNS strategies against the threats posed

  2. Inhibitory effect of endostatin combined with paclitaxel-cisplatin on breast cancer in xenograft-bearing mice

    PubMed Central

    SUN, JIANGUO; DENG, LI; DUAN, YUZHONG; CHEN, FANGLIN; WANG, XINXIN; LI, DEZHI; CHEN, ZHENGTANG

    2012-01-01

    In the present study, we aimed to investigate the tumor-inhibiting effects of recombinant human endostatin (rhES) combined with paclitaxel-cisplatin (TP regimen) on human breast cancer in xenograft-bearing nude mice. A total of 24 mice bearing human breast cancer xenografts were administered both rhES and TP, TP alone, rhES alone or saline. The tumor growth inhibition was observed. Serum vascular endothelial growth factor (VEGF) levels and microvessel density (MVD) were determined by ELISA and immunohistochemistry, respectively. Cell apoptosis was detected using terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) staining. Survival time was observed in another 24 nude mice with the same treatment. MVD expression in the group administered rhES and TP was lower than that in the other groups (P<0.05); serum VEGF levels in the combined drug group were lower compared to the other groups; the apoptotic index increased in the combined drug group. We conclude that the effect of the TP regimen combined with rhES on breast cancer is better than that of the TP regimen alone. PMID:22969862

  3. Boswellic acid disables signal transduction of IL-6-STAT-3 in Ehrlich ascites tumor bearing irradiated mice.

    PubMed

    Moustafa, Enas Mahmoud; Thabet, Noura Magdy; Azab, Khaled Shaaban

    2016-08-01

    Boswellic acid (BA) is known for its ability to trigger apoptosis as well as to inhibit angiogenesis in tumor tissue. In this study, we investigated the effect of BA on the IL-6-STAT-3 signalling pathway in irradiated mice bearing solid tumors of Ehrlich ascites carcinoma (EAC). For this, we administered BA (25 mg·(kg body mass)(-1)·day(-1), by intraperitoneal injection) to mice with EAC, and then exposed them to 4 Gy of gamma radiation. Data analyses of the results revealed a specific impact from BA on IL-6R mRNA and survivin mRNA in EACs and irradiated EAC-bearing mice. Also, significant improvements were observed in the protein expression of JAK-1, P-JAK-1, STAT-3, P-STAT-3, and caspase-3, as well as VEGF and IL-6 levels. We propose that BA interfered with IL-6-STAT-3 signal transduction, thereby preventing the activation of caspase-3 and subsequently triggering the process of apoptosis. However, the alternative angiogenesis pathway, which includes the over-expression of VEGF and which depends on IL-6-STAT-3 signalling, was inhibited by the action of BA. Thus, we recommend that therapeutic strategies for cancer should include treatment with BA.

  4. In vivo tumor inhibitory effects of nutritional rice bran supplement MGN-3/Biobran on Ehrlich carcinoma-bearing mice.

    PubMed

    Badr El-Din, Nariman K; Noaman, Eman; Ghoneum, Mamdooh

    2008-01-01

    This study was undertaken to investigate the in vivo anti-tumor activity of MGN-3/Biobran, a modified arabinoxylan rice bran. Swiss albino mice were inoculated intramuscularly in the right thigh with Ehrlich ascites carcinoma (EAC) cells. On Day 8, mice bearing a solid Ehrlich carcinoma (SEC) tumor were treated with MGN-3 via intraperitoneal injection. Tumor growth, cytokine production, and apoptotic effect of MGN-3 were examined. MGN-3 caused a highly significant delay in both tumor volume (63.27%) and tumor weight (45.2%) as compared to controls (P < 0.01). The mechanisms by which MGN-3 exerts its antitumor effect seem to involve its ability to induce apoptosis and immune modulation. MGN-3 induced a 1.8-fold increase in the percentage of apoptotic SEC cells as determined by flow cytometry and the histopathological examination. In addition, MGN-3 influenced plasma cytokine production by increasing the levels of tumor necrosis factor-alpha and interferon-gamma, while downregulating levels of the immune suppressing cytokine interleukin-10. Data also showed that non-tumor-bearing mice intramuscularly injected with MGN-3 resulted in a twofold increase in natural killer activity. No adverse side effects due to MGN-3 treatment were observed; all animals displayed normal feeding/drinking and life activity patterns. These data may have clinical implications for the treatment of solid cancers.

  5. Progression of motor deficits in glioma-bearing mice: impact of CNF1 therapy at symptomatic stages.

    PubMed

    Vannini, Eleonora; Maltese, Federica; Olimpico, Francesco; Fabbri, Alessia; Costa, Mario; Caleo, Matteo; Baroncelli, Laura

    2017-02-15

    Glioblastoma (GBM) is the most aggressive type of brain tumor. In this context, animal models represent excellent tools for the early detection and longitudinal mapping of neuronal dysfunction, that are critical in the preclinical validation of new therapeutic strategies. In a mouse glioma model, we developed sensitive behavioral readouts that allow early recognizing and following neurological symptoms. We injected GL261 cells into the primary motor cortex of syngenic mice and we used a battery of behavioral tests to longitudinally monitor the dysfunction induced by tumor growth. Grip strength test revealed an early onset of functional deficit associated to the glioma growth, with a significant forelimb weakness appearing 9 days after tumor inoculation. A later deficit was observed in the rotarod and in the grid walk tasks. Using this model, we found reduced tumor growth and maintenance of behavioral functions following treatment with Cytotoxic Necrotizing Factor 1 (CNF1) at a symptomatic stage. Our data provide a detailed and precise examination of how tumor growth reverberates on the behavioral functions of glioma-bearing mice, providing normative data for the study of therapeutic strategies for glioma treatment. The reduced tumor volume and robust functional sparing observed in CNF1-treated, glioma-bearing mice strengthen the notion that CNF1 delivery is a promising strategy for glioma therapy.

  6. Ameliorative influence of Urtica dioica L against cisplatin-induced toxicity in mice bearing Ehrlich ascites carcinoma.

    PubMed

    Özkol, Halil; Musa, Davut; Tuluce, Yasin; Koyuncu, Ismail

    2012-07-01

    Cisplatin (CP) is a widely used cytotoxic agent against cancer, and high doses of CP have been known to cause nephrotoxicity and hepatotoxicity. Some reports claim that antioxidants can reduce CP-induced toxicity. This study investigated the hepatoprotective, nephroprotective, and antioxidant activity of Urtica dioica L methanolic extract (UDME) against CP toxicity in Erhlich ascites tumor (EAT)-bearing mice. Levels of serum hepatic enzymes, renal function markers, and oxidant/antioxidant parameters of liver tissue were measured. Mice were inoculated with EAT on day 0 and treated with nothing else for 24 hours. After a single dose of CP administration on day 1, the extract was given at the doses of 50, 100, 200, and 400 mg/kg body weight daily during 6 days. Almost all doses of UDME performed a significant (P < 0.05) preventive role against CP toxicity by decreasing aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, blood urea nitrogen, creatinine, lipid peroxidation, protein oxidation levels, and myeloperoxidase activity, as well as increasing reduced glutathione content, superoxide dismutase, catalase, glutathione S-transferase, and glutathione peroxidase activities. This suggests that UDME has a protective capacity and antioxidant activity against CP toxicity in EAT-bearing mice, probably by promoting antioxidative defense systems.

  7. Anti-Gr-1 antibody depletion fails to eliminate hepatic myeloid-derived suppressor cells in tumor-bearing mice.

    PubMed

    Ma, Chi; Kapanadze, Tamar; Gamrekelashvili, Jaba; Manns, Michael P; Korangy, Firouzeh; Greten, Tim F

    2012-12-01

    Recent studies show that the liver is a preferred organ for the accumulation of MDSC. In this study, we examined the effect of systemic RB6-8C5 treatment on hepatic MDSC in tumor-bearing mice. EL4 tumor-bearing mice were injected i.p. with RB6-8C5, and hepatic, splenic, and blood MDSCs were analyzed by flow cytometry. Unexpectedly, hepatic MDSC remained in the liver, although RB6-8C5 completely eliminated them from the spleen and peripheral blood 24 h after treatment. Secondary antibody staining confirmed the presence of RB6-8C5-bound MDSC in the liver of mice with s.c. tumors. Similar observations were made in two other (colon and melanoma) tumor models. Whereas RB6-8C5 injection induced cell death of hepatic MDSC, as shown by Annexin V/7-AAD staining, these cells were replaced immediately, leading to a constant, increased frequency of hepatic MDSC. Adoptively transferred MDSC migrated preferentially to the liver after RB6-8C5 treatment, suggesting that hepatic MDSCs are reconstituted rapidly after depletion. Finally, hepatic MDSC remained immunosuppressive despite RB6-8C5 injection. Our study demonstrates that RB6-8C5 is not suitable for depletion of hepatic MDSCs and analysis of their function.

  8. Photodynamic activity of BAM-SiPc, an unsymmetrical bisamino silicon(IV) phthalocyanine, in tumour-bearing nude mice

    PubMed Central

    Leung, S C H; Lo, P-C; Ng, D K P; Liu, W-K; Fung, K-P; Fong, W-P

    2008-01-01

    Background and purpose Ever since the discovery of photodynamic therapy, there has been a continuous search for more potent photosensitizers. Towards that end, we have synthesized a number of novel phthalocyanine derivatives. The unsymmetrical bisamino silicon(IV) phthalocyanine BAM-SiPc is one of the most potent compounds. In in vitro cell culture, it exhibits high phototoxicity against a number of cancer cell lines. Experimental approach In the present investigation, the in vivo effect of BAM-SiPc was studied in the tumour-bearing nude mice model. The biodistribution of BAM-SiPc was followed to evaluate its tumour selectivity and rate of clearance. The tumour volume in the hepatocarcinoma HepG2- and the colorectal adenocarcinoma HT29-bearing nude mice was measured after photodynamic therapy. The level of intrinsic toxicity induced was also investigated. Finally, the metabolism of BAM-SiPc in the ‘normal' WRL68 liver cells and the hepatocarcinoma HepG2 cells was compared. Key results The results not only showed significant tumour regression of HepG2 and growth inhibition of HT29 in the tumour-bearing nude mice, but also no apparent hepatic or cardiac injury with the protocol used. Histological analyses showed that apoptosis was induced in the solid tumour. BAM-SiPc could be metabolized by WRL68 liver cells but not by the hepatocarcinoma HepG2 cells. Unfortunately, BAM-SiPc did not show any specific targeting towards the tumour tissue. Conclusions and implications The efficiency of BAM-SiPc in inhibiting tumour growth makes it a good candidate for further evaluation. Enhancement of its uptake in tumour tissue by conjugation with biomolecules is currently under investigation. PMID:18332853

  9. Effects of intrabone marrow-bone marrow transplantation plus adult thymus transplantation on survival of mice bearing leukemia.

    PubMed

    Zhang, Yuming; Hosaka, Naoki; Cui, Yunze; Shi, Ming; Li, Ming; Li, Qing; Ikehara, Susumu

    2012-06-10

    We recently found that allogeneic intrabone marrow-bone marrow transplantation (IBM-BMT) plus adult thymus transplantation (ATT) from the same donor is effective in mice bearing solid tumors. In the current study, we examined the effects of this strategy on the survival of mice with leukemia. One week after intravenous injection of 1×10(6) leukemic cells (EL-4, H-2(b)) into 8-week-old B6 (H-2(b)) mice, the mice were 8 Gy irradiated and transplanted with 1×10(7) bone marrow cells (BMCs) from 8-week-old BALB/c mice (H-2(d)) by IBM-BMT with or without donor lymphocyte infusion (DLI) or ATT. All the mice without treatment died within 70 days after injection of EL-4. About 40% of those treated with IBM-BMT alone died within 100 days due to tumor relapse. In contrast, those treated with IBM-BMT+DLI or ATT showed the longest survival rate without relapse of leukemia. In addition, the former showed less graft versus host disease (GVHD) than the latter. The mice treated with IBM-BMT+ATT also showed an intermediate percentage of effector memory (EM) and central memory (CM) cells between those treated with BMT alone and those treated with IBM-BMT+DLI. The numbers and functions of T cells increased in those treated with IBM-BMT+ATT with interleukin-2 and interferon-γ production. These results suggest that IBM-BMT+ATT is effective in the treatment of leukemia with strong graft versus leukemia without increased risk of GVHD.

  10. Bone loss during partial weight bearing (1/6th gravity) is mitigated by resistance and aerobic exercise in mice

    NASA Astrophysics Data System (ADS)

    Boudreaux, R. D.; Metzger, C. E.; Macias, B. R.; Shirazi-Fard, Y.; Hogan, H. A.; Bloomfield, S. A.

    2014-06-01

    Astronauts on long duration missions continue to experience bone loss, as much as 1-2% each month, for up to 4.5 years after a mission. Mechanical loading of bone with exercise has been shown to increase bone formation, mass, and geometry. The aim of this study was to compare the efficacy of two exercise protocols during a period of reduced gravitational loading (1/6th body weight) in mice. Since muscle contractions via resistance exercise impart the largest physiological loads on the skeleton, we hypothesized that resistance training (via vertical tower climbing) would better protect against the deleterious musculoskeletal effects of reduced gravitational weight bearing when compared to endurance exercise (treadmill running). Young adult female BALB/cBYJ mice were randomly assigned to three groups: 1/6 g (G/6; n=6), 1/6 g with treadmill running (G/6+RUN; n=8), or 1/6 g with vertical tower climbing (G/6+CLB; n=9). Exercise was performed five times per week. Reduced weight bearing for 21 days was achieved through a novel harness suspension system. Treadmill velocity (12-20 m/min) and daily run time duration (32-51 min) increased incrementally throughout the study. Bone geometry and volumetric bone mineral density (vBMD) at proximal metaphysis and mid-diaphysis tibia were assessed by in vivo peripheral quantitative computed tomography (pQCT) on days 0 and 21 and standard dynamic histomorphometry was performed on undemineralized sections of the mid-diaphysis after tissue harvest. G/6 caused a significant decrease (P<0.001) in proximal tibia metaphysis total vBMD (-9.6%). These reductions of tibia metaphyseal vBMD in G/6 mice were mitigated in both G/6+RUN and G/6+CLB groups (P<0.05). After 21 days of G/6, we saw an absolute increase in tibia mid-diaphysis vBMD and in distal metaphysis femur vBMD in both G/6+RUN and G/6+CLB mice (P<0.05). Substantial increases in endocortical and periosteal mineralizing surface (MS/BS) at mid-diaphysis tibia in G/6+CLB demonstrate that

  11. Melanoma-targeted delivery system (part 2): Synthesis, radioiodination and biological evaluation in B16F0 bearing mice.

    PubMed

    El Aissi, Radhia; Miladi, Imen; Chezal, Jean-Michel; Chavignon, Olivier; Miot-Noirault, Elisabeth; Moreau, Emmanuel

    2016-09-14

    Here we report the synthesis and radiolabelling with iodine-125 of a melanoma-selective prodrug (17a*) and its parent drug IUdR. The in vivo and ex vivo biodistributions of [(125)I](17a*) and [(125)I]IUdR were evaluated in a model of melanoma B16F0-bearing mice. The pharmacokinetic profile of [(125)I](17a*) suggests rapid release of the active drug [(125)I]IUdR after i.v. administration of [(125)I](17a*). Preliminary metabolism studies in dedicated compartments (i.e. blood, urine and tumour) yielded results consistent with this hypothesis.

  12. Presence of a receptor for the active component of Iscador in ascites fluid of tumour bearing mice.

    PubMed

    Kuttan, G; Vasudevan, D M; Kuttan, R

    1989-12-01

    Tumour bearing mice exhibit a specific "receptor" in the ascites fluid which binds with the active component isolated from Iscador. This "receptor" was found to be a protein which inhibited the cytotoxicity of Iscador and its isolated active component at low concentration. The receptor protein was also found in the sonicates of tumour cells which are susceptible to the action of Iscador but not in lymphocytes which were not susceptible to Iscador or its isolated active component. The receptor was separated on a Sephadex G-50 column. Activity was lost upon heat denaturation and dialysis.

  13. Effect of acetylation on monoclonal antibody ZCE-025 Fab': Distribution in normal and tumor-bearing mice

    SciTech Connect

    Tarburton, J.P.; Halpern, S.E.; Hagan, P.L.; Sudora, E.; Chen, A.; Fridman, D.M.; Pfaff, A.E. )

    1990-04-01

    Studies were performed to determine in vitro and in vivo effects of acetylation on Fab' fragments of ZCE-025, a monoclonal anti-CEA antibody. Isoelectric focusing revealed a drop in isoelectric point of 1.7 pI units following acetylation. Biodistribution studies of acetylated and nonacetylated (111In)Fab' were performed in normal BALB/c mice and in nude mice bearing the T-380 CEA-producing human colon tumor. The acetylated fragments remained in the vascular compartment longer and had significantly diminished renal uptake of 111In compared to controls. While acetylation itself effected a 50% drop in immunoreactivity, tumor uptake of the acetylated and nonacetylated 111In-labeled Fab' fragments was comparable, with the exception of one data point, through 72 h.

  14. The antitumor effects of tetrodotoxin and/or doxorubicin on Ehrlich ascites carcinoma-bearing female mice.

    PubMed

    El-Dayem, Samiha M Abd; Fouda, Fatma M; Ali, Elham H A; Motelp, Bosy A Abd El

    2013-06-01

    The study aimed to investigate the antitumor effect of tetrodotoxin (TTX) and/or doxorubicin (DOX) on Ehrlich ascites carcinoma (EAC)-bearing mice through the investigated biochemical parameters. TTX and/or DOX with or without N-acetylcystiene were administrated after 10 days into EAC-female mice for a period of 2 weeks in six equal doses. Treatment with TTX or DOX caused a significant decrease in the mean tumor weight and an increase in the cumulative mean survival time when compared with EAC group. All the treatments reduced the elevated liver tumor markers and increased liver antioxidant enzymes under investigation in comparison with EAC. Hepatic cells, suffered severely from degeneration and karriolysis in EAC group, revealed some improvement as appearance of healthy hepatocytes by TTX treatment. The present results suggested that TTX had a more powerful inhibitor effect on EAC growth than DOX and TTX plus DOX treatments reflected by antitumor biochemical and histological studies.

  15. Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts.

    PubMed

    Shen, Yuanyuan; Pi, Zhaoke; Yan, Fei; Yeh, Chih-Kuang; Zeng, Xiaojun; Diao, Xianfen; Hu, Yaxin; Chen, Siping; Chen, Xin; Zheng, Hairong

    2017-01-01

    Paclitaxel liposomes (PTX-LIPO) are a clinically promising antineoplastic drug formulation for the treatment of various extracranial cancers, excluding glioblastoma. A main reason for this is the presence of the blood-brain barrier (BBB) or blood-tumor barrier (BTB), preventing liposomal drugs from crossing at a therapeutically meaningful level. Focused ultrasound (FUS) in conjunction with microbubbles (MBs) has been suggested in many studies to be an effective approach to increase the BBB or BTB permeability. In this study, we investigated the feasibility of enhancing the delivery of PTX-LIPO in intracranial glioblastoma-bearing nude mice using pulsed low-intensity FUS exposure in the presence of MBs. Our results showed that the delivery efficiency of PTX-LIPO could be effectively improved in terms of the penetration of both the BBB in vitro and BTB in vivo by pulsed FUS sonication with a 10 ms pulse length and 1 Hz pulse repetition frequency at 0.64 MPa peak-rarefactional pressure in the presence of MBs. Quantitative analysis showed that a 2-fold higher drug concentration had accumulated in the glioblastoma 3 h after FUS treatment, with 7.20±1.18 µg PTX per g glioma tissue. Longitudinal magnetic resonance imaging analysis illustrated that the intracranial glioblastoma progression in nude mice treated with PTX-LIPO delivered via FUS with MBs was suppressed consistently for 4 weeks compared to the untreated group. The medium survival time of these tumor-bearing nude mice was significantly prolonged by 20.8%, compared to the untreated nude mice. Immunohistochemical analysis further confirmed the antiproliferation effect and cell apoptosis induction. Our study demonstrated that noninvasive low-intensity FUS with MBs can be used as an effective approach to deliver PTX-LIPO in order to improve their chemotherapy efficacy toward glioblastoma.

  16. Deficient interleukin 2 activity in MRL/Mp and C57BL/6J mice bearing the lpr gene.

    PubMed

    Wofsy, D; Murphy, E D; Roths, J B; Dauphinée, M J; Kipper, S B; Talal, N

    1981-11-01

    Spleen cells from MRL-lpr and B6-lpr mice have a marked defect in the ability to produce interleukin 2 (IL-2) in response to concanavalin A stimulation. This defect precedes the onset of clinical illness, increases with age, and eventually becomes virtually absolute. It is not due to cellular suppression of IL-2 production, nor does it reflect the presence of a soluble inhibitor of IL-2 activity. Failure to restore IL-2 production with macrophage-replacing factors, such as interleukin 1 and phorbol myristic acetate, suggests that IL-2 deficiency reflects a primary T cell defect rather than a macrophage defect. MRL-lpr and B6-lpr spleen cells also have an age-dependent reduction in IL-2 response that apparently results from a deficiency of cell surface receptors for IL-2. Congenic MRL-+/+ and B6-+/+ mice, which lack the lpr gene responsible for accelerated autoimmunity and lymphoproliferation, have normal IL-2 activity. These findings suggest that a defect in IL-2 activity may contribute to impaired immunoregulation in mice bearing the lpr gene. The absence of such a defect in MRL-+/+ and B6-+/+ mice further suggests that a single autosomal recessive gene is responsible for IL-2 deficiency.

  17. Excess iron undermined bone load-bearing capacity through tumor necrosis factor-α-dependent osteoclastic activation in mice

    PubMed Central

    LI, JUNPING; HOU, YANLI; ZHANG, SHUPING; JI, HONG; RONG, HAIQIN; QU, GUANGBO; LIU, SIJIN

    2013-01-01

    Iron overload has been associated with bone mass loss. To elucidate the effects of excess iron on bone metabolism, an iron-overloading mouse model was established by administering iron-dextran at 250 mg/kg to female BALB/c mice. After 4 weeks, the mice were sacrificed and the biomechanical properties of the femurs were examined. The results suggested a notable decrease of the maximal bending stress and the modulus of bending elasticity in the femurs obtained from the excess iron-treated mice compared to the control mice. The levels of the serum osteocalcin, C-telopeptide of type I collagen (CTX-1) and tumor necrosis factor-α (TNF-α) were measured in order to investigate the underlying mechanism responsible for the excess iron-induced bone strength reduction. Overall, the results suggested that iron overload resulted in a marked reduction of bone load-bearing capacity through a TNF-triggered osteoclast differentiation and resorption mechanism. PMID:24648899

  18. Dietary rice component, Oryzanol, inhibits tumor growth in tumor-bearing Mice

    USDA-ARS?s Scientific Manuscript database

    Scope: We investigated the effects of rice bran and components on tumor growth in mice. Methods and results: Mice fed standard diets supplemented with rice bran, '-oryzanol, Ricetrienol®, ferulic acid, or phytic acid for 2 weeks were inoculated with CT-26 colon cancer cells and fed the same diet fo...

  19. Th1 Cytokine Production Induced by Lactobacillus acidophilus in BALB/c Mice Bearing Transplanted Breast Tumor

    PubMed Central

    Imani Fooladi, Abbas Ali; Yazdi, Mohammad Hossein; Pourmand, Mohammad Reza; Mirshafiey, Abbas; Hassan, Zuhair Mohammad; Azizi, Taghi; Mahdavi, Mehdi; Soltan Dallal, Mohammad Mehdi

    2015-01-01

    Background: The immunomodulative effects of Lactic Acid Bacteria as probiotics have been already demonstrated. Objectives: The current study aimed to evaluate the effect of oral administration of Lactobacillus acidophilus on the immune responses and patterns of cytokine production in the BALB/c mice bearing breast cancer. Materials and Methods: The current study used thirty inbred BALB/c mice, six- to eight-week-old; they were divided into two groups of 15 each. One group was used as control in each assay. The L. acidophilus (ATCC4356) used in the study was inoculated in MRS broth and cultivated overnight at 37°C under anaerobic conditions, then collected by centrifugation, and re-suspended in Phosphate-buffered Saline (PBS) media. After preparation of the proper amount of the suspension, it was orally administered to the mice via gavage and the control mice received an equal volume of PBS in the same manner. Results: The results showed that oral administration of L. acidophilus as a potent immunostimulator agent could motivate the proliferation of immune cells. Moreover, it could increase the production of IFN-γ and decrease the production of IL-4, known as Th2 cytokines, in the spleen cell culture. The results showed that the survival time of the L. acidophilus administered mice significantly increased in comparison to that of the control mice. Conclusions: The current study findings suggested that L. acidophilus can promote immune responses with Th1 bias and may increase the antitumor response. Further, the consumption of this probiotic strain may help to manage the immune response in tumor condition, but more studies are needed to investigate the other mechanisms of this effect. PMID:26034546

  20. Th1 Cytokine Production Induced by Lactobacillus acidophilus in BALB/c Mice Bearing Transplanted Breast Tumor.

    PubMed

    Imani Fooladi, Abbas Ali; Yazdi, Mohammad Hossein; Pourmand, Mohammad Reza; Mirshafiey, Abbas; Hassan, Zuhair Mohammad; Azizi, Taghi; Mahdavi, Mehdi; Soltan Dallal, Mohammad Mehdi

    2015-04-01

    The immunomodulative effects of Lactic Acid Bacteria as probiotics have been already demonstrated. The current study aimed to evaluate the effect of oral administration of Lactobacillus acidophilus on the immune responses and patterns of cytokine production in the BALB/c mice bearing breast cancer. The current study used thirty inbred BALB/c mice, six- to eight-week-old; they were divided into two groups of 15 each. One group was used as control in each assay. The L. acidophilus (ATCC4356) used in the study was inoculated in MRS broth and cultivated overnight at 37°C under anaerobic conditions, then collected by centrifugation, and re-suspended in Phosphate-buffered Saline (PBS) media. After preparation of the proper amount of the suspension, it was orally administered to the mice via gavage and the control mice received an equal volume of PBS in the same manner. The results showed that oral administration of L. acidophilus as a potent immunostimulator agent could motivate the proliferation of immune cells. Moreover, it could increase the production of IFN-γ and decrease the production of IL-4, known as Th2 cytokines, in the spleen cell culture. The results showed that the survival time of the L. acidophilus administered mice significantly increased in comparison to that of the control mice. The current study findings suggested that L. acidophilus can promote immune responses with Th1 bias and may increase the antitumor response. Further, the consumption of this probiotic strain may help to manage the immune response in tumor condition, but more studies are needed to investigate the other mechanisms of this effect.

  1. Rebamipide does not interfere with the antitumor effect of radiotherapy or chemotherapy in human oral tumor-bearing nude mice.

    PubMed

    Shibamori, Masafumi; Sato, Masayuki; Uematsu, Naoya; Nakashima, Takako; Sato, Asuka; Yamamura, Yoshiya; Sasabe, Hiroyuki; Umehara, Ken; Sakurai, Kazushi

    2015-09-01

    Recent studies have shown that rebamipide, which suppresses reactive oxygen species, prevents chemoradiotherapy-induced oral mucositis in patients with head and neck cancers. However, anticancer action of radiotherapy and chemotherapy is believed to be partially associated with generation of reactive oxygen species. The aim of this study was to determine whether rebamipide interferes with the antitumor action of radiotherapy and chemotherapy. The effect of rebamipide on tumor cell growth was investigated using a human oral squamous carcinoma cell line, HSC-2, in vitro and in vivo. Rebamipide showed no significant effect on cell or tumor growth in HSC-2 tumor-bearing nude mice. Influences of rebamipide on the antitumor action of radiotherapy and of chemotherapy with cisplatin or docetaxel were investigated using the same animal model. In radiotherapy, the tumor was treated with 2.5 Gy of X-rays for 5 days, and rebamipide (300 mg/kg p.o.) was administered during irradiation periods. In chemotherapy, tumor-bearing mice were treated once with cisplatin (8 mg/kg, i.v.) or docetaxel (15 mg/kg i.v.) and rebamipide (300 mg/kg p.o.) was administered for 5 days following the antitumor drug treatment. Rebamipide did not interfere with the antitumor action of radiotherapy and chemotherapy. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  2. Extravasation and transcytosis of liposomes in Kaposi's sarcoma-like dermal lesions of transgenic mice bearing the HIV tat gene.

    PubMed

    Huang, S K; Martin, F J; Jay, G; Vogel, J; Papahadjopoulos, D; Friend, D S

    1993-07-01

    Transgenic mice bearing the HIV tat gene develop dermal lesions resembling a common malignant tumor in AIDS, Kaposi's sarcoma (KS). To evaluate the permeability characteristics of these lesions and the therapeutic potential of drug-carrying liposomes, we have studied the localization of sterically stabilized liposomes, which show long circulation time in blood and increased accumulation in tumors. Liposomes encapsulating colloidal gold were injected intravenously into transgenic mice bearing KS lesions, and tissues were processed 24 hours later for both electron microscopy and for light microscopy with silver enhancement. Liposomes and silver marker were detected predominantly in the dermis surrounding the early and mature KS lesions, which were characterized by a proliferation of fibroblast-like spindle cells and abnormal blood vessels close to the epidermis. The silver-enhanced gold marker often surrounded vascular channels and scattered erythrocytes. As determined by electron microscopy, some spindle cells and macrophages had ingested intact liposomes. Transendothelial transport of liposomes was observed both through open channels between endothelial cells and also through endothelial cells lining intact vessels. Both extravasation and transcytosis of liposomes through irregular endothelium were much higher in KS lesions than in the adjacent normal skin. The high accumulation of sterically stabilized liposomes in KS lesions and their intracellular uptake by some spindle cells enhances their potential as carriers of chemotherapeutic agents against this neoplasm.

  3. Effect-enhancing and toxicity-reducing activity of usnic acid in ascitic tumor-bearing mice treated with bleomycin.

    PubMed

    Su, Zu-Qing; Liu, Yu-Hong; Guo, Hui-Zhen; Sun, Chao-Yue; Xie, Jian-Hui; Li, Yu-Cui; Chen, Jian-Nan; Lai, Xiao-Ping; Su, Zi-Ren; Chen, Hai-Ming

    2017-03-08

    Usnic acid (UA) can be found in certain lichen species. Growing evidence suggests that UA possesses antitumoral, antioxidative and anti-inflammatory activities. Bleomycin (BLM) is widely used in the treatment of malignant ascites, however, it unexpectedly causes pulmonary fibrosis (PF). Researches show that excessive inflammatory response and oxidative stress in lung tissue is conspicuous causes of BLM-induced PF. Here we investigated mechanism underlying the effect-enhancing and toxicity-reducing activity of UA on H22-bearing mice treated with BLM. UA combined with BLM was significantly more effective than BLM alone in inhibiting the tumor growth, arresting the cell cycle at G0/G1 phase, and promoting the cleaved caspase-3 and cleaved caspase-8 activities to induce cancer cellular apoptosis. The mechanism may be associated with the transcriptional regulation of p53/p21/Cyclin pathway. Furthermore, UA effectively moderated the histopathological changes, reduced the content of MDA, HYP, TNF-α, IL-1β, IL-6 and TGF-β1, and increased the level of SOD when combined with BLM in lung tissues of H22-bearing mice, which was believed to be related to the inhibition on the protein level of p-Smad2/3 and enhancement of Smad7 expression. These findings suggested that UA might be a potential effect-enhancing and toxicity-reducing candidate for BLM in the treatment of malignant ascites.

  4. Anti-Tumor Effect of Steamed Codonopsis lanceolata in H22 Tumor-Bearing Mice and Its Possible Mechanism

    PubMed Central

    Li, Wei; Xu, Qi; He, Yu-Fang; Liu, Ying; Yang, Shu-Bao; Wang, Zi; Zhang, Jing; Zhao, Li-Chun

    2015-01-01

    Although previous studies confirmed that steaming and the fermentation process could significantly improve the cognitive-enhancement and neuroprotective effects of Codonopsis lanceolata, the anti-tumor efficacy of steamed C. lanceolata (SCL) and what mechanisms are involved remain largely unknown. The present study was designed to evaluate the anti-tumor effect in vivo of SCL in H22 tumor-bearing mice. The results clearly indicated that SCL could not only inhibit the tumor growth, but also prolong the survival time of H22 tumor-bearing mice. Besides, the serum levels of cytokines, such as interferon gamma (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-2 (IL-2), were enhanced by SCL administration. The observations of Hoechst 33258 staining demonstrated that SCL was able to induce tumor cell apoptosis. Finally, immunohistochemical analysis revealed that SCL treatment significantly increased Bax expression and decreased Bcl-2 and vascular endothelial growth factor (VEGF) expression of H22 tumor tissues in a dose-dependent manner. Moreover, LC/MS analysis of SCL indicated that it mainly contained lobetyolin and six saponins. Taken all together, the findings in the present study clearly demonstrated that SCL inhibited the H22 tumor growth in vivo at least partly via improving the immune functions, inducing apoptosis and inhibiting angiogenesis. PMID:26426041

  5. Green tea and its major components ameliorate immune dysfunction in mice bearing Lewis lung carcinoma and treated with the carcinogen NNK.

    PubMed

    Zhu, M; Gong, Y; Yang, Z; Ge, G; Han, C; Chen, J

    1999-01-01

    The protective effects of tea and/or its components on dysfunction of immune functions during tumor growth and carcinogenesis in mice were studied using two experimental models: C57/BL6J mice transplanted with Lewis lung carcinoma (LLC) and Kunming mice treated with a single dose of 4-(methylnitrosamino-)-1-(3-pyridyl)-1-butanone (NNK). In C57/BL6J mice bearing LLC, the weight of the thymus decreased, the proportion of CD4(+)-positive T lymphocytes and the ratio of CD4+ to CD8+ decreased, luminol-enhanced chemiluminescence of white blood cells in peripheral blood stimulated by zymosan increased, and plaque-forming cells (PFC) decreased. However, in LLC-bearing mice given green tea as drinking water, all immune functions were improved, along with inhibition of tumor growth. In Kunming mice treated with NNK, during the four weeks of observation, their immunologic indicators, such as phagocytosis of macrophages in the abdominal cavity, luminol-enhanced chemiluminescence of white blood cells, plaque-forming cells, and delayed-type hypersensitivity, increased or decreased to various extents compared with normal controls. However, these changes were significantly prevented in the mice given green tea, mixed tea, or tea polyphenol as drinking water. In conclusion, tea and its components ameliorated immune dysfunction in mice bearing LLC or treated with the carcinogen NNK.

  6. Increased Atherosclerosis and Endothelial Dysfunction in Mice Bearing Constitutively Deacetylated Alleles of Foxo1 Gene*

    PubMed Central

    Qiang, Li; Tsuchiya, Kyoichiro; Kim-Muller, Ja-Young; Lin, Hua V.; Welch, Carrie; Accili, Domenico

    2012-01-01

    Complications of atherosclerosis are the leading cause of death of patients with type 2 (insulin-resistant) diabetes. Understanding the mechanisms by which insulin resistance and hyperglycemia contribute to atherogenesis in key target tissues (liver, vessel wall, hematopoietic cells) can assist in the design of therapeutic approaches. We have shown that hyperglycemia induces FoxO1 deacetylation and that targeted knock-in of alleles encoding constitutively deacetylated FoxO1 in mice (Foxo1KR/KR) improves hepatic lipid metabolism and decreases macrophage inflammation, setting the stage for a potential anti-atherogenic effect of this mutation. Surprisingly, we report here that when Foxo1KR/KR mice are intercrossed with low density lipoprotein receptor knock-out mice (Ldlr−/−), they develop larger aortic root atherosclerotic lesions than Ldlr−/− controls despite lower plasma cholesterol and triglyceride levels. The phenotype is unaffected by transplanting bone marrow from Ldlr−/− mice into Foxo1KR/KR mice, indicating that it is independent of hematopoietic cells and suggesting that the primary lesion in Foxo1KR/KR mice occurs in the vessel wall. Experiments in isolated endothelial cells from Foxo1KR/KR mice indicate that deacetylation favors FoxO1 nuclear accumulation and exerts target gene-specific effects, resulting in higher Icam1 and Tnfα expression and increased monocyte adhesion. The data indicate that FoxO1 deacetylation can promote vascular endothelial changes conducive to atherosclerotic plaque formation. PMID:22389493

  7. Epidermal I-J-bearing cells are responsible for transferable suppressor cell generation after immunization of mice with ultraviolet radiation-treated epidermal cells

    SciTech Connect

    Granstein, R.D.

    1985-03-01

    Subcutaneous immunization of mice with hapten-coupled, ultraviolet radiation (UVR)-treated epidermal cells (EC) results in a hyporesponsive delayed-type hypersensitivity (DTH) response associated with the appearance of afferent-acting, hapten-specific T suppressor (Ts) cells. Depletion of I-J-bearing cells from the EC population prior to UVR-exposure and hapten coupling prevents the appearance of these Ts cells. However, non-UVR-treated EC depleted of I-J-bearing cells and hapten-coupled are capable of immunizing mice for a DTH response. Therefore, the set of I-J-bearing EC appears to be distinct from classic Langerhans cells. A novel set of I-J-bearing EC appears to be responsible for Ts activation after subcutaneous immunization with hapten-coupled UVR-treated EC.

  8. Experimental treatment of breast cancer-bearing BALB/c mice by artemisinin and transferrin-loaded magnetic nanoliposomes.

    PubMed

    Gharib, Amir; Faezizadeh, Zohreh; Mesbah-Namin, Seyed Ali Reza; Saravani, Ramin

    2015-05-01

    The combination of artemisinin and transferrin exhibits versatile anticancer activities. In previous, we successfully prepared artemisinin and transferrin-loaded magnetic nanoliposomes and evaluated their anti-proliferative activity against MCF-7 and MDA-MB-231 cell lines in vitro. In this study, we investigate the in vivo anti-breast cancer activity of artemisinin and transferrin-loaded magnetic nanoliposome against breast transplanted tumors in BALB/c mice model. Artemisinin and transferrin-loaded magnetic nanoliposomes were prepared and characterized for some physiochemical properties. Pieces of tumor tissue from the breast cancer-bearing BALB/c mice were transplanted subcutaneously to the syngeneic female BALB/c mice. In the presence of the external magnet that placed at the breast tumor site, the tissue distribution and tumor-suppressing effects of prepared nanoliposomes on tumor growth was evaluated. The prepared nanoliposomes have fine spherical shape, rough surface, nano-sized diameter and magnetic properties. At 2 h after treatment, the intravenous administration of artemisinin and transferrin-loaded magnetic nanoliposomes followed using the magnetic field approximately produced 10- and 5.5-fold higher levels of artemisinin and transferrin in the tumors, respectively, compared with free artemisinin and transferrin. Moreover, in the presence of an external magnetic field, the prepared nanoliposomes could significantly induce apoptosis in the mice breast cancer cells as well as could reduce tumor volume in tumorized mice at 15 days after treatment. The data suggested that the artemisinin and transferrin-loaded magnetic nanoliposomes would be a good choice for the breast tumor-targeted therapy, due to its high targeting efficiency.

  9. Experimental treatment of breast cancer-bearing BALB/c mice by artemisinin and transferrin-loaded magnetic nanoliposomes

    PubMed Central

    Gharib, Amir; Faezizadeh, Zohreh; Mesbah-Namin, Seyed Ali Reza; Saravani, Ramin

    2015-01-01

    Background: The combination of artemisinin and transferrin exhibits versatile anticancer activities. In previous, we successfully prepared artemisinin and transferrin-loaded magnetic nanoliposomes and evaluated their anti-proliferative activity against MCF-7 and MDA-MB-231 cell lines in vitro. In this study, we investigate the in vivo anti-breast cancer activity of artemisinin and transferrin-loaded magnetic nanoliposome against breast transplanted tumors in BALB/c mice model. Materials and Methods: Artemisinin and transferrin-loaded magnetic nanoliposomes were prepared and characterized for some physiochemical properties. Pieces of tumor tissue from the breast cancer-bearing BALB/c mice were transplanted subcutaneously to the syngeneic female BALB/c mice. In the presence of the external magnet that placed at the breast tumor site, the tissue distribution and tumor-suppressing effects of prepared nanoliposomes on tumor growth was evaluated. Results: The prepared nanoliposomes have fine spherical shape, rough surface, nano-sized diameter and magnetic properties. At 2 h after treatment, the intravenous administration of artemisinin and transferrin-loaded magnetic nanoliposomes followed using the magnetic field approximately produced 10- and 5.5-fold higher levels of artemisinin and transferrin in the tumors, respectively, compared with free artemisinin and transferrin. Moreover, in the presence of an external magnetic field, the prepared nanoliposomes could significantly induce apoptosis in the mice breast cancer cells as well as could reduce tumor volume in tumorized mice at 15 days after treatment. Conclusion: The data suggested that the artemisinin and transferrin-loaded magnetic nanoliposomes would be a good choice for the breast tumor-targeted therapy, due to its high targeting efficiency. PMID:26109756

  10. Antitumor activity and underlying mechanisms of ganopoly, the refined polysaccharides extracted from Ganoderma lucidum, in mice.

    PubMed

    Gao, Yihuai; Gao, He; Chan, Eli; Tang, Wenbo; Xu, Anlong; Yang, Hongyuan; Huang, Min; Lan, Jin; Li, Xiaotian; Duan, Wei; Xu, Congjian; Zhou, Shufeng

    2005-01-01

    Ganopoly is an aqueous polysaccharide fraction extracted from G. lucidum by patented biochemical technique and has been marketed as an over-the-counter product for chronic diseases including cancer and hepatopathy in many Asian countries. This study was undertaken to explore the anti-tumour effect and the underlying mechanisms of Ganopoly in mice and human tumor cell lines. The maximum tolerated dose (MTD) of Ganopoly in mice was estimated to be 100 mg/kg from a pilot study. Treatment of mice with oral Ganopoly for 10 days significantly reduced the tumour weight of sarcoma-180 in a dose-dependent manner, with inhibition rates of 32.3, 48.2 and 84.9% and growth delays of 1.5, 3.5, and 13.1 days at 20, 50, and 100 mg/kg, respectively. Incubation of Ganopoly at 0.05-1.0 mg/ml for 48 hours showed little or negligible cytotoxicity against human tumor CaSki, SiHa, Hep3B, HepG2, HCT116 HT29, and MCF7 cells in vitro. In contrast, 10 mg/ml of Ganopoly caused significant cytotoxicity in all tumour cells tested except MCF7, with marked apoptotic effect observed in CaSki, HepG2, and HCT116 cells, as indicated by nuclear staining and DNA fragmentation. In addition, Ganopoly enhanced concanavalin A-stimulated proliferation of murine splenocytes by 35.3% at 10 mg/ml, and stimulated the production of nitric oxide in thioglycollate-primed murine peritoneal macrophages in a concentration-dependent manner over 0.05-10 mg/ml. Addition of Ganopoly at 1 mg/ ml to murine peritoneal macrophages also potentiated lipopolysaccharide-induced nitric oxide production by 64.2%. Treatment of healthy mice or mice bearing sarsoma-180 with oral Ganopoly over 20-100 mg/kg for 7 day significantly increased the expression of both TNF-alpha and IFN-gamma (at both mRNA and protein levels) in splenocytes in a dose-dependent manner. Moreover, treatment of Ganopoly over 20-100 mg/kg significantly increased cytotoxic T lymphocyte cytotoxicity and NK activity in mice. The overall findings indicated that

  11. Lenalidomide enhances the curative effect of a therapeutic vaccine and reverses immune suppression in mice bearing established lymphomas

    PubMed Central

    Sakamaki, Ippei; Kwak, Larry W.; Cha, Soung-chul; Yi, Qing; Lerman, Beatrisa; Chen, Jian; Surapaneni, Sekhar; Bateman, Scott; Qin, Hong

    2015-01-01

    Immunomodulatory drugs (IMiDs) are effective therapeutic agents with direct inhibitory effects on malignant B- and plasma cells and immunomodulatory effects on the T cell activation. This dual function of IMiDs makes them appealing candidates for combination with an cancer vaccine. We investigated the immune stimulatory effects of lenalidomide, administrated to mice in doses which provided comparable pharmacokinetics to human patients, on the potency of a novel fusion DNA lymphoma vaccine. The combination was curative in the majority of mice with 8d pre-established syngeneic A20 lymphomas, compared with vaccine or lenalidomide alone and induced immune memory. In vivo depletion experiments established the requirement for effector CD8+ and CD4+ T cells in protective immunity. Unexpectedly, lenalidomide alone was also associated with reduced numbers of systemic MDSC and Treg in tumor-bearing, but not naïve mice, an effect that was independent of simple tumor burden reduction. These results confirm and extend results from other models describing the effect of lenalidomide on enhancing T-cell immunity highlight the potency of this effect, and provide a rational for clinical application. Independently, a novel mechanism of action reversing tumor-induced immune suppression by MDSC is suggested. PMID:23765229

  12. Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice.

    PubMed

    Gray, Sarah K; McGee-Lawrence, Meghan E; Sanders, Jennifer L; Condon, Keith W; Tsai, Chung-Jui; Donahue, Seth W

    2012-09-01

    Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that has deleterious consequences in muscle and bone, leading to decreased mobility, progressive osteoporosis, and premature death. Patients with DMD experience a higher-than-average fracture rate, particularly in the proximal and distal femur and proximal tibia. The dystrophin-deficient mdx mouse is a model of DMD that demonstrates muscle degeneration and fibrosis and osteoporosis. Parathyroid hormone, an effective anabolic agent for post-menopausal and glucocorticoid-induced osteoporosis, has not been explored for DMD. Black bear parathyroid hormone (bbPTH) has been implicated in the maintenance of bone properties during extended periods of disuse (hibernation). We cloned bbPTH and found 9 amino acid residue differences from human PTH. Apoptosis was mitigated and cAMP was activated by bbPTH in osteoblast cultures. We administered 28nmol/kg of bbPTH 1-84 to 4-week old male mdx and wild type mice via daily (5×/week) subcutaneous injection for 6 weeks. Vehicle-treated mdx mice had 44% lower trabecular bone volume fraction than wild type mice. No changes were found in femoral cortical bone geometry or mechanical properties with bbPTH treatment in wild type mice, and only medio-lateral moment of inertia changed with bbPTH treatment in mdx femurs. However, μCT analyses of the trabecular regions of the distal femur and proximal tibia showed marked increases in bone volume fraction with bbPTH treatment, with a greater anabolic response (7-fold increase) in mdx mice than wild type mice (2-fold increase). Trabecular number increased in mdx long bone, but not wild type bone. Additionally, greater osteoblast area and decreased osteoclast area were observed with bbPTH treatment in mdx mice. The heightened response to PTH in mdx bone compared to wild type suggests a link between dystrophin deficiency, altered calcium signaling, and bone. These findings support further investigation of PTH as an anabolic

  13. Effects of herbal medicine on human uterine tumor-bearing nude mice

    PubMed Central

    Ohh, Mi Hyang; Kim, Seong Jin; Han, Jong Kwon; Pak, Sok Cheon; Chee, Kew-mahn

    2016-01-01

    Aim: Uterine leiomyomas are the most common benign uterine neoplasms associated with significant morbidity. Herbal formulas capable of restoring yin-yang balance by dispersing blood stasis may be useful for managing fibroid symptoms. Materials and Methods: In this study, the antitumor properties of three herbs viz., Trogopterus xanthipes Milen-Edwards, Paeonia lactiflora Pallas, and Ulmus davidiana Planch were evaluated in nude mice injected intravenously with human malignant myomas. Tumor fragments were xenografted subcutaneously through a flank incision in female mice. The mice entered the study for 8 weeks when their tumors reached the threshold volume (260 mm3). The mice were randomly allocated to receive subcutaneous injections of normal saline (Group 1; negative control), P. lactiflora Pallas (Group 2), U. davidiana Planch (Group 3), T. xanthipes Milen-Edwards (Group 4), and intravenous injections of paclitaxel (Group 5; positive control). The weight and tumor volume were measured, followed by histopathology. Results: A few cases of abdominal distention and death were observed in the negative control group. Furthermore, a considerable enlargement of the liver and spleen was observed in the negative control group at autopsy with a gradual increase in body weight during the experiment. The mean tumor volume which increased in negative control mice reduced in mice treated with herbal remedies or paclitaxel from day 14 onwards (P < 0.05). The degree of necrosis and apoptosis induction from herbal treatments was similar to that of paclitaxel. Conclusion: Collectively, three herbs viz., T. xanthipes Milen-Edwards, P. lactiflora Pallas, and U. davidiana Planch were able to induce necrosis and apoptosis of uterine leiomyoma cells, proving antitumor properties against uterine fibroids. PMID:27757274

  14. Mixed lymphocyte reactivity against normal cells by splenic lymphocytes from tumor-bearing mice : I. Studies of vigorous immune responsiveness induced in f(1) mice by parental strain tumor cells.

    PubMed

    Devlin, R G; McCurdy, J D; Baronowsky, P E

    1974-01-01

    The establishment of an intimate connection between autoimmunity and neoplasia would require the demonstration of an experimentally induced, tumor-dependent autoimmune process. For this reason, we have studied cellular immune reactions of mice bearing a transplantable leukemia (L1210). Spleen cells from hybrid BDF(1) mice bearing the L1210 tumor (BDFt) reacted vigorously in mixed lymphocyte culture with mitomycin-treated, normal spleen cells from mice of the parental strain from which the L1210 tumor was derived (DBA/2). Spleen cells from nontumor-bearing BDF(1) mice reacted only weakly with these parental cells. The BDFt cells likewise did not respond when cultured with mitomycin-treated spleen cells from the other parental strain (C57B1/6). The vigorous mixed lymphocyte reaction (MLR) by BDFt cells against normal parental cells of the same strain as the tumor was not due to a double exposure of the reacting cells to histocompatibility antigens shared by tumor cells and normal parental cells. The response of cells from tumor-bearing F(1) mice against normal parental cells seen in these experiments suggests the possibility of the induction of an autoimmune-like process against host lymphocytes by spleen cells from leukemic mice. Theoretically such a phenomenon would considerably reduce an animal's ability to mount an immune attack against malignant cells.

  15. Anti-tumor and immunomodulatory activities of an exopolysaccharide from Rhizopus nigricans on CT26 tumor-bearing mice.

    PubMed

    Zhu, Lei; Cao, Jianfeng; Chen, Guochuang; Xu, Yanghui; Lu, Jingbo; Fang, Fang; Chen, Kaoshan

    2016-07-01

    This study was aimed to investigate the anti-tumor and immunomodulatory activities of an exopolysaccharide (EPS) from Rhizopus nigricans. Our results showed EPS could significantly inhibit the tumor growth and increase the immune organs index of CT26 tumor-bearing mice. EPS treatment increased the productions of interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α) levels in serum. The increase of percentage of CD8(+) cytotoxic T cells among total spleen T lymphocyte was also observed. Furthermore, EPS remarkably stimulate spleen lymphocytes proliferation in the absence or presence of mitogens. In addition, we found that EPS had synergistic effect with chemotherapy and improved immunosuppressive effect induced by 5-Fu. In summary, these findings indicated that the antitumor effects of EPS might be partly due to immune function activation and it might have potential to be used in the treatment for colorectal cancer.

  16. Dose Effect of Rhenium (I)-diselenoether as Anticancer Drug in Resistant Breast Tumor-bearing Mice After Repeated Administrations.

    PubMed

    Collery, Philippe; Santoni, François; Ciccolini, Joseph; Tran, Thi Ngoc Nga; Mohsen, Ahmed; Desmaele, Didier

    2016-11-01

    Rhenium (I)-diselenoether has shown promising antiproliferative efficacy in both in vitro and in vivo models. However, the maximal tolerated dose and dose-effect relationships have not been fully addressed for this compound. Here, we evaluated the tolerance and efficacy of three dose-levels (namely 10, 40 and 100 mg/kg) intraperitoneally administered daily over 28 days in mice bearing the resistant MDA-MB231 breast cancer cell line. The upper dose was found to be toxic and was reduced to 60 mg/kg. The 10 mg/kg dose well tolerated, whereas 40 mg/kg was associated with 10% mortality (LD10). Both 10 and 40 mg/kg dosing achieved a significantly similar regression of tumor growth compared with untreated animals. This study suggests that 10 mg/kg daily is the recommended dose for rhenium (I) diselenoether. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  17. Skeletal muscle atrophy is attenuated in tumor-bearing mice under chemotherapy by treatment with fish oil and selenium.

    PubMed

    Wang, Hang; Li, Tsung-Lin; Hsia, Simon; Su, I-Li; Chan, Yi-Lin; Wu, Chang-Jer

    2015-04-10

    Chemotherapy can cause cachexia, which is manifested by weight loss, inflammation and muscle atrophy. However, the mechanisms of tumor and chemotherapy on skeletal muscle proteolysis, remained unclear. In this report, we demonstrated that tumor-induced myostatin in turn induced TNF-α, thus activating calcium-dependent and proteasomal protein degradation. Chemotherapy activated myostatin-mediated proteolysis and muscle atrophy by elevating IL-6. In tumor-bearing mice under chemotherapy, supplementation with fish oil and selenium prevented a rise in IL-6, TNF-α and myostatin and muscle atrophy. The findings presented here allow us to better understand the molecular basis of cancer cachexia and potentiate nutrition supplementation in future cancer chemotherapy.

  18. Skeletal muscle atrophy is attenuated in tumor-bearing mice under chemotherapy by treatment with fish oil and selenium

    PubMed Central

    Wang, Hang; Li, Tsung-Lin; Hsia, Simon; Su, I-Li; Chan, Yi-Lin; Wu, Chang-Jer

    2015-01-01

    Chemotherapy can cause cachexia, which is manifested by weight loss, inflammation and muscle atrophy. However, the mechanisms of tumor and chemotherapy on skeletal muscle proteolysis, remained unclear. In this report, we demonstrated that tumor-induced myostatin in turn induced TNF-α, thus activating calcium-dependent and proteasomal protein degradation. Chemotherapy activated myostatin-mediated proteolysis and muscle atrophy by elevating IL-6. In tumor-bearing mice under chemotherapy, supplementation with fish oil and selenium prevented a rise in IL-6, TNF-α and myostatin and muscle atrophy. The findings presented here allow us to better understand the molecular basis of cancer cachexia and potentiate nutrition supplementation in future cancer chemotherapy. PMID:25797259

  19. Potent anti-tumor effects of EGFR-targeted hybrid peptide on mice bearing liver metastases.

    PubMed

    Gaowa, Arong; Horibe, Tomohisa; Kohno, Masayuki; Harada, Hiroshi; Hiraoka, Masahiro; Kawakami, Koji

    2016-01-01

    In this study, we investigated the therapeutic efficacy of EGFR2R-lytic hybrid peptide for the treatment of liver metastasis from colon carcinoma. The cytotoxic activity of the hybrid peptide against luciferase-expressing human colon cancer (HCT-116-luc) cells was determined by the WST-8 assay. The experimental mouse model of liver metastases was generated by splenic injection of HCT-116-luc cells. The hybrid peptide was intravenously injected into mice the day after cell implantation at a dose of 5 mg/kg and this was repeated on alternate days for a total of 7 doses. Saline-treated mice were used as controls. Tumor growth and therapeutic responses were monitored by an IVIS imaging system. It was shown that the hybrid peptide exhibited potent cytotoxic activity against HCT-116-luc cells and the liver metastases were significantly reduced after intravenous injections of hybrid peptide compared with controls. Furthermore, Kaplan–Meier analysis showed that hybrid peptide-treated mice had significantly longer survival than controls. In addition, bright-field and ex vivo imaging of liver tissue revealed that mice treated with the hybrid peptide had significantly fewer tumors compared with controls. These results demonstrated that the EGFR2R-lytic hybrid peptide is a potential treatment option for patients with colorectal cancer metastases in the liver.

  20. Sialoadhesin expression by bone marrow macrophages derived from Ehrlich-tumor-bearing mice.

    PubMed

    Kusmartsev, S; Ruiz de Morales, J M; Rullas, J; Danilets, M G; Subiza, J L

    1999-12-01

    Sialoadhesin (sheep erythrocyte receptor, SER) is a macrophage-restricted adhesion molecule that binds certain sialylated ligands. It is borne by bone marrow stromal macrophages, promoting the interaction with developing myeloid cells, and by a subset of tissue macrophages involved in antigen presentation and activation of tumor-reactive T cells. The expression of sialoadhesin on SER+ macrophages is not constitutive but requires the continuous supply of a sialoadhesin-inducing serum factor. Tumor growth is often associated with marked alterations of myelopoiesis and impairment of T cell activation; yet the expression of sialoadhesin in macrophages derived from tumor bearers has not been addressed. The aim of this study was to assess whether Ehrlich tumor (ET) - a murine mammary carcinoma - growth may modify the sialoadhesin expression by bone marrow macrophages and/or sialoadhesin-inducing activity in ET-bearing sera. Moreover, putative functional sialoadhesin inhibitors produced by ET cells were tested. The results indicate that bone marrow cells from ET bearers show a seven- to eight-fold decrease in SER+ cells as detected by flow cytometry. This is accompanied by an overall decrease in sheep erythrocyte binding to tumor-bearer-derived bone marrow cells, but also by lower numbers of plastic-adherent cells. Functional sialoadhesin expression is preserved at the single-cell level and no inhibitors are found in ET-bearing sera or ET cell culture supernatants. Tumor progression does not impair the sialoadhesin-inducing activity of ET-bearing sera, or the ability of SER- macrophages (e.g. peritoneal macrophages) to respond to such an induction. In conclusion, while SER+ macrophages are greatly decreased in bone marrow from ET bearers, this is not due to a down-regulation of sialoadhesin expression, nor to an impairment of sialoadhesin-inducing factor or to the presence of sialoadhesin-binding moieties of tumor origin, but, more likely, to a decrease of fully mature

  1. Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts.

    PubMed

    Houba, P H; Boven, E; van der Meulen-Muileman, I H; Leenders, R G; Scheeren, J W; Pinedo, H M; Haisma, H J

    1999-03-15

    N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-beta-glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug DNR-GA3 was selectively activated by human beta-glucuronidase present in tumor tissue. We determined the pharmacokinetics and distribution of DNR-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3, FMa, A2780, and MRI-H-207). Administration of DNR at 10 mg/kg i.v. (maximum tolerated dose) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 12.18 microM (t = 1 min). DNR-GA3 at 100 mg/kg i.v. (approximately 50% of the maximum tolerated dose [MTD]) resulted in a peak plasma concentration of DNR that was 28-fold lower than that after DNR itself; in normal tissues, prodrug injection resulted in 5- to 23-fold lower DNR concentrations. DNR showed a relatively poor uptake into OVCAR-3 tumors with a peak concentration of 2.05 nmol x g(-1) after injection. In the same xenograft, DNR-GA3 resulted in a significantly higher DNR peak concentration of 3.45 nmol x g(-1) (P < 0.05). The higher area under the curve of DNR in tumor tissue after DNR-GA3 than after DNR itself would be the result of prodrug activation by beta-glucuronidase. In this respect, a considerably higher beta-glucuronidase activity was found in tumor tissue when compared to plasma. The specific activation of DNR-GA3 by beta-glucuronidase at the tumor site relative to normal organs leads to a more tumor-selective therapy, resulting in greater efficacy without increased toxicity.

  2. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination.

    PubMed

    Kusmartsev, Sergei; Cheng, Fengdong; Yu, Bin; Nefedova, Yulia; Sotomayor, Eduardo; Lush, Richard; Gabrilovich, Dmitry

    2003-08-01

    Tumor-induced immunosuppression is one of the crucial mechanisms of tumor evasion of immune surveillance. It contributes greatly to the failure of cancer vaccines. Immature myeloid cells (ImCs) play an important role in tumor-induced immunosuppression. These cells accumulate in large numbers in tumor-bearing hosts and directly inhibit T-cell functions via various mechanisms. In this study, we tried to eliminate ImCs in an attempt to improve antitumor response. In vivo administration of all-trans-retinoic acid (ATRA) dramatically reduced the presence of ImCs in all tested tumor models. This effect was not because of a direct antitumor effect of ATRA or decreased production of growth factors by tumor cells. Experiments with adoptive transfer demonstrated that ATRA differentiated ImC in vivo into mature dendritic cells, macrophages, and granulocytes. Decreased presence of ImC in tumor-bearing mice noticeably improved CD4- and CD8-mediated tumor-specific immune response. Combination of ATRA with two different types of cancer vaccines in two different tumor models significantly prolonged the antitumor effect of the treatment. These data suggest that elimination of ImC with ATRA may open an opportunity to improve the effect of cancer vaccines.

  3. Tuftsin-bearing liposomes as rifampin vehicles in treatment of tuberculosis in mice.

    PubMed Central

    Agarwal, A; Kandpal, H; Gupta, H P; Singh, N B; Gupta, C M

    1994-01-01

    The antitubercular activity of rifampin was considerably increased when it was encapsulated in egg phosphatidylcholine liposomes. A further increase in the activity was observed when the macrophage activator tetrapeptide tuftsin was grafted on the surface of the drug-loaded liposomes. Intermittent treatments (twice weekly) with these preparations were significantly more effective than the continuous treatments. Rifampin delivered twice weekly for 2 weeks in tuftsin-bearing liposomes was at least 2,000 times more effective than the free drug in lowering the load of lung bacilli in infected animals. However, pretreatment with drug-free tuftsin-bearing liposomes did not render the pretreated animals resistant to the Mycobacterium tuberculosis infections, neither did it appreciably increase the chemotherapeutic efficacy of the liposomized rifampin. These results clearly demonstrate that liposome targeting to macrophages could considerably increase the antitubercular activity of liposomized drugs such as rifampin. Also, it shows that immunoprophylactic treatment with macrophage activators such as tuftsin does not afford any advantage in treatment of tuberculosis infections, presumably because of inactivation of the primed macrophages by the mycobacterial sulfatides. PMID:8203859

  4. Anticancer activity of cissampelos pareira against dalton's lymphoma ascites bearing mice

    PubMed Central

    Thavamani, B. Samuel; Mathew, Molly; Dhanabal, S. P.

    2014-01-01

    Background: Cissampelos pareira (Menispermaceae) is used in folk Indian system of alternative medicine, for its analgesic, antipyretic, diuretic, antilithic, and emmenagogue properties. Objective: To evaluate Cissampelos pareira (C. pareira) for in vitro cytotoxicity and in vivo antitumor activity against Dalton's Lymphoma Ascites (DLA) cells in Swiss mice. Materials and Methods: Cissampelos pareira was successively extracted using different solvents. In vitro cytotoxicity was assessed by the MTT assay. An in vivo study was carried out in methanol extract. Twenty-four hours after intraperitoneal inoculation of the DLA cells in mice, the methanol extract of C. pariera (MECP) was administered at 200 and 400 mg/kg body weight for 14 consecutive days. On day 14, six mice were sacrificed and the rest were kept alive for assessment of increase in life-span. The antitumor effect was assessed by evaluating the packed cell volume, viable tumor cell count, increase in body weight, and increase in life-span. The hematological and serum biochemical parameters and anti-oxidant properties were assessed by estimating the superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation. Results: Methanol Extract of Cissampelos pariera (MECP) showed a potent cytotoxic activity, with an IC50 value of 95.5 μg/ml and a significant (P < 0.001) decrease in packed cell volume, viable cell count, and an increased lifespan (54 and 72%). The hematological and serum biochemical profiles were restored to normal levels in MECP-treated mice. The MECP-treated group significantly (P < 0.001) decreased SOD, lipid peroxidation, and CAT to normal. Conclusion: This study demonstrated that C. pariera exhibited significant in vitro and in vivo anti-tumor activities and that it was reasonably imputable to its increasing endogenous mechanism of antioxidant property. PMID:25210304

  5. Eccentric contraction-induced myofiber growth in tumor-bearing mice.

    PubMed

    Hardee, Justin P; Mangum, Joshua E; Gao, Song; Sato, Shuichi; Hetzler, Kimbell L; Puppa, Melissa J; Fix, Dennis K; Carson, James A

    2016-01-01

    Cancer cachexia is characterized by the progressive loss of skeletal muscle mass. While mouse skeletal muscle's response to an acute bout of stimulated low-frequency concentric muscle contractions is disrupted by cachexia, gaps remain in our understanding of cachexia's effects on eccentric contraction-induced muscle growth. The purpose of this study was to determine whether repeated bouts of stimulated high-frequency eccentric muscle contractions [high-frequency electrical muscle stimulation (HFES)] could stimulate myofiber growth during cancer cachexia progression, and whether this training disrupted muscle signaling associated with wasting. Male Apc(Min/+) mice initiating cachexia (N = 9) performed seven bouts of HFES-induced eccentric contractions of the left tibialis anterior muscle over 2 wk. The right tibialis anterior served as the control, and mice were killed 48 h after the last stimulation. Age-matched C57BL/6 mice (N = 9) served as wild-type controls. Apc(Min/+) mice lost body weight, muscle mass, and type IIA, IIX, and IIB myofiber cross-sectional area. HFES increased myofiber cross-sectional area of all fiber types, regardless of cachexia. Cachexia increased muscle noncontractile tissue, which was attenuated by HFES. Cachexia decreased the percentage of high succinate dehydrogenase activity myofibers, which was increased by HFES, regardless of cachexia. While cachexia activated AMP kinase, STAT3, and ERK1/2 signaling, HFES decreased AMP kinase phosphorylation, independent of the suppression of STAT3. These results demonstrate that cachectic skeletal muscle can initiate a growth response to repeated eccentric muscle contractions, despite the presence of a systemic cachectic environment.

  6. Magnetite Nanoparticles Inhibit Tumor Growth and Upregulate the Expression of P53/P16 in Ehrlich Solid Carcinoma Bearing Mice

    PubMed Central

    Bassiony, Heba; Sabet, Salwa; Salah El-Din, Taher A.; Mohamed, Mona M.; El-Ghor, Akmal A.

    2014-01-01

    Background Magnetite nanoparticles (MNPs) have been widely used as contrast agents and have promising approaches in cancer treatment. In the present study we used Ehrlich solid carcinoma (ESC) bearing mice as a model to investigate MNPs antitumor activity, their effect on expression of p53 and p16 genes as an indicator for apoptotic induction in tumor tissues. Method MNPs coated with ascorbic acid (size: 25.0±5.0 nm) were synthesized by co-precipitation method and characterized. Ehrlich mice model were treated with MNPs using 60 mg/Kg day by day for 14 injections; intratumorally (IT) or intraperitoneally (IP). Tumor size, pathological changes and iron content in tumor and normal muscle tissues were assessed. We also assessed changes in expression levels of p53 and p16 genes in addition to p53 protein level by immunohistochemistry. Results Our results revealed that tumor growth was significantly reduced by IT and IP MNPs injection compared to untreated tumor. A significant increase in p53 and p16 mRNA expression was detected in Ehrlich solid tumors of IT and IP treated groups compared to untreated Ehrlich solid tumor. This increase was accompanied with increase in p53 protein expression. It is worth mentioning that no significant difference in expression of p53 and p16 could be detected between IT ESC and control group. Conclusion MNPs might be more effective in breast cancer treatment if injected intratumorally to be directed to the tumor tissues. PMID:25375144

  7. Magnetite nanoparticles inhibit tumor growth and upregulate the expression of p53/p16 in Ehrlich solid carcinoma bearing mice.

    PubMed

    Bassiony, Heba; Sabet, Salwa; Salah El-Din, Taher A; Mohamed, Mona M; El-Ghor, Akmal A

    2014-01-01

    Magnetite nanoparticles (MNPs) have been widely used as contrast agents and have promising approaches in cancer treatment. In the present study we used Ehrlich solid carcinoma (ESC) bearing mice as a model to investigate MNPs antitumor activity, their effect on expression of p53 and p16 genes as an indicator for apoptotic induction in tumor tissues. MNPs coated with ascorbic acid (size: 25.0±5.0 nm) were synthesized by co-precipitation method and characterized. Ehrlich mice model were treated with MNPs using 60 mg/Kg day by day for 14 injections; intratumorally (IT) or intraperitoneally (IP). Tumor size, pathological changes and iron content in tumor and normal muscle tissues were assessed. We also assessed changes in expression levels of p53 and p16 genes in addition to p53 protein level by immunohistochemistry. Our results revealed that tumor growth was significantly reduced by IT and IP MNPs injection compared to untreated tumor. A significant increase in p53 and p16 mRNA expression was detected in Ehrlich solid tumors of IT and IP treated groups compared to untreated Ehrlich solid tumor. This increase was accompanied with increase in p53 protein expression. It is worth mentioning that no significant difference in expression of p53 and p16 could be detected between IT ESC and control group. MNPs might be more effective in breast cancer treatment if injected intratumorally to be directed to the tumor tissues.

  8. Dendritic cells pulsed with glioma lysates induce immunity against syngeneic intracranial gliomas and increase survival of tumor-bearing mice.

    PubMed

    Pellegatta, S; Poliani, P L; Corno, D; Grisoli, M; Cusimano, M; Ubiali, F; Baggi, F; Bruzzone, M G; Finocchiaro, G

    2006-07-01

    In recent years, the use of dendritic cells (DC), the most powerful antigen presenting cells, has been proposed for the creation of vaccines against gliomas. This approach has been demonstrated to be safe and non-toxic in phase I or I-II trials (2, 3). Immunotherapy plays a central role in the search for new treatments for glioblastoma multiforme (GBM). In particular, several phase I studies have been performed using DC pulsed by GBM proteins as a vaccine for patients with relapsing GBM. The studies demonstrated that DC vaccination is safe and may produce a significant increase in overall survival. As the first step in the preparation of appropriate conditions for a clinical evaluation in Italy, we have performed pre-clinical experiments on immune-competent mice injected intra-cerebrally with syngeneic GL261GBM cells and treated subcutaneously and intra-tumorally with DC loaded with a GL261 homogenate. These results show that vaccination with DC pulsed with a tumor lysate increases considerably survival in mice bearing intracranial glioblastomas and supports the development of DC-based clinical trials for patients with glioblastomas that do not respond to standard therapies.

  9. Production of a novel multi-epitope peptide vaccine for cancer immunotherapy in TC-1 tumor-bearing mice.

    PubMed

    Nezafat, Navid; Sadraeian, Mohammad; Rahbar, Mohammad Reza; Khoshnoud, Mohammad Javad; Mohkam, Milad; Gholami, Ahmad; Banihashemi, Mehrzad; Ghasemi, Younes

    2015-01-01

    In our previous research, several bioinformatic strategies were utilized to design an efficient multi-epitope peptide vaccine (MEV) against cancer. The designed vaccine consists of Wilms tumor-1 (WT-1) and human papillomavirus (HPV) E7 cytotoxic T lymphocyte (CTL) epitopes, tetanus toxin fragment C (TTFrC) and HLA-DR epitope (PADRE) helper T lymphocyte (HTL) epitopes and heparin-binding hemagglutinin (HBHA) as an immunostimulatory adjuvant. All segments were fused together by suitable linkers. In the current study, we cloned and expressed the designed MEV in E. coli. We subsequently performed in vivo preventative and therapeutic assays to evaluate antitumor efficacy of the vaccine against the HPV-16 E7-expressing murine tumor cell line TC-1 as a model for cancer immunotherapy. The results showed that in preventive experiments, vaccination with MEV significantly augmented the IgG antibody titer and the percentage of tumor-free mice compared to control groups (PBS and E7). Moreover, in therapeutic experiments, vaccination with MEV led to a reduction in the number of metastatic nodules, lung weights and the ratio of lung weights to body weights compared to other groups. In sum, our epitope vaccine could efficiently induce preventive and therapeutic antitumor immunity in TC-1 tumor bearing mice.

  10. Metronomic Cordycepin Therapy Prolongs Survival of Oral Cancer-Bearing Mice and Inhibits Epithelial-Mesenchymal Transition.

    PubMed

    Su, Nai-Wen; Wu, Shu-Hua; Chi, Chih-Wen; Liu, Chung-Ji; Tsai, Tung-Hu; Chen, Yu-Jen

    2017-04-13

    Cordycepin (3'-deoxyadenosine) is a natural compound abundantly found in Cordyceps sinesis in natural and fermented sources. In this study, we examined the effects of cordycepin in a human oral squamous cell carcinoma (OSCC) xenograft model. Cordycepin was administered in a regular, low-dose and prolonged schedule metronomic therapy. Two doses of cordycepin (25 mg/kg, 50 mg/kg) were administrated five days a week for eight consecutive weeks. The tumor volumes were reduced and survival time was significantly prolonged from 30.3 ± 0.9 days (control group) to 56 days (50 mg/kg group, the day of tumor-bearing mice were sacrificed for welfare consideration). The weights of mice did not change and liver, renal, and hematologic functions were not compromised. Cordycepin inhibited the OSCC cell viability in vitro (IC50 122.4-125.2 μM). Furthermore, morphological characteristics of apoptosis, increased caspase-3 activity and G2/M cell cycle arrest were observed. In wound healing assay, cordycepin restrained the OSCC cell migration. Cordycepin upregulated E-cadherin and downregulated N-cadherin protein expression, implying inhibition of epithelial-mesenchymal transition (EMT). The immunohistochemical staining of xenograft tumor with E-cadherin and vimentin validated in vitro results. In conclusion, metronomic cordycepin therapy showed effective tumor control, prolonged survival and low toxicities. Cytotoxicity against cancer cells with apoptotic features and EMT inhibition were observed.

  11. PET/CT Based In Vivo Evaluation of 64Cu Labelled Nanodiscs in Tumor Bearing Mice

    PubMed Central

    Huda, Pie; Binderup, Tina; Pedersen, Martin Cramer; Midtgaard, Søren Roi; Elema, Dennis Ringkjøbing; Kjær, Andreas; Jensen, Mikael; Arleth, Lise

    2015-01-01

    64Cu radiolabelled nanodiscs based on the 11 α-helix MSP1E3D1 protein and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine lipids were, for the first time, followed in vivo by positron emission tomography for evaluating the biodistribution of nanodiscs. A cancer tumor bearing mouse model was used for the investigations, and it was found that the approximately 13 nm nanodiscs, due to their size, permeate deeply into cancer tissue. This makes them promising candidates for both drug delivery purposes and as advanced imaging agents. For the radiolabelling, a simple approach for 64Cu radiolabelling of proteins via a chelating agent, DOTA, was developed. The reaction was performed at sufficiently mild conditions to be compatible with labelling of the protein part of a lipid-protein particle while fully conserving the particle structure including the amphipathic protein fold. PMID:26132074

  12. Image-guided microbeam irradiation to brain tumour bearing mice using a carbon nanotube x-ray source array

    NASA Astrophysics Data System (ADS)

    Zhang, Lei; Yuan, Hong; Burk, Laurel M.; Inscoe, Christy R.; Hadsell, Michael J.; Chtcheprov, Pavel; Lee, Yueh Z.; Lu, Jianping; Chang, Sha; Zhou, Otto

    2014-03-01

    Microbeam radiation therapy (MRT) is a promising experimental and preclinical radiotherapy method for cancer treatment. Synchrotron based MRT experiments have shown that spatially fractionated microbeam radiation has the unique capability of preferentially eradicating tumour cells while sparing normal tissue in brain tumour bearing animal models. We recently demonstrated the feasibility of generating orthovoltage microbeam radiation with an adjustable microbeam width using a carbon nanotube based x-ray source array. Here we report the preliminary results from our efforts in developing an image guidance procedure for the targeted delivery of the narrow microbeams to the small tumour region in the mouse brain. Magnetic resonance imaging was used for tumour identification, and on-board x-ray radiography was used for imaging of landmarks without contrast agents. The two images were aligned using 2D rigid body image registration to determine the relative position of the tumour with respect to a landmark. The targeting accuracy and consistency were evaluated by first irradiating a group of mice inoculated with U87 human glioma brain tumours using the present protocol and then determining the locations of the microbeam radiation tracks using γ-H2AX immunofluorescence staining. The histology results showed that among 14 mice irradiated, 11 received the prescribed number of microbeams on the targeted tumour, with an average localization accuracy of 454 µm measured directly from the histology (537 µm if measured from the registered histological images). Two mice received one of the three prescribed microbeams on the tumour site. One mouse was excluded from the analysis due to tissue staining errors.

  13. Image-guided microbeam irradiation to brain tumour bearing mice using a carbon nanotube x-ray source array.

    PubMed

    Zhang, Lei; Yuan, Hong; Burk, Laurel M; Inscoe, Christy R; Hadsell, Michael J; Chtcheprov, Pavel; Lee, Yueh Z; Lu, Jianping; Chang, Sha; Zhou, Otto

    2014-03-07

    Microbeam radiation therapy (MRT) is a promising experimental and preclinical radiotherapy method for cancer treatment. Synchrotron based MRT experiments have shown that spatially fractionated microbeam radiation has the unique capability of preferentially eradicating tumour cells while sparing normal tissue in brain tumour bearing animal models. We recently demonstrated the feasibility of generating orthovoltage microbeam radiation with an adjustable microbeam width using a carbon nanotube based x-ray source array. Here we report the preliminary results from our efforts in developing an image guidance procedure for the targeted delivery of the narrow microbeams to the small tumour region in the mouse brain. Magnetic resonance imaging was used for tumour identification, and on-board x-ray radiography was used for imaging of landmarks without contrast agents. The two images were aligned using 2D rigid body image registration to determine the relative position of the tumour with respect to a landmark. The targeting accuracy and consistency were evaluated by first irradiating a group of mice inoculated with U87 human glioma brain tumours using the present protocol and then determining the locations of the microbeam radiation tracks using γ-H2AX immunofluorescence staining. The histology results showed that among 14 mice irradiated, 11 received the prescribed number of microbeams on the targeted tumour, with an average localization accuracy of 454 µm measured directly from the histology (537 µm if measured from the registered histological images). Two mice received one of the three prescribed microbeams on the tumour site. One mouse was excluded from the analysis due to tissue staining errors.

  14. [Immunoscintigraphy of anti-type IV collagenase monoclonal antibody in nude mice bearing human lung cancer xenograft].

    PubMed

    Dai, Yao; Jia, Bing; Wang, Fan; Du, Jin; Shang, Bo-Yang; Zhen, Yong-Su

    2003-12-01

    Matrix metalloproteinases (MMPs)play the important role in many steps of tumor growth and metastasis. Type IV collagenase, which is a key member of MMPs family, has been viewed as a promising target in tumor study. The aim of this study was to evaluate the tumor-specific distribution of the anti-type IV collagenase monoclonal antibody (mAb) 3G11 by radioimaging in tumor-bearing nude mice. MAb 3G11 purified by affinity chromatography was labeled with either 131- or 125- iodide by the Iodogen method. Immunoreactivity of mAb 3G11 was determined by ELISA. (131)I-labeled 3G11 was incubated in three different media at 37 Celsius degree and its in vitro stability was tested. Normal BALB/c mice were injected intravenously with 388.5 kBq per mouse of (125)I-labeled 3G11 to explore the pharmacokinetic patterns. The scintigraphic images of human lung carcinoma PG xenografts grown subcutaneously in BALB/c nude mice were made after intravenously administrating of 6.44 MBq per mouse of (131)I-labeled 3G11. MAb 3G11 was more than 98% in purity via affinity purification. The immunoreactivity of mAb 3G11 decreased by approximately 10%-20% after cold iodination. Patterns of blood clearance of mAb 3G11 was defined as two-compartment model, with T(1/2alpha) and T(1/2beta) calculated to be 7.2 h and 345.2 h, respectively. (131)I-labeled 3G11 was almost stable in vitro for 72 h. A clear image of the xenografted tumor was obtained at 72 h, and it further improved at 120 h. MAb 3G11 showed high specificity and affinity with tumor tissue through scintiscanning.

  15. [Lethal effects of nanoliposome encapsulated cisplatin on Saos-2 cells and its distribution in nude mice bearing human].

    PubMed

    Wang, Guo Wen; Guo, Wei; Tang, Xiao Dong; Peng, Chang Liang; Zhao, Hui

    2009-10-18

    To investigate the killing effect of nanoliposome encapsulated cisplatin (NLE-CDDP) on human osteosarcoma cell line Saos-2 and explore the distribution of platinum (Pt) in tumor-bearing mice. Saos-2 cells were cultured at different concentrations of NLE-CDDP. MTT assay, inverted microscopic observation and flow cytometry assay(FCM)were used to observe the antiproliferative effect of NLE-CDDP on the human osteosarcoma cells. Antitumor effect of NLE-CDDP was determined using the xenografts models of human osteosarcoma cell Saos-2 in nude mice. The Pt concentration in the tissues of tumor-transplanted mice was determined by atomic spectrophotometer. When treated at different concentrations of NLE-CDDP for 24-96 hours, the survival rate of Saos-2 cells decreased significantly(P<0.05). At the same time point, the inhibitory effect of NLE-CDDP was stronger than that of CDDP;Degeneration and necrosis of Saos-2 cells increased; the apoptosis increased and the S phase reduced. This study demonstrated that NLE-CDDP had obvious anti-tumor activity. Within 1 hour of injection, in NLE-CDDP group plasma platinum concentration was 4.4-fold that in CDDP group; 2 hours later, platinum was not detected in the blood of CDDP group; 24 hours later, platinum still could be detected in NLE-CDDP group at 2.76 mumol/L. During the first hour after injection of NLE-CDDP, the platinum content of the kidney was 50% less than that of CDDP group. Platinum in NLE-CDDP group showed rapid higher accumulation in the liver, spleen and tumor compared with CDDP group, and within 24 hours platinum reached the peak concentration in the spleen. The antitumor efficacy of NLE-CDDP on Saos-2 tumor is higher than that CDDP alone, and its mechanism is delaying rapid clearance from circulation.

  16. Effects of load-bearing exercise on skeletal structure and mechanics differ between outbred populations of mice.

    PubMed

    Wallace, Ian J; Judex, Stefan; Demes, Brigitte

    2015-03-01

    Effects of load-bearing exercise on skeletal structure and mechanical properties can vary between inbred strains of mice. Here, we examine whether such variation also exists at the population level. An experiment was performed with two outbred mouse stocks that have been reproductively isolated for >120 generations (Hsd:ICR, Crl:CD1). Growing females from each stock were either treated with a treadmill-running regimen for 1 month or served as controls. Limb forces were recorded with a force plate and cage activity monitored to verify that they were similar between stocks. After the experiment, femoral cortical and trabecular bone structure were quantified with micro-CT in the mid-diaphysis and distal metaphysis, respectively, and diaphyseal structural strength was determined with mechanical testing. Among Hsd:ICR mice, running led to significant improvements in diaphyseal bone quantity, structural geometry, and mechanical properties, as well as enhanced trabecular morphology. In contrast, among Crl:CD1 mice, the same running regimen had little effect on cortical and trabecular structure and significantly reduced diaphyseal resistance to fracture. In neither stock was body mass, muscle mass, or cage activity level different between runners and controls. Given that most environmental variables were controlled in this study, the differential effects of exercise on Hsd:ICR and Crl:CD1 bones were likely due to genetic differences between stocks. These results suggest that the benefits of loading for bone may vary between human populations (e.g., ethnic groups), in which case exercise programs and technologies designed to promote bone health with mechanical signals may be more advantageous to certain populations than others.

  17. Neem tree (Azadirachta indica) extract specifically suppresses the growth of tumors in H22-bearing Kunming mice.

    PubMed

    He, Zhenxiang; Jiang, Cuihua; Zhang, Jian; Yin, Zhiqi; Yin, Zengfang; Zhu, Yunfeng; Fu, Jie

    Recently, neem tree (Azadirachta indica) extract (NTE) has been reported to have various antitumor activities against gastric, breast, prostate, and skin cancer, respectively. The current study was designed to evaluate the effect of NTE on hepatic cancer in a mouse model. The possible side effects elicited by NTE were also evaluated. The components in NTE were analyzed by liquid chromatography-mass spectrometry (LC-MS). H22 cells-bearing Kumming mice were generated by injecting H22 cells subcutaneously into the right forelimb armpit of the mice. Then the mice were treated daily for 27 days with NTE (150, 300, and 600 mg/kg body weight) by intragastric administration, using carboxymethyl cellulose (CMC, 1%) as blank control and cyclophosphamide (CTX, 20 mg/kg) as positive control. The antitumor effect of NTE was evaluated by assessment of survival rate, body weight, tumor volume and weight, tumor histology, thymus and spleen indexes, and liver histology. The tumor weight and volume in groups of NTE and CTX were significantly lower than those in the CMC group. The survival rate in the NTE group receiving the high dose (600 mg/kg) was significantly higher than that in the CTX and CMC groups. Compared with CTX, NTE was observed to have a tumor-specific cytotoxicity without impairing the normal liver tissue. Additionally, the higher indexes of thymus and spleen indicated that NTE could facilitate the growth of immune organs. The results indicate that NTE is a promising candidate for the antitumor treatment with high efficacy and safety.

  18. Image-guided microbeam irradiation to brain tumour bearing mice using a carbon nanotube X-ray source array

    PubMed Central

    Zhang, Lei; Yuan, Hong; Burk, Laurel M; Inscoe, Christy R; Hadsell, Michael J; Chtcheprov, Pavel; Lee, Yueh Z; Lu, Jianping; Chang, Sha; Zhou, Otto

    2014-01-01

    Microbeam radiation therapy (MRT) is a promising experimental and preclinical radiotherapy method for cancer treatment. Synchrotron based MRT experiments have shown that spatially fractionated microbeam radiation has the unique capability of preferentially eradicating tumour cells while sparing normal tissue in brain tumour bearing animal models. We recently demonstrated the feasibility of generating orthovoltage microbeam radiation with an adjustable microbeam width using a carbon nanotube based X-ray source array. Here we report the preliminary results from our efforts in developing an image guidance procedure for the targeted delivery of the narrow microbeams to the small tumour region in the mouse brain. Magnetic resonance imaging was used for tumour identification, and on-board X-ray radiography was used for imaging of landmarks without contrast agents. The two images were aligned using 2D rigid body image registration to determine the relative position of the tumour with respect to a landmark. The targeting accuracy and consistency were evaluated by first irradiating a group of mice inoculated with U87 human glioma brain tumours using the present protocol and then determining the locations of the microbeam radiation tracks using γ-H2AX immunofluorescence staining. The histology results showed that among 14 mice irradiated, 11 received the prescribed number of microbeams on the targeted tumour, with an average localization accuracy of 454 μm measured directly from the histology (537 μm if measured from the registered histological images). Two mice received one of the three prescribed microbeams on the tumour site. One mouse was excluded from the analysis due to tissue staining errors. PMID:24556798

  19. Vaccine Efficacy in Senescent Mice Challenged with Recombinant SARS-CoV Bearing Epidemic and Zoonotic Spike Variants

    PubMed Central

    Deming, Damon; Sheahan, Timothy; Heise, Mark; Yount, Boyd; Davis, Nancy; Sims, Amy; Suthar, Mehul; Harkema, Jack; Whitmore, Alan; Pickles, Raymond; West, Ande; Donaldson, Eric; Curtis, Kristopher; Johnston, Robert; Baric, Ralph

    2006-01-01

    eosinophilic infiltrates within the lungs of SARS-CoV–challenged mice. VRP-N–induced pathology presented at day 4, peaked around day 7, and persisted through day 14, and was likely mediated by cellular immune responses. Conclusions This study identifies gaps and challenges in vaccine design for controlling future SARS-CoV zoonosis, especially in vulnerable elderly populations. The availability of a SARS-CoV virus bearing heterologous S glycoproteins provides a robust challenge inoculum for evaluating vaccine efficacy against zoonotic strains, the most likely source of future outbreaks. PMID:17194199

  20. Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants.

    PubMed

    Deming, Damon; Sheahan, Timothy; Heise, Mark; Yount, Boyd; Davis, Nancy; Sims, Amy; Suthar, Mehul; Harkema, Jack; Whitmore, Alan; Pickles, Raymond; West, Ande; Donaldson, Eric; Curtis, Kristopher; Johnston, Robert; Baric, Ralph

    2006-12-01

    the lungs of SARS-CoV-challenged mice. VRP-N-induced pathology presented at day 4, peaked around day 7, and persisted through day 14, and was likely mediated by cellular immune responses. This study identifies gaps and challenges in vaccine design for controlling future SARS-CoV zoonosis, especially in vulnerable elderly populations. The availability of a SARS-CoV virus bearing heterologous S glycoproteins provides a robust challenge inoculum for evaluating vaccine efficacy against zoonotic strains, the most likely source of future outbreaks.

  1. Effects of Feijining Decoction on vascular endothelial growth factor protein expression and changes of T cell subsets in Lewis lung carcinoma-bearing mice.

    PubMed

    Zhou, Lijiang; Pan, Yuzhen; Xing, Yuqing; Gao, Hong; Xie, Xiaodong; Yin, Dongfeng

    2015-05-01

    Angiogenesis is crucial for cancer growth and metastasis. T cells are also key members of the adaptive immunity against tumorigenesis. The aim of the present study was to observe the effects of Feijining Decoction (FJND) on vascular endothelial growth factor (VEGF) protein expression and T cell subsets [cluster of differentiation 4(+)(CD4(+)) and CD8(+) T lymphocyte] in Lewis lung carcinoma (LLC)-bearing mice. C57BL/6J mice were subcutaneously implanted with LLC cells. Forty carcinoma-bearing mice were randomly assigned to four groups (10 animals/group). The control group (CG) were the untreated group, the cisplatinum (DDP) group (DG) mice were treated with DDP, the FJND group (FG) were treated with FJND and the FJND + DDP group (FDG) were treated with FJND and DDP. Western blot and flow cytometry were used to evaluate the VEGF protein expression of tumor tissue and T cell subsets of the spleen. Spontaneous activity in 5 min was observed by the photoelectric counting method. DDP + FJND (FDG group) markedly inhibited tumor growth compared to the DG mice. The protein expression of VEGF was significantly downregulated in the carcinoma of FG mice compared to CG mice. VEGF protein expression was significantly reduced in FDG compared to DG mice. In the FG mice, the splenic CD4(+) and CD4(+)/CD8(+) cells were significantly increased compared to the CG mice, and the splenic CD4(+) cells in the FDG mice were significantly increased compared to the DG group. In conclusion, FJND can inhibit tumor growth by downregulating VEGF protein expression and improving the immune function.

  2. Effects of Feijining Decoction on vascular endothelial growth factor protein expression and changes of T cell subsets in Lewis lung carcinoma-bearing mice

    PubMed Central

    ZHOU, LIJIANG; PAN, YUZHEN; XING, YUQING; GAO, HONG; XIE, XIAODONG; YIN, DONGFENG

    2015-01-01

    Angiogenesis is crucial for cancer growth and metastasis. T cells are also key members of the adaptive immunity against tumorigenesis. The aim of the present study was to observe the effects of Feijining Decoction (FJND) on vascular endothelial growth factor (VEGF) protein expression and T cell subsets [cluster of differentiation 4+(CD4+) and CD8+ T lymphocyte] in Lewis lung carcinoma (LLC)-bearing mice. C57BL/6J mice were subcutaneously implanted with LLC cells. Forty carcinoma-bearing mice were randomly assigned to four groups (10 animals/group). The control group (CG) were the untreated group, the cisplatinum (DDP) group (DG) mice were treated with DDP, the FJND group (FG) were treated with FJND and the FJND + DDP group (FDG) were treated with FJND and DDP. Western blot and flow cytometry were used to evaluate the VEGF protein expression of tumor tissue and T cell subsets of the spleen. Spontaneous activity in 5 min was observed by the photoelectric counting method. DDP + FJND (FDG group) markedly inhibited tumor growth compared to the DG mice. The protein expression of VEGF was significantly downregulated in the carcinoma of FG mice compared to CG mice. VEGF protein expression was significantly reduced in FDG compared to DG mice. In the FG mice, the splenic CD4+ and CD4+/CD8+ cells were significantly increased compared to the CG mice, and the splenic CD4+ cells in the FDG mice were significantly increased compared to the DG group. In conclusion, FJND can inhibit tumor growth by downregulating VEGF protein expression and improving the immune function. PMID:26137245

  3. Effect of hesperidin on mice bearing Ehrlich solid carcinoma maintained on doxorubicin.

    PubMed

    Khedr, Naglaa F; Khalil, Rania M

    2015-12-01

    Doxorubicin (DOX) is widely used in cancer therapy of many carcinomas types. Unfortunately, DOX is not sufficiently effective in many cases, and increasing the dosage of it is limited due to its systemic toxicity. A citrus flavonoid hesperidin (HES) is proved to be potent antioxidant and protective agent against many diseases including cancer. In this context, the objective of this study was to examine effect of HES along with DOX on solid Ehrlich carcinoma (SEC) in mice. Forty male mice were divided into four equal groups (n = 10): control SEC, DOX, HES, and DOX + HES. HES (50 mg/kg body weight orally) was given day after day for 16 days along with DOX (4 mg/kg body weight i.p. injection) for 5 cycles every 4 days in ESC-inoculated mice. After 20 days, tumor volume, tumor weight, survival rate, tumor glutathione, nitric oxide content, and serum glutathione were determined. Tumor tissue was examined for histopathological and immunohistochemical study for p53 and VEGF. Tumor resistance for mdr1a gene was assessed in tumor tissue by RT-PCR. HES induced significant increase in tissue and serum glutathione with significant decrease in tumor volume and tumor weight. A possible role of HES to modulate gene expression of mdr1a in tumor tissue was established. In addition, HES alleviated the histopathological changes with significant decrease in p53 and VEGF expression. The use of HES as adjuvant therapy with DOX would enhance the therapeutic efficacy and alleviate the resistance to DOX in treatment of solid tumors.

  4. Safety assessment of ovarian cryopreservation and transplantation in nude mice bearing human epithelial ovarian cancer.

    PubMed

    Zhu, Gen-Hai; Wang, Sheng-Tan; Yang, Zhao-Xin; Cai, Jun-Hong; Chen, Chun-Ying; Yao, Mao-Zhong; Hong, Lan; He, Guo-Li; Yang, Shu-Ying

    2012-01-01

    Nude mice with orthotopic transplantation of human ovarian epithelial cancer were used to investigate screening criteria for paraneoplastic normal ovarian tissue and the security of the freezing and thawing for ovarian tissue transplantation. Expression of CK-7, CA125, P53, survivin, MMP-2/TIMP- 2 in paraneoplastic normal ovarian tissues were detected by RT-PCR as well as immunohistochemistry. The tissues of the groups with all negative indicators of RT-PCR, all negative indicators of immunohistochemistry, negative expression of CK-7, CA125 and survivin, positive expression of CK-7, CA125 and survivin, cancer tissues and normal ovarian tissues of nude mice were used for freezing and thawing transplantation, to analyze overt and occult carcinogenesis rates after transplantation. When all indicators or the main indicators, CK-7, CA125 and survivin, were negative, tumorigenesis did not occur after transplantation. In addition the occult carcinogenesis rate was lower than in the group with positive expression of CK-7, CA125 and survivin (P<0.01). After subcutaneous and orthotopic transplantation of ovarian tissues, rates did not change (P>0.05). There was no statistical significance among rates after transplantation of ovarian tissues which were obtained under different severity conditions (P>0.05). Negative expression of CK-7, CA125 and survivin can be treated as screening criteria for security of ovarian tissues for transplantation. Immunohistochemical methods can be used as the primary detection approach. Both subcutaneous and orthotopic transplantation are safe. The initial severity does not affect the carcinogenesis rate after tissue transplantation. Freezing and thawing ovarian tissue transplantation in nude mice with human epithelial ovarian carcinoma is feasible and safe.

  5. Influence of polychemotherapy on the morphology of metastases and kidney of resistant RLS-bearing mice.

    PubMed

    Zonov, E V; Voronina, E I; Zenkova, M A; Ageeva, T A; Ryabchikova, E I

    2013-03-01

    Polychemotherapy (PCT), widely used for the antitumor treatment has a pronounced toxic effect on the organism, and its cytostatic effect sometimes is canceled by multidrug resistance of a neoplasia. Comprehension of the nature and development of pathological changes caused by the PCT during the treatment of cancer is very important to improve the efficiency of the therapy and to clarify the mechanisms of tumor-host interactions. This study was aimed to examine PCT impact on kidney cells and tissues in mice with transplanted resistant lymphosacroma (RLS) and to analyze morphology of metastases of the tumor in kidney during PCT. Male mice CBA/LacSto (55 animals) were intramuscularly implanted in the right hind paw by 105 cells/ml of tumor RLS (a diffuse large B-cell lymphosarcoma) with multi-drug resistance (MDR) phenotype. Mice received combination of cyclophosphamide (50 mg/kg), oncovin (0.1 mg/kg), hydroxydaunorubicin (4 mg/kg), and prednisone (5 mg/kg) accordingly to CHOP scheme each 7 days after inoculation of the tumor. The kidneys were sampled on days 1, 3 and 7 after each series of injection of PCT preparations and processed for light and electron microscopy, immunohistochemical analysis of Ki-67 and Apaf-1 proteins also was performed. Tumor RLS produced metastases comprised of small cells in the kidneys of mice after 8 days post inoculation. Application of PCT resulted in destruction of small-cell metastases and development of many large-cell metastases in kidney. Application of PCT induced the development of prominent damage of nephron cells, primarily in S3 segments of proximal tubules. Even one series of PCT caused reduction of basal plasma folds in these cells and alteration of mitochondria. Damage of proximal tubules and involvement of distal tubules, renal bodies and interstitial tissue in the pathologic process, increased during the experiment. This work presents the description of morphological changes in kidney as well as of the tumor metastases

  6. Metabolism of proteins and glycoproteins in tumour bearing mice treated with Aeromonas L-asparaginase.

    PubMed

    Benny, P J; Muraleedhara, K G; Sreejith, K; Jayashree, G

    1996-12-01

    L-asparaginase, isolated in our laboratory, from Aeromonas had been found to be antileukaemic. In the present study, changes in the levels of proteins and glycoproteins in leukaemic mice and under treatment with Aeromonas L-asparaginase have been compared. Levels of protein bound hexose, fucose and sialic acid which were increased during leukaemia attained normal levels when treated with L-asparaginase. The increased blood urea level declined significantly during enzyme therapy. Effects of L-asparaginase are compared with 'Leunase', a commercially available drug used in the treatment of leukaemia.

  7. Mixed lymphocyte reactivity against normal cells by splenic lymphocytes from tumor-bearing mice : ii. Studies of autoimmune-like activity in completely syngeneic and semisyngeneic systems.

    PubMed

    Devlin, R G; McCurdy, J D; Baronowsky, P E

    1974-01-01

    A possible consequence of an antilymphocytic autoimmune process would be serious impairment of an animal's ability to destroy tumor cells. One measure of autoimmune reactivity of this type would be the demonstration of cellular immune responsiveness by cells from tumor-bearing mice against syngeneic normal cells. These experiments demonstrate that spleen cells from mice bearing a lymphocytic leukemia of identical histocompatability type as the host mounted a vigorous immune response against normal syngeneic cells in a mixed lymphocyte reaction (MLR). Moreover, ascitic cells from leukemic mice responded significantly to normal syngeneic spleen cells in MLR's. The former reactions are usually much more vigorous than the responses of normal to malignant cells. These results are discussed in terms of the relationship between autoimmunity and neoplasia. Alternative explanations necessitated by the dangers involved in the interpretation of the immunology of transplantable tumors are considered.

  8. Dietary rice bran component γ-oryzanol inhibits tumor growth in tumor-bearing mice.

    PubMed

    Kim, Sung Phil; Kang, Mi Young; Nam, Seok Hyun; Friedman, Mendel

    2012-06-01

    We investigated the effects of rice bran and components on tumor growth in mice. Mice fed standard diets supplemented with rice bran, γ-oryzanol, Ricetrienol®, ferulic acid, or phytic acid for 2 weeks were inoculated with CT-26 colon cancer cells and fed the same diet for two additional weeks. Tumor mass was significantly lower in the γ-oryzanol and less so in the phytic acid group. Tumor inhibition was associated with the following biomarkers: increases in cytolytic activity of splenic natural killer (NK) cells; partial restoration of nitric oxide production and phagocytosis in peritoneal macrophages increases in released the pro-inflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6 from macrophages; and reductions in the number of blood vessels inside the tumor. Pro-angiogenic biomarkers vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and 5-lipoxygenase-5 (5-LOX) were also significantly reduced in mRNA and protein expression by tumor genes. ELISA of tumor cells confirmed reduced expression of COX-2 and 5-LOX up to 30%. Reduced COX-2 and 5-LOX expression downregulated VEGF and inhibited neoangiogenesis inside the tumors. Induction of NK activity, activation of macrophages, and inhibition of angiogenesis seem to contribute to the inhibitory mechanism of tumor regression by γ-oryzanol. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Phenotypic dynamics of microglial and monocyte-derived cells in glioblastoma-bearing mice

    PubMed Central

    Ricard, Clément; Tchoghandjian, Aurélie; Luche, Hervé; Grenot, Pierre; Figarella-Branger, Dominique; Rougon, Geneviève; Malissen, Marie; Debarbieux, Franck

    2016-01-01

    Inflammatory cells, an integral component of tumor evolution, are present in Glioblastomas multiforme (GBM). To address the cellular basis and dynamics of the inflammatory microenvironment in GBM, we established an orthotopic syngenic model by grafting GL261-DsRed cells in immunocompetent transgenic LysM-EGFP//CD11c-EYFP reporter mice. We combined dynamic spectral two-photon imaging with multiparametric cytometry and multicolor immunostaining to characterize spatio-temporal distribution, morphology and activity of microglia and blood-derived infiltrating myeloid cells in live mice. Early stages of tumor development were dominated by microglial EYFP+ cells invading the tumor, followed by massive recruitment of circulating LysM-EGFP+ cells. Fluorescent invading cells were conventional XCR1+ and monocyte-derived dendritic cells distributed in subpopulations of different maturation stages, located in different areas relative to the tumor core. The lethal stage of the disease was characterized by the progressive accumulation of EGFP+/EYFP+ monocyte-derived dendritic cells. This local phenotypic regulation of monocyte subtypes marked a transition in the immune response. PMID:27193333

  10. Exposure of tumor-bearing mice to extremely high-frequency electromagnetic radiation modifies the composition of fatty acids in thymocytes and tumor tissue.

    PubMed

    Gapeyev, Andrew B; Kulagina, Tatiana P; Aripovsky, Alexander V

    2013-08-01

    To test the participation of fatty acids (FA) in antitumor effects of extremely high-frequency electromagnetic radiation (EHF EMR), the changes in the FA composition in the thymus, liver, blood plasma, muscle tissue, and tumor tissue in mice with Ehrlich solid carcinoma exposed to EHF EMR were studied. Normal and tumor-bearing mice were exposed to EHF EMR with effective parameters (42.2 GHz, 0.1 mW/cm2, 20 min daily during five consecutive days beginning the first day after the inoculation of tumor cells). Fatty acid composition of various organs and tissues of mice were determined using a gas chromatography. It was shown that the exposure of normal mice to EHF EMR or tumor growth significantly increased the content of monounsaturated FA (MUFA) and decreased the content of polyunsaturated FA (PUFA) in all tissues examined. Exposure of tumor-bearing mice to EHF EMR led to the recovery of FA composition in thymocytes to the state that is typical for normal animals. In other tissues of tumor-bearing mice, the exposure to EHF EMR did not induce considerable changes that would be significantly distinguished between disturbances caused by EHF EMR exposure or tumor growth separately. In tumor tissue which is characterized by elevated level of MUFA, the exposure to EHF EMR significantly decreased the summary content of MUFA and increased the summary content of PUFA. The recovery of the FA composition in thymocytes and the modification of the FA composition in the tumor under the influence of EHF EMR on tumor-bearing animals may have crucial importance for elucidating the mechanisms of antitumor effects of the electromagnetic radiation.

  11. Presence of neutrophil-bearing antigen in lymphoid organs of immune mice.

    PubMed

    Maletto, Belkys A; Ropolo, Andrea S; Alignani, Diego O; Liscovsky, Miriam V; Ranocchia, Romina P; Moron, Victor Gabriel; Pistoresi-Palencia, María C

    2006-11-01

    Neutrophils play a crucial early role during the innate response, but little is known about their possible contribution when an adaptive immune response is installed. A robust neutrophilia and a T helper 1 (Th1) immune response are present after immunization with Complete Freund Adjuvant (CFA). We show that when FITC-labeled OVA was injected into the footpad of OVA/CFA immunized mice, the main OVA-FITC+ cells recruited in draining popliteal lymph nodes (LNs) were neutrophils, with most of them arriving at the LN by means of lymphatic vessels. The development of this OVA-FITC+ neutrophil influx requires an immune response against OVA. The OVA-FITC+ neutrophils present in LNs displayed mainly intracellular TNF-alpha, and their depletion resulted in an increase in the specific IL-5 levels. These data provide new evidence about the role played by neutrophils in vivo in adaptive immunity.

  12. Composition and mechanism of antitumor effects of Hericium erinaceus mushroom extracts in tumor-bearing mice.

    PubMed

    Kim, Sung Phil; Kang, Mi Young; Kim, Jae Ho; Nam, Seok Hyun; Friedman, Mendel

    2011-09-28

    We investigated antitumor effects of the following four extracts of freeze-dried Hericium erinaceus mushrooms in Balb/c mice intracutaneously transplanted on the backs with CT-26 colon cancer cells: HWE, hot water extraction by boiling in water for 3 h; MWE, microwaving in 50% ethanol/water at 60 W for 3 min; and ACE and AKE, boiling in 1% HCl or 3% NaOH for 2 h. HWE and MWE with a higher content of β-glucans, determined by an assay kit, than ACE and MKE were active in all bioassays. Gas chromatography/mass spectrometry analyses showed the presence of 40, 27, 16, and 13 compounds, respectively, in the four extracts. Daily intraperitoneal (ip) injections of HWE and MWE for 2 weeks significantly reduced tumor weights by 38 and 41%. Tumor regressions were associated with changes in the following cancer biomarkers as compared to phosphate buffer (PBS)-treated control mice: 2.7- and 2.4-fold increases in cytolytic activity of splenic natural killer (NK) cells; restored nitric oxide production and phagocytosis in peritoneal macrophages to 95-98% of normal levels; ∼2-fold increase in released pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6 from macrophages; and ∼56 and ∼60% reductions in the number of blood vessels inside the tumor. The pro-angiogenic factors vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2), and 5-lipoxygenase (5-LOX) were also significantly reduced in mRNA and protein expression by tumor genes. Enzyme-linked immunosorbent assay of tumor cells confirmed reduced expression of COX-2 and 5-LOX (32 and 31%). Reduced COX-2 and 5-LOX expression down-regulated VEGF expression, resulting in inhibition of neo-angiogenesis inside the tumors. The results indicate that induction of NK activity, activation of macrophages, and inhibition of angiogenesis all contribute to the mechanism of reduction of tumor size.

  13. Effect of Alstonia scholaris in enhancing the anticancer activity of berberine in the Ehrlich ascites carcinoma-bearing mice.

    PubMed

    Jagetia, Ganesh Chandra; Baliga, Manjeshwar Shrinath

    2004-01-01

    The chemomodulatory activity of Alstonia scholaris extract (ASE) was studied in combination with berberine hydrochloride (BCL), a topoisomerase inhibitor, in Ehrlich ascites carcinoma-bearing mice. The tumor-bearing animals were injected with various doses of ASE, and 8 mg/kg of BCL (one-fifth of the 50% lethal dose) was combined with different doses of ASE (60-240 mg/kg). The combination of 180 mg/kg of ASE with 8 mg/kg of BCL showed the greatest antitumor effect; the number of tumor-free survivors was more, and the median survival time and the average survival time increased up to 47 and 40.5 days, respectively, when compared with either treatment alone. Similarly, when 180 mg/kg of ASE was combined with different doses of BCL (2-12 mg/kg), a dose-dependent increase in the anticancer activity was observed up to 8 mg/kg of BCL. However, a further increase in the BCL dose to 10 and 12 mg/kg resulted in toxic side effects. The best effect was observed when 180 mg/kg of ASE was combined with 6 or 8 mg/kg of BCL, where an increase in the antineoplastic activity was reported. The efficacy of the combination of 180 mg/kg of ASE was also tested with 6 mg/kg body weight of BCL in various stages of tumorigenesis, and it was effective when given in the early stages, although the efficiency decreased with an increase in the tumor developmental stages.

  14. Disposition and metabolism of O6-alkylguanine-DNA alkyltransferase inhibitor in nude mice bearing human melanoma.

    PubMed

    Cussac, C; Mounetou, E; Rapp, M; Madelmont, J C; Maurizis, J C; Labarre, P; Chollet, P; Chabard, J L; Godeneche, D; Baudry, J P

    1994-01-01

    Tumor resistances to chloroethylnitrosourea (CENU) are mainly due to O6-alkylguanine-DNA alkyltransferase (AGT). Our laboratory has synthesized a new water-soluble AGT inhibitor. O6-benzyl-N-acetylguanosine (BNAG). We have shown that this compound is able to deplete AGT activity on M4Beu human melanoma cells and to enhance the antitumor power of CENU N'-[2-chloroethyl]-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (cystemustine) towards the M4Beu melanoma grafted on nude mice. With a view to determining the best combination BNAG/CENUs conditions, we have studied the distribution and metabolism of BNAG in nude mice bearing M4Beu human melanoma. BNAG, labelled with carbon-14 on the benzyl group, was administered by single i.v. dose of 40 mg/kg. Blood analysis showed that the main radioactive compound was unchanged molecule, and only a small part was found as hippuric acid resulting from the metabolic cleavage of the benzyl group. BNAG and hippuric acid were mainly eliminated in the urine. Unchanged BNAG blood kinetics showed three phases: blood epuration (t1/2 (1) = 13 min), reabsorption and elimination (t1/2 (2) = 1.7 hr). This kinetic profile is probably due to an enterohepatic cycle. BNAG is distributed in several tissues (kidney, liver, skin, duodenum, colon, tumor) but not in the central nervous system, suggesting a poor blood-brain crossing. Because an important part of the administered dose is not metabolized, high unchanged BNAG level remains in most tissues, including M4Beu tumor, and AGT depletion can occur several hours after dosing.

  15. Antitumor and immunomodulatory effects of low-dose 5-FU on hepatoma 22 tumor-bearing mice

    PubMed Central

    CAO, ZHIYUN; ZHANG, ZHIDENG; HUANG, ZHENGRONG; WANG, RONGPING; YANG, AILIAN; LIAO, LIANMING; DU, JIAN

    2014-01-01

    Low-dose 5-fluorouracil (5-FU), a widely used chemotherapeutic, has been reported to have immunomodulatory effects. This study aimed to evaluate the optimal dose of 5-FU that produces antitumor and immunomodulatory effects. In a hepatoma 22 tumor-bearing mouse model, 0, 10, 20 and 40 mg/kg 5-FU (i.p.) was administered for 10 days. Tumor weight and volume were measured, thymus index (TI) and spleen index (SI) were calculated, and the number of white blood cells (WBCs) and lymphocytes (LYs) were counted following treatment. The percentages of CD3+, CD4+, CD8+ and natural killer (NK) cells were measured by flow cytometry. In addition, the body weights of the mice were measured and the average diet consumption was calculated. Administration of 5-FU produced a potent antitumor effect in a dose-dependent manner (P<0.01). At 20 and 40 mg/kg, a significant reduction of body weight and food consumption was observed. TI and SI decreased in the 20- and 40-mg/kg groups (P<0.01) for 10 days. The number of WBCs significantly decreased in each group (P<0.01); however, the number of LYs only decreased in the 40-mg/kg group (P<0.01). Percentages of CD3+ and CD4+ cells were increased in the 10- and 20-mg/kg groups (P<0.01). Thus, 5-FU at 10 mg/kg inhibits tumor growth while maintaining the immune function of the mice. 5-FU may exert its antitumor effect at a low dose with low toxicity and stimulate the host immune system. Future clinical trials taking into account the immunostimulatory capacity of chemotherapeutic agents are desirable for certain patients. PMID:24660037

  16. Comparison of hypoxic cell radiosensitizers, KIN-804, KIN-844, KIN-806 and TX-1877, on brain and liver metabolizing capacities in mice bearing Ehrlich ascites carcinoma.

    PubMed

    Abou-Bedair, Farid Ahmed; Hori, Hitoshi; Nagasawa, Hideko; Uto, Yoshihiro; Abu-Zeid, Medhat; Inayama, Seiichi

    2002-05-01

    The biochemical effects of the 2-nitroimidazole hypoxic cell radiosensitizers KIN-804, KIN-806, and their analogues KIN-844 and TX-1877 on brain acetylcholinesterase (AChE) and hepatic free radical scavenging systems, such as reduced glutathione (GSH) and glucose-6-phosphate dehydrogenase (G-6-PDH) levels, and hepatic antioxidants, such as superoxide dismutase (SOD) and catalase, were evaluated in Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The assay of brain AChE revealed nonsignificant changes with all drugs examined. To evaluate the hepatic metabolic capacity, groups of mice were divided into control, EAC-inoculated, 10-Gy local gamma-irradiated, and KIN-804, KIN-844, KIN-806, or TX-1877 (50 mg/kg body weight, i.p.) groups, and gamma-irradiation was combined with each drug. EAC inoculation markedly suppressed GSH, G-6-PDH, SOD, and catalase levels. On the other hand, treatment with gamma-irradiation significantly enhanced them. The treatment of EAC-bearing mice with each drug alone in the absence of gamma-irradiation revealed that KIN-806 and its derivative TX-1877 showed antitumor activity through their significant recovery of GSH and SOD levels, respectively, in the EAC-bearing mice group. Similarly, the combined treatment of EAC-bearing mice with gamma-irradiation with each of the drugs tested showed that KIN-806 and TX-1877 significantly increased GSH and SOD, and to a lesser extent G-6-PDH and catalase levels. On the other hand, KIN-804 and KIN-844 had only a nonsignificant effect on all parameters examined. In conclusion, these data reveal that the administration of KIN-806 and TX-1877 with or without subsequent gamma-irradiation, resulted in significant recovery of GSH and SOD activities that were inhibited by EAC inoculation.

  17. Pharmacokinetics of doxorubicin after intratumoral injection using a thermosensitive hydrogel in tumor-bearing mice.

    PubMed

    Al-Abd, Ahmed M; Hong, Ki-Yun; Song, Soo-Chang; Kuh, Hyo-Jeong

    2010-02-25

    A novel, thermosensitive hydrogel, poly(organophosphazene), is an injectable drug delivery system that transforms from sol to gel at body temperature. Doxorubicin (DOX) is a cytotoxic drug used for the treatment of several solid tumors. Due to its acute cardiac toxicity, DOX is a good candidate for local chemo-drug delivery system. In this study, we evaluated the pharmacokinetics of DOX (30 mg/kg) when given as an intratumoral injection using poly(organophosphazene) hydrogel in mice with human gastric tumor xenografts. DOX was formulated at 0.6% into a 10% hydrogel, and 40% and 90% of the dose was released in a sustained manner over 5 weeks in vitro and in vivo, respectively. The hydrogel mass was well retained over 7 weeks, and T(1/2beta, tumor) was 1.8-fold longer than that of the solution, but the 2.2-fold lower C(max, tumor), produced a similar AUC(tumor) and antitumor effect. However, solution caused a 2-fold higher systemic exposure (AUC(plasma)), which resulted in significant mortality due to acute cardiac toxicity. These data indicate that hydrogel formulation may have similar efficacy but lower systemic exposure than aqueous solution. In conclusion, poly(organophosphazene) showed adequate characteristics for local intratumoral delivery of DOX, including dose capacity, local retention, and minimal systemic spill-over. The safety and biocompatibility of poly(organophosphazene) should be further evaluated and its application should be extended to other anticancer agents. Copyright 2009 Elsevier B.V. All rights reserved.

  18. Mathematical modeling of tumor growth and metastatic spreading: validation in tumor-bearing mice.

    PubMed

    Hartung, Niklas; Mollard, Séverine; Barbolosi, Dominique; Benabdallah, Assia; Chapuisat, Guillemette; Henry, Gerard; Giacometti, Sarah; Iliadis, Athanassios; Ciccolini, Joseph; Faivre, Christian; Hubert, Florence

    2014-11-15

    Defining tumor stage at diagnosis is a pivotal point for clinical decisions about patient treatment strategies. In this respect, early detection of occult metastasis invisible to current imaging methods would have a major impact on best care and long-term survival. Mathematical models that describe metastatic spreading might estimate the risk of metastasis when no clinical evidence is available. In this study, we adapted a top-down model to make such estimates. The model was constituted by a transport equation describing metastatic growth and endowed with a boundary condition for metastatic emission. Model predictions were compared with experimental results from orthotopic breast tumor xenograft experiments conducted in Nod/Scidγ mice. Primary tumor growth, metastatic spread and growth were monitored by 3D bioluminescence tomography. A tailored computational approach allowed the use of Monolix software for mixed-effects modeling with a partial differential equation model. Primary tumor growth was described best by Bertalanffy, West, and Gompertz models, which involve an initial exponential growth phase. All other tested models were rejected. The best metastatic model involved two parameters describing metastatic spreading and growth, respectively. Visual predictive check, analysis of residuals, and a bootstrap study validated the model. Coefficients of determination were [Formula: see text] for primary tumor growth and [Formula: see text] for metastatic growth. The data-based model development revealed several biologically significant findings. First, information on both growth and spreading can be obtained from measures of total metastatic burden. Second, the postulated link between primary tumor size and emission rate is validated. Finally, fast growing peritoneal metastases can only be described by such a complex partial differential equation model and not by ordinary differential equation models. This work advances efforts to predict metastatic spreading

  19. Synthesis of a nickel tetracarboranylphenylporphyrin for boron neutron-capture therapy: biodistribution and toxicity in tumor-bearing mice.

    PubMed

    Miura, M; Micca, P L; Fisher, C D; Heinrichs, J C; Donaldson, J A; Finkel, G C; Slatkin, D N

    1996-09-27

    Nickel-2,3,7,8,12,13,17,18-octaacetic acid-5,10,15,20-tetra-[3-carboranyl-methoxyphenyl]-porphyrin octamethylester (NiTCP) was given in a Cremophor EL, a polyethoxylated castor oil, and propylene glycol emulsion to BALB/c mice bearing transplanted s.c. KHJJ mammary carcinomas. A total dose of 244 microg NiTCP/gram body weight (gbw) (54 microg B/gbw) was given in 6 i.p. injections over a 32 hr period. Observations of behavior and changes in body weight and chemical and hematological blood tests indicated little or no toxicity from NiTCP over a period of 6-90 hr after injections. Boron concentrations near tumor margins were 160-180 microg B/g at 41-90 hr after the last injection. Tumor:normal brain boron concentration ratios reached approx. 10:1 and tumor:blood ratios reached approx. 250:1 after 4 days. There was no evidence of thrombocytopenia or other potentially important toxicities. Our findings place NiTCP among the leading candidates for pre-clinical experiments aimed toward improvement upon the compounds being tested for boron neutron-capture therapy of glioblastoma multiforme.

  20. A new 111In-bleomycin complex for tumor imaging: preparation, stability, and distribution in glioma-bearing mice

    SciTech Connect

    Hou, D.Y.; Hoch, H.; Johnston, G.S.; Tsou, K.C.; Jones, A.E.; Farkas, R.J.; Miller, E.E.

    1984-03-01

    A new 111In-bleomycin complex (111In-BLMC) is here reported. Its radiochemical purity was 99% by thin-layer chromatography (TLC) (Rf 0.65) and in 5% agarose gel electrophoresis in 0.02 M NaHCO3 it migrated toward the anode. Autoradiographs of TLC and gel electrophoresis plates showed no change on storage for 3 weeks. Urine and plasma from untreated or glioma-bearing mice after injection of 111In-BLMC were analyzed by TLC and gel electrophoresis. Results indicated stability in vivo, nonbinding to transferrin, affinity to viable tumor, and excretion faster than 111In-BLM-B2, 111In-BLM, or 57Co-BLM. Tissue distributions 24 hr after injection of radiopharmaceutical showed activity ratios of tumor to blood, muscle, and brain of 13.1, 12.4, and 81.6, respectively, which were significantly higher than those for previously prepared 111In-BLM-B2 or 111In-BLM (except for brain, 0.05 less than P less than 0.1). The new 111In-BLM complex may be useful in clinical imaging and for combining radionuclide radiotherapy and chemotherapy.

  1. Alterations in macrophages and monocytes from tumor-bearing mice: evidence of local and systemic immune impairment.

    PubMed

    Torroella-Kouri, Marta; Rodríguez, Dayron; Caso, Raul

    2013-12-01

    Macrophages are cells of the innate immune system involved in critical activities such as maintaining tissue homeostasis and immune surveillance. Pro-inflammatory macrophages M1 are responsible for the inflammatory response, while M2 macrophages are associated with the immunosuppressive repair phase of tissue remodeling. Most cancers are associated with chronic inflammation, and a high number of macrophages in tumors have been associated with tumor progression. Much effort has been made in elucidating the mechanisms through which macrophages contribute to tumor development, yet much less is known about the initial mechanisms by which tumors modify macrophages. Our work has focused on identifying the mechanisms by which macrophages from tumor hosts are modified by tumors. We have shown that peritoneal macrophages are significantly altered in mice bearing advanced mammary tumors and are not M1 or M2 polarized, but express a mixture of both transcriptional programs. These macrophages are less differentiated and more prone to apoptosis, resulting in increased myelopoiesis as a compensation to regenerate macrophage progenitors in the marrow. Macrophages in the tumor microenvironment are also neither M1 nor M2 cells and through a display of different mechanisms are even more impaired than their peripheral counterparts. Finally, systemic blood monocytes, precursors of tissue macrophages, are also altered in tumor bearers and show a mixed program of pro- and anti-inflammatory functions. We conclude that there is evidence for local and systemic immune impairment in tumor hosts.

  2. Biodistribution and Pharmacokinetics of EGFR-Targeted Thiolated Gelatin Nanoparticles Following Systemic Administration in Pancreatic Tumor-Bearing Mice

    PubMed Central

    Xu, Jing; Gattacceca, Florence; Amiji, Mansoor

    2013-01-01

    The objective of this study was to evaluate qualitative and quantitative biodistribution of epidermal growth factor receptor (EGFR)-targeted thiolated type B gelatin nanoparticles in vivo in a subcutaneous human pancreatic adenocarcinoma (Panc-1) bearing female SCID Beige mice. EGFR-targeted nanoparticles showed preferential and sustained accumulation in the tumor mass, especially at early time points. Higher blood concentrations and higher tumor accumulations were observed with PEG-modified and EGFR-targeted nanoparticles during the study (AUClast: 17.38 and 19.56 %ID/mL*h in blood, 187 and 322 %ID/g*h in tumor for PEG-modified and EGFR-targeted nanoparticles, respectively), as compared to control, unmodified particles (AUClast: 10.71 %ID/mL*h in blood and 138 %ID/g*h in tumor). EGFR-targeted nanoparticles displayed almost twice tumor targeting efficiency than either PEG-modified or the unmodified nanoparticles, highlighting the efficacy of the active targeting strategy. In conclusion, this study shows that EGFR-targeted and PEG-modified nanoparticles were suitable vehicles for specific systemic delivery in subcutaneous Panc-1 tumor xenograft models. PMID:23544877

  3. Effect of cadmium exposure on primary tumor growth and cell-mediated cytotoxicity in mice bearing MSB sarcomas.

    PubMed

    Kerkvliet, N I; Koller, L D; Baecher, L G; Brauner, J A

    1979-08-01

    In vivo MSB tumor growth and cell-mediated cytotoxicity (CMC) to MSB tumor cells in vitro were studied in male C57BL/6 mice exposed to 0, 3, 30, or 300 ppm Cd as CdCl2 in their drinking water for 21 weeks prior to and during tumor growth. CMC was assessed on days 5, 12, and 19 post injection with the use of both a 51Cr release assay and a 51Cr post-label assay. Cd exposure significantly inhibited the growth of MSB tumors in vivo and enhanced the levels of CMC in the tumor-bearing hosts. Peak levels of CMC on day 12 post tumor injection were significantly increased in Cd-exposed animals. However, whereas the inhibition of tumor growth was directly dependent on the dose of Cd, the enhancement of CMC was inversely related to dosage. These data suggested that other mechanisms in addition to increased CMC were involved in tumor growth inhibition. Possible factors such as direct inhibition of tumor growth by Cd and decreased serum blocking levels in Cd-exposed animals are discussed.

  4. Biochemical and pathological studies on the effects of levamisole and chlorambucil on Ehrlich ascites carcinoma-bearing mice.

    PubMed

    Salem, Fakhry S; Badr, Mohamed O T; Neamat-Allah, Ahmed N F

    2011-01-01

    Clinicopathological studies on the effects of combining immunostimulant drugs (levamisole) with anti-cancer drugs (chlorambucil) revealed the enhancement of the latter against Ehrlich ascites carcinoma-bearing mice and resulted in a reduction in the size of tumour. An evaluation of liver and kidney functions showed a significant increase of alanine transaminase (ALT), aspartate transaminase (AST) and creatinine in all groups. Histopathological studies of one group that received an intraperitoneal injection of Ehrlich ascites carcinoma cells (2.5 × 10⁶) showed that hepatic parenchyma revealed degenerative changes. The portal area was oedematous and showed rounded cell aggregations. Cell death within hypertrophied Kupper cells was observed in some hepatic cells. The neoplastic emboli could be seen either inside blood vessels or hepatic sinusoids, while another group which had been treated orally with a combination of Leukeran(™) (0.2 mg/kg body weight) and levamisole (5 mg/kg body weight) revealed that hepatic parenchyma revealed massive necrosis with proliferative bile duct epithelium. No neoplastic cells were observed without the hepatic parenchyma, while the renal cortex presented a large number of lymphocytes and plasma cells forming bands or aggregates, mainly around the blood vessels. It was concluded that the addition of levamisole to chlorambucil improved the anti-cancer effect of chlorambucil against Ehrlich ascites carcinoma. However, it had adverse effects on the liver and kidneys as shown by liver and kidney function tests and confirmed by histopathology.

  5. A novel TLR7 agonist reverses NK cell anergy and cures RMA-S lymphoma-bearing mice.

    PubMed

    Wiedemann, Gabriela Maria; Jacobi, Severin Johannes; Chaloupka, Michael; Krächan, Angelina; Hamm, Svetlana; Strobl, Stefan; Baumgartner, Roland; Rothenfusser, Simon; Duewell, Peter; Endres, Stefan; Kobold, Sebastian

    2016-07-01

    Toll-like receptor 7 (TLR7) agonists are potent immune stimulants able to overcome cancer-associated immune suppression. Due to dose-limiting systemic toxicities, only the topically applied TLR7 agonist (imiquimod) has been approved for therapy of skin tumors. There is a need for TLR7-activating compounds with equivalent efficacy but less toxicity. SC1, a novel small molecule agonist for TLR7, is a potent type-1 interferon inducer, comparable to the reference TLR7 agonist resiquimod, yet with lower induction of proinflammatory cytokines. In vivo, SC1 activates NK cells in a TLR7-dependent manner. Mice bearing the NK cell-sensitive lymphoma RMA-S are cured by repeated s. c. administrations of SC1 as efficiently as by the administration of resiquimod. No relevant toxicities were observed. Mechanistically, SC1 reverses NK cell anergy and restores NK cell-mediated tumor cell killing in an IFN-α-dependent manner. TLR7 targeting by SC1-based compounds may form an attractive strategy to activate NK cell responses for cancer therapy.

  6. Cerenkov luminescence tomography of aminopeptidase N (APN/CD13) expression in mice bearing HT1080 tumors.

    PubMed

    Hu, Zhenhua; Yang, Weidong; Ma, Xiaowei; Ma, Wenhui; Qu, Xiaochao; Liang, Jimin; Wang, Jing; Tian, Jie

    2013-05-01

    In vivo imaging of aminopeptidase N (APN/CD13) expression is crucial for the early detection of cancer. This study attempted to show that APN/CD13 expression can be imaged and quantified with novel Cerenkov luminescence tomography (CLT). Na131I with various activities was placed at different depths in a tissue-mimicking phantom, and various porcine tissues and luminescent images were acquired. The binding of 131I-NGR with human fibrosarcoma HT1080 and human colon cancer HT-29 cells was detected with Cerenkov luminescence imaging (CLI). Nude mice bearing HT-1080 tumors were imaged after injection with 131I-NGR using both planar and tomographic CLI methods. The penetration depth increased with ascending activity of Na131I. There was a robust linear correlation between the optical signal intensity and the HT1080 cell numbers (r2 = .9691), as well as the activity (r2 = .9860). The three-dimensional visualization CLT results clearly showed that 131I-NGR uptake in tumor tissues represented a high expression of the APN/CD13 receptor. CLT also allowed quantifying 131I-NGR uptake in tumor tissues showing an average activity of 0.1388 ± 4.6788E-6 MBq in tumor tissues. Our study indicated that 131I-NGR combined with CLT allowed us to image and quantify tumor-associated APN/CD13 expression noninvasively. The promising CLT technique could be potentially used for sensitively evaluating tumor angiogenesis in vivo.

  7. Cytosine deaminase-expressing human neural stem cells inhibit tumor growth in prostate cancer-bearing mice.

    PubMed

    Lee, Hong Jun; Doo, Seung Whan; Kim, Dae Hong; Cha, Young Joo; Kim, Jae Heon; Song, Yun Seob; Kim, Seung U

    2013-07-10

    Prostate cancer is the most common malignancy among men. Prostate cancer-related deaths are largely attributable to the development of hormone resistance in the tumor. No effective chemotherapy has yet been developed for advanced prostate cancer. It is desirable if a drug can be delivered directly and specifically to prostate cancer cells. Stem cells have selective migration ability toward cancer cells and therapeutic genes can be easily transduced into stem cells. In one form of gene therapy for cancer, the stem cells carry a gene encoding an enzyme that transforms an inert prodrug into a toxic product. Cytosine deaminase (CD) transforms the pro-drug 5-fluorocytosine into highly cytotoxic 5-fluorouracil (5-FU). The migration of the genetically modified stem cells was monitored by molecular magnetic resonance imaging, after labeling the stem cells with fluorescent magnetic nanoparticles (MNPs). Human neural stem cells encoding CD (HB1.F3.CD) were prepared and labeled with MNP. In tumor-bearing C57B mice, systemically transplanted HB1.F3.CD stem cells migrated toward the tumor and in combination with prodrug 5-FC, the volume of tumor implant was significantly reduced. These findings may contribute to development of a new selective chemotherapeutic strategy against prostate cancer.

  8. A novel TLR7 agonist reverses NK cell anergy and cures RMA-S lymphoma-bearing mice

    PubMed Central

    Wiedemann, Gabriela Maria; Jacobi, Severin Johannes; Chaloupka, Michael; Krächan, Angelina; Hamm, Svetlana; Strobl, Stefan; Baumgartner, Roland; Rothenfusser, Simon; Duewell, Peter; Endres, Stefan; Kobold, Sebastian

    2016-01-01

    ABSTRACT Toll-like receptor 7 (TLR7) agonists are potent immune stimulants able to overcome cancer-associated immune suppression. Due to dose-limiting systemic toxicities, only the topically applied TLR7 agonist (imiquimod) has been approved for therapy of skin tumors. There is a need for TLR7-activating compounds with equivalent efficacy but less toxicity. SC1, a novel small molecule agonist for TLR7, is a potent type-1 interferon inducer, comparable to the reference TLR7 agonist resiquimod, yet with lower induction of proinflammatory cytokines. In vivo, SC1 activates NK cells in a TLR7-dependent manner. Mice bearing the NK cell-sensitive lymphoma RMA-S are cured by repeated s. c. administrations of SC1 as efficiently as by the administration of resiquimod. No relevant toxicities were observed. Mechanistically, SC1 reverses NK cell anergy and restores NK cell-mediated tumor cell killing in an IFN-α-dependent manner. TLR7 targeting by SC1-based compounds may form an attractive strategy to activate NK cell responses for cancer therapy. PMID:27622045

  9. Near-Infrared Fluorescence Imaging of Carbonic Anhydrase IX in Athymic Mice Bearing HT-29 Tumor Xenografts

    PubMed Central

    2016-01-01

    Near-infrared fluorescence (NIRF) imaging technology is a highly sensitive imaging modality and has been widely used in noninvasively studying the status of receptor expression in small animal models, with an appropriate NIRF probe targeting a specific receptor. In this report, Cy5.5-conjugated anti-CAIX monoclonal antibody (Mab-Cy5.5) was evaluated in athymic mice bearing HT-29 tumor xenografts in order to investigate the effect of conjugate on tumor targeting efficacy. In vitro binding studies showed that Mab-Cy5.5 could specifically bind to the cells which expressed CAIX. Results from in vivo imaging showed that HT-29 tumor xenografts can be clearly visualized at 48 h after injection of Mab-Cy5.5, and in the blocking experiment, free anti-CAIX antibody effectively blocked the concentration of Mab-Cy5.5 in the tumors. Western blotting and immunohistochemistry analysis of HT-29 tumor xenografts verified the expression of CAIX in HT-29 tumors. Mab-Cy5.5 could specifically bind to the tumors which expressed CAIX. These results suggested that Mab-Cy5.5 was suitable for CAIX expression imaging in the preclinical research. PMID:27652266

  10. Dextran-functionalized magnetic fluid mediating magnetohyperthermia for treatment of Ehrlich-solid-tumor-bearing mice: toxicological and histopathological evaluations.

    PubMed

    Miranda-Vilela, Ana Luisa; Yamamoto, Kelly Reis; Miranda, Kely Lopes Caiado; Matos, Breno Noronha; de Almeida, Marcos Célio; Longo, João Paulo Figueiró; de Souza Filho, José; Fernandes, Juliana Menezes Soares; Sartoratto, Patrícia Pommé Confessori; Lacava, Zulmira Guerrero Marques

    2014-04-01

    Dextran-functionalized maghemite fluid (DexMF) has been tested to treat Ehrlich-solid-tumor-bearing mice, evidencing its potential use in mediating magnetohyperthermia in breast cancer treatment. However, although magnetic nanoparticles tend to accumulate in tumor tissues, part of the nanomaterial can reach the blood stream, and then the organism. The aim of this study was to investigate the acute systemic effects of the intratumoral injection of DexMF mediating magnetohyperthermia in the treatment of an advanced clinical Ehrlich-solid-tumor, assessed through histopathological analyses of liver, kidneys, heart and spleen, comet assay, micronucleus test, hemogram, and serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, creatinine, and urea. The tumor's histopathology and morphometry were used to assess its aggressiveness and regression. DexMF mediating hyperthermia was effective in containing tumor aggressiveness and in inducing tumor regression, besides showing no toxic effects. Its physical characteristics also suggest that it is safe to use in other biomedical applications.

  11. Effect of Sipjeondaebo-Tang on Cancer-Induced Anorexia and Cachexia in CT-26 Tumor-Bearing Mice

    PubMed Central

    Jung, Ki Yong; Woo, Sang-Mi; Jun, Chan-Yong; Park, Jong Hyeong; Shin, Yong Cheol; Ko, Seong-Gyu

    2014-01-01

    Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia. PMID:24963216

  12. Effect of Sipjeondaebo-tang on cancer-induced anorexia and cachexia in CT-26 tumor-bearing mice.

    PubMed

    Choi, Youn Kyung; Jung, Ki Yong; Woo, Sang-Mi; Yun, Yee Jin; Jun, Chan-Yong; Park, Jong Hyeong; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong-Gyu

    2014-01-01

    Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor- α (TNF- α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia.

  13. Topically applied Melaleuca alternifolia (tea tree) oil causes direct anti-cancer cytotoxicity in subcutaneous tumour bearing mice.

    PubMed

    Ireland, Demelza J; Greay, Sara J; Hooper, Cornelia M; Kissick, Haydn T; Filion, Pierre; Riley, Thomas V; Beilharz, Manfred W

    2012-08-01

    Melaleuca alternifolia (tea tree) oil (TTO) applied topically in a dilute (10%) dimethyl sulphoxide (DMSO) formulation exerts a rapid anti-cancer effect after a short treatment protocol. Tumour clearance is associated with skin irritation mediated by neutrophils which quickly and completely resolves upon treatment cessation. To examine the mechanism of action underlying the anti-cancer activity of TTO. Immune cell changes in subcutaneous tumour bearing mice in response to topically applied TTO treatments were assessed by flow cytometry and immunohistochemistry. Direct cytotoxicity of TTO on tumour cells in vivo was assessed by transmission electron microscopy. Neutrophils accumulate in the skin following topical 10% TTO/DMSO treatment but are not required for tumour clearance as neutrophil depletion did not abrogate the anti-cancer effect. Topically applied 10% TTO/DMSO, but not neat TTO, induces an accumulation and activation of dendritic cells and an accumulation of T cells. Although topical application of 10% TTO/DMSO appears to activate an immune response, anti-tumour efficacy is mediated by a direct effect on tumour cells in vivo. The direct cytotoxicity of TTO in vivo appears to be associated with TTO penetration. Future studies should focus on enhancing the direct cytotoxicity of TTO by increasing penetration through skin to achieve a higher in situ terpene concentration. This coupled with boosting a more specific anti-tumour immune response will likely result in long term clearance of tumours. Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  14. Water-soluble aluminium phthalocyanine–polymer conjugates for PDT: photodynamic activities and pharmacokinetics in tumour-bearing mice

    PubMed Central

    Brasseur, N; Ouellet, R; Madeleine, C La; Lier, J E van

    1999-01-01

    The potential use of unsubstituted aluminium phthalocyanine (AlClPc) as a sensitizer for photodynamic therapy (PDT) of cancer has not been fully exploited in spite of its higher efficiency as compared to the sulphonated derivatives. This is largely due to the strong hydrophobic character of AlClPc which renders the material difficult to formulate for in vivo administration. We prepared two water-soluble derivatives of AlClPc by axial coordination of polyethyleneglycol (PEG, MW 2000) or polyvinylalcohol (PVA, MW 13 000–23 000) to the central aluminium ion. Their photodynamic activities were evaluated in vitro against the EMT-6 mouse mammary tumour cells and in vivo against the EMT-6 and the colon carcinoma Colo-26 tumours implanted intradermally in Balb/c mice. Pharmacokinetics were studied in the EMT-6 tumour-bearing mice. After 1 h incubation, the light dose required to kill 90% of cells (LD90) was at least three times less for AlClPc (Cremophor emulsion) as compared to AlPc–PEG and AlPc–PVA, while after 24 h incubation all three preparations were highly phototoxic. All three dye preparations induced complete EMT-6 tumour regression in 75–100% of animals at a low drug dose (0.25 μmol kg−1) following PDT (400 J cm−2, 650–700 nm) at 24 h pi. Complete tumour regression in the Colo-26 tumour model was obtained in 30% of mice at a dose of 2 μmol kg−1. In the non-cured animals, AlPc–PVA induced the most significant tumour growth delay. This dye showed a prolonged plasma half-life (6.8 h) as compared to AlClPc (2.6 h) and AlPc–PEG (23 min), lower retention by liver and spleen and higher tumour-to-skin and tumour-to-muscle ratios. Our data demonstrate that addition of hydrophilic axial ligands to AlPc, while modifying in vitro and in vivo kinetics, does not reduce the PDT efficiency of the parent molecule. Moreover, in the case of the polyvinylalcohol derivative, axial coordination confers advantageous pharmacokinetics to AlPc, which makes this

  15. Amelioration of skewed Th1/Th2 balance in tumor-bearing and asthma-induced mice by oral administration of Agaricus blazei extracts.

    PubMed

    Takimoto, Hiroaki; Kato, Hanano; Kaneko, Masahiro; Kumazawa, Yoshio

    2008-01-01

    We showed in a previous study that hot-water extracts of Agaricus blazei (Agaricus extracts) had anti-tumor activity to Meth A fibrosarcoma, but it remains unclear whether the Agaricus extracts ameliorate the skewed balance of type-1 T helper (Th1) and type-2 T helper (Th2) cells. We examined whether Agaricus extracts effect the skewed Th1/Th2 balance in tumor-bearing and asthma-induced mice. When Meth A-bearing mice were given orally either Agaricus extracts or water once a day starting 5 days after tumor implantation, spleen T cells, prepared from tumor-bearing mice treated with Agaricus extracts, in response to anti-CD3 monoclonal antibody produced significantly higher levels of interferon gamma (IFN-gamma) than that of controls. The mRNA expression of IFN-gamma-inducing protein 10 and the frequency of CD69(+) or CD49d(+) cells, among activated T cells infiltrated into tumors, significantly increased in Agaricus-treated mice, compared with those of tumor-controls. In asthma-induced mice, treatment with the Agaricus extracts caused significant downregulation of OVA-specific antibody responses of IgG1 and IgE but not of IgG2a, and significantly decreased total cell numbers, levels of interleukin 5, and eosinophil numbers in bronchial alveolar lavage fluids. IFN-gamma production by anti-CD3-stimulated spleen cells, obtained from Agaricus-treated mice, significantly increased. Our results strongly suggest that oral administration of Agaricus extracts ameliorates the Th1/Th2 balance from the Th2-skewed conditions.

  16. Baccatin III, a precursor for the semisynthesis of paclitaxel, inhibits the accumulation and suppressive activity of myeloid-derived suppressor cells in tumor-bearing mice.

    PubMed

    Lee, Young-Hee; Lee, Young-Ran; Park, Chan-Su; Im, Sun-A; Song, Sukgil; Hong, Jin Tae; Whang, Bang Yeon; Kim, Kyungjae; Lee, Chong-Kil

    2014-08-01

    Myeloid-derived suppressor cells (MDSCs) mediate tumor-associated immune suppression in both cancer patients and tumor-bearing animals. Reduction or elimination of MDSCs reduces the rate of tumor progression and improves cancer therapies that employ mechanisms of immunity. Here we show that baccatin III, which is the precursor for the semisynthesis of paclitaxel, exerts anti-tumor immunomodulatory activity in very low doses (0.05-0.5mg/kg), although it is regarded as an inactive derivative of paclitaxel. Oral administration of baccatin III significantly reduced the growth of tumors induced by engrafting BALB/c mice with either 4 T1 mammary carcinoma or CT26 colon cancer cells. Baccatin III (0.5mg/kg) did not exert anti-tumor activity in athymic nude mice. Baccatin III decreased the accumulation of MDSCs in the spleens of the tumor-bearing mice. Furthermore, MDSCs isolated from baccatin III-treated mice, compared with those isolated from vehicle-treated mice, had a significantly reduced suppressive effect on T cells treated with the anti-CD3 and anti-CD28 monoclonal antibodies. Moreover, these cells produced significantly reduced amounts of reactive oxygen species and nitric oxide. These results suggest that baccatin III reduced tumor progression by inhibiting the accumulation and suppressive function of MDSCs. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Targeting superoxide dismutase to renal proximal tubule cells inhibits nephrotoxicity of cisplatin and increases the survival of cancer-bearing mice.

    PubMed

    Nishikawa, M; Nagatomi, H; Nishijima, M; Ohira, G; Chang, B J; Sato, E; Inoue, M

    2001-10-10

    Because cis-diamminedichloroplatinum(II) (cisplatin) which generates reactive oxygen species induces renal dysfunction, administration of a large dose for killing cancer cells is highly limited. We recently synthesized a cationic superoxide dismutase (SOD) (hexamethylenediamine-conjugated SOD, AH-SOD) which rapidly accumulates in renal proximal tubule cells and inhibits oxidative injury of the kidney. Treatment of Ehrlich ascites tumor cells (EATC)-bearing mice with cisplatin sufficient for killing tumor cells increased their motality. The motality of cisplatin-treated EATC-bearing mice was markedly decreased by AH-SOD. These results suggest that targeting SOD to renal proximal tubule cells might permit the administration of high doses of cisplatin and related anticancer agents without causing renal injury.

  18. Chelerythrine delayed tumor growth and increased survival duration of Dalton's lymphoma bearing BALB/c H(2d) mice by activation of NK cells in vivo.

    PubMed

    Kumar, Sanjay; Tomar, Munendra Singh; Acharya, Arbind

    2015-01-01

    The aims of the present investigation were to evaluate the antitumor effect of chelerythrine (CHE) on in vivo growth and survival duration of BALB/c (H2d) mice bearing Dalton's lymphoma (DL) and enhanced function of tumor associated NK cells (TANK cells). BALB/c (H2d) mice at 8-10 weeks of age of either sex were used. Increasing concentration of CHE (1.25, 2.5, and 5.0 mg/kg), staurosporine (0.625, 1.0, 1.5, and 2.0 mg/kg) and cyclophosphamide (25, 50, 100, and 200 mg/kg) were administered intraperitoneally and tumor regression and survival duration of tumor bearing host were determined, and thereafter expression of NKG2D and NKG2A on TANK cells were detected. Our results show that treatment with 2.5 mg/kg of CHE results in a significant reduction in mean tumor volume and increased survival duration of DL bearing BALB/c (H2d) mice when compared to control. Activating receptor NKG2D on TANK cells were observed upregulated in contrast to inhibitory receptor NKG2A. CHE reduced mean tumor volume and increased survival duration of DL bearing BALB/c (H2d) mice. Increased expression of activating receptor NKG2D on TANK cells results in recovery of immunosuppression during tumor progression. Therefore, CHE could be a potential anticancer therapeutic agent that may be used to replace chemo-radio-therapy in future.

  19. Subcutaneous injection of water-soluble multi-walled carbon nanotubes in tumor-bearing mice boosts the host immune activity

    NASA Astrophysics Data System (ADS)

    Meng, Jie; Yang, Man; Jia, Fumin; Kong, Hua; Zhang, Weiqi; Wang, Chaoying; Xing, Jianmin; Xie, Sishen; Xu, Haiyan

    2010-04-01

    The immunological responses induced by oxidized water-soluble multi-walled carbon nanotubes on a hepatocarcinoma tumor-bearing mice model via a local administration of subcutaneous injection were investigated. Experimental results show that the subcutaneously injected carbon nanotubes induced significant activation of the complement system, promoted inflammatory cytokines' production and stimulated macrophages' phagocytosis and activation. All of these responses increased the general activity of the host immune system and inhibited the progression of tumor growth.

  20. Dietary supplementation with a specific combination of high protein, leucine, and fish oil improves muscle function and daily activity in tumour-bearing cachectic mice.

    PubMed

    van Norren, K; Kegler, D; Argilés, J M; Luiking, Y; Gorselink, M; Laviano, A; Arts, K; Faber, J; Jansen, H; van der Beek, E M; van Helvoort, A

    2009-03-10

    Cancer cachexia is characterised by metabolic alterations leading to loss of adipose tissue and lean body mass and directly compromises physical performance and the quality of life of cancer patients. In a murine cancer cachectic model, the effects of dietary supplementation with a specific combination of high protein, leucine and fish oil on weight loss, muscle function and physical activity were investigated. Male CD2F1 mice, 6-7 weeks old, were divided into body weight-matched groups: (1) control, (2) tumour-bearing, and (3) tumour-bearing receiving experimental diets. Tumours were induced by s.c. inoculation with murine colon adenocarcinoma (C26) cells. Food intake, body mass, tumour size and 24 h-activity were monitored. Then, 20 days after tumour/vehicle inoculation, the animals were killed and muscle function was tested ex vivo. Tumour-bearing mice showed reduced carcass, muscle and fat mass compared with controls. EDL muscle performance and total daily activity were impaired in the tumour-bearing mice. Addition of single nutrients resulted in no or modest effects. However, supplementation of the diet with the all-in combination of high protein, leucine and fish oil significantly reduced loss of carcass, muscle and fat mass (loss in mass 45, 52 and 65% of TB-con, respectively (P<0.02)) and improved muscle performance (loss of max force reduced to 55-64% of TB-con (P<0.05)). Moreover, total daily activity normalised after intervention with the specific nutritional combination (50% of the reduction in activity of TB-con (P<0.05)). In conclusion, a nutritional combination of high protein, leucine and fish oil reduced cachectic symptoms and improved functional performance in cancer cachectic mice. Comparison of the nutritional combination with its individual modules revealed additive effects of the single components provided.

  1. Anorexia and cachexia in prostaglandin EP1 and EP3 subtype receptor knockout mice bearing a tumor with high intrinsic PGE2 production and prostaglandin related cachexia.

    PubMed

    Wang, W; Andersson, M; Lönnroth, C; Svanberg, E; Lundholm, K

    2005-03-01

    Previous studies in our laboratory have suggested that prostaglandin (PG) E2 is involved in anorexia/cachexia development in MCG 101 tumor-bearing mice. However, the role of COX pathways in the pathogenesis of cancer anorexia/cachexia is not fully resolved. In the present study, we investigated the role of PGE receptors subtype EP1 and EP3 on the development of anorexia in MCG 101-bearing mice. Our results show that the absence of host EP1 or EP3 receptors did not alter the magnitude of anorexia in tumor-bearers. However, anorexia in tumor-bearing EP1 and EP3 knockouts was not improved by indomethacin treatment as observed in wild type tumor-bearers. By contrast, indomethacin improved body composition similar in EP1 and EP3 knockouts as well as in wild type tumor-bearing animals and tumor growth was retarded in EP1 and promoted in EP3 knock outs. Our results demonstrate that host EP1 and EP3 receptors are involved in the control of local tumor growth, which translates into anorexia, this being the main cause of metabolic adaptive alterations to explain weight loss in this model. Brain EP1 and EP3 subtype receptors do not seem to directly control anorexia, which leaves EP2 and EP4 as potential candidates.

  2. Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 suppresses tumor growth in breast cancer-bearing mice by negatively regulating myeloid-derived suppressor cell functions.

    PubMed

    Hong, Hye-Jin; Lim, Hui Xuan; Song, Ju Han; Lee, Arim; Kim, Eugene; Cho, Daeho; Cohen, Edward P; Kim, Tae Sung

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) are one of the most important cell types that contribute to negative regulation of immune responses in the tumor microenvironment. Recently, aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1), a novel pleiotropic cytokine, was identified as an antitumor protein that inhibits angiogenesis and induces antitumor responses. However, the effect of AIMP1 on MDSCs in the tumor environment remains unclear. In the present study, we demonstrated that AIMP1 significantly inhibited tumor growth in 4T1 breast cancer-bearing mice and reduced MDSCs population of tumor sites and spleens of tumor-bearing mice. AIMP1 reduced expansion of MDSCs from bone marrow-derived cells in the tumor-conditioned media. AIMP1 also negatively regulated suppressive activities of MDSCs by inhibiting IL-6 and NO production, and Arg-1 expression. Furthermore, treatment of breast cancer-bearing mice with AIMP1 decreased the capacity of MDSCs to suppress T cell proliferation and Treg cell induction. Western blot and inhibition experiments showed that downregulation of MDSCs functions by AIMP1 may result from attenuated activation of STATs, Akt, and ERK. These findings indicate that AIMP1 plays an essential role in negative regulation of suppressive functions of MDSCs. Therefore, it has a significant potential as a therapeutic agent for cancer treatment.

  3. Adjuvant effect of Pluchea quitoc extract on the resistance of tumor-bearing mice by modulation of the host hematopoietic response.

    PubMed

    Queiroz, M L; Justo, G Z; Valadares, M C; Pereira-da-Silva, F R; Müller, A H

    2001-05-01

    Progressive tumor growth is regularly accompanied by changes in the cellular constituents of the immune system. Evidence suggests that soluble factors generated during tumor growth can affect the amount of granulocyte-macrophage progenitors. In vitro colony growth of progenitor cells may be an early indicator of the cellular changes associated with tumor growth. Pluchea quitoc has been previously found to modulate the hematopoietic response during bacterial infection. This study was designed to investigate the effects of P. quitoc on the growth and differentiation of bone marrow granulocyte-macrophage progenitor cells (CFU-GM) in Ehrlich ascites tumor-bearing mice. In contrast to the myelosuppression developed in the tumor-bearing animals, treatment with P. quitoc ethanolic extract (250, 500 or 1000 mg/kg) for 3 consecutive days after tumor challenge reversibly stimulated myelopoiesis, restoring the number of CFU-GM to normal. This same dose-schedule also increased colony formation in normal mice as compared to controls. In addi tion, P. quitoc significantly enhanced survival of tumor-bearing mice. These results suggest an immunoregulatory role for P. quitoc in counteracting the tumor-induced myelopoietic suppression as well as usefulness as adjuvant treatment of cancer.

  4. Alteration of the exDNA profile in blood serum of LLC-bearing mice under the decrease of tumour invasion potential by bovine pancreatic DNase I treatment

    PubMed Central

    Brenner, Evgenyi V.; Kurilshikov, Alexander M.; Patutina, Olga A.; Zenkova, Marina A.

    2017-01-01

    Taking into account recently obtained data indicating the participation of circulating extracellular DNA (exDNA) in tumorigenesis, enzymes with deoxyribonucleic activity have again been considered as potential antitumour and antimetastatic drugs. Previously, using murine Lewis lung carcinoma and hepatocellular carcinoma A1 tumour models, we have shown the antimetastatic activity of bovine DNase I, which correlates with an increase of DNase activity and a decrease of exDNA concentration in the blood serum of tumour-bearing mice. In this work, using next-generation sequencing on the ABS SOLiD™ 5.500 platform, we performed a search for molecular targets of DNase I by comparing the exDNA profiles of healthy animals, untreated animals with Lewis lung carcinoma (LLC) and those with LLC treated with DNase I. We found that upon DNase I treatment of LLC-bearing mice, together with inhibition of metastasis, a number of strong alterations in the patterns of exDNA were observed. The major differences in exDNA profiles between groups were: i) the level of GC-poor sequences increased during tumour development was reduced to that of healthy mice; ii) levels of sequences corresponding to tumour-associated genes Hmga2, Myc and Jun were reduced in the DNase I-treated group in comparison with non-treated mice; iii) 224 types of tandem repeat over-presented in untreated LLC-bearing mice were significantly reduced after DNase I treatment. The most important result obtained in the work is that DNase I decreased the level of B-subfamily repeats having homology to human ALU repeats, known as markers of carcinogenesis, to the level of healthy animals. Thus, the obtained data lead us to suppose that circulating exDNA plays a role in tumour dissemination, and alteration of multiple molecular targets in the bloodstream by DNase I reduces the invasive potential of tumours. PMID:28222152

  5. Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice

    PubMed Central

    Garcia-Areas, Ramon; Libreros, Stephania; Amat, Samantha; Keating, Patricia; Carrio, Roberto; Robinson, Phillip; Blieden, Clifford; Iragavarapu-Charyulu, Vijaya

    2014-01-01

    Semaphorins are a large family of molecules involved in axonal guidance during the development of the nervous system and have been recently shown to have both angiogenic and anti-angiogenic properties. Specifically, semaphorin 7A (SEMA7A) has been reported to have a chemotactic activity in neurogenesis and to be an immune modulator through α1β1integrins. SEMA7A has been shown to promote monocyte chemotaxis and induce them to produce proinflammatory mediators. In this study we explored the role of SEMA7A in a murine model of breast cancer. We show that SEMA7A is highly expressed by DA-3 murine mammary tumor cells in comparison to normal mammary cells (EpH4), and that peritoneal elicited macrophages from mammary tumor-bearing mice also express SEMA7A at higher levels compared to those derived from normal mice. We also show that murine macrophages treated with recombinant murine SEMA7A significantly increased their expression of proangiogenic molecule CXCL2/MIP-2. Gene silencing of SEMA7A in peritoneal elicited macrophages from DA-3 tumor-bearing mice resulted in decreased CXCL2/MIP-2 expression. Mice implanted with SEMA7A silenced tumor cells showed decreased angiogenesis in the tumors compared to the wild type tumors. Furthermore, peritoneal elicited macrophages from mice bearing SEMA7A-silenced tumors produce significantly (p < 0.01) lower levels of angiogenic proteins, such as CXCL2/MIP-2, CXCL1, and MMP-9, compared to those from control DA-3 mammary tumors. We postulate that SEMA7A in mammary carcinomas may skew monocytes into a pro-tumorigenic phenotype to support tumor growth. SEMA7A could prove to be valuable in establishing new research avenues toward unraveling important tumor-host immune interactions in breast cancer patients. PMID:24550834

  6. Avastin® in combination with gemcitabine and cisplatin significantly inhibits tumor angiogenesis and increases the survival rate of human A549 tumor-bearing mice

    PubMed Central

    LIU, YING; XIA, XIZHENG; ZHOU, MINGKAI; LIU, XIAOJUN

    2015-01-01

    The aim of this study was to investigate the effect of Avastin® in combination with gemcitabine and cisplatin (GP) on the tumor growth of A549 tumor-bearing mice and the potential anti-tumor mechanism. A total of 30 human A549 tumor-bearing nude mice were randomly divided into the Avastin, chemotherapy and combined treatment groups for treatment with an intraperitoneal injection of Avastin (5 mg/kg) (Avastin group); an intraperitoneal injection of gemcitabine (4 mg/kg) and cisplatin (4 mg/kg) (chemotherapy group); or intraperitoneal injections of Avastin and GP (combined treatment group). The mice were observed for 30 days and the tumor growth, survival and body weight of the mice in the three groups were analyzed. The protein level of vascular endothelial growth factor (VEGF) in the tumor tissues was analyzed by ELISA. The vascular density and structural changes of the tumor were analyzed using immunohistochemistry. Compared with the Avastin and chemotherapy groups, the tumor growth of mice in the combined treatment group was significantly inhibited, and the survival rate of the mice was increased significantly. No difference in body weight was observed among the three groups of mice (P>0.05). The levels of VEGF in the combined treatment group tumor tissues were significantly reduced compared with those in the chemotherapy group tumor tissues (P<0.05). Furthermore, the vessel density of the tumor tissue in the combined treatment group was significantly reduced compared with that in the chemotherapy group (P<0.05), and the number of normal vessels in the combined treatment group tumors was significantly higher than that in the chemotherapy group tumors after 7 days of treatment (P<0.05). In conclusion, Avastin can significantly decrease the level of VEGF in tumor tissue, inhibit tumor angiogenesis and promote the normalization of tumor vascular structure, which may explain the enhanced efficacy of Avastin in combination with chemotherapy. PMID:26136956

  7. Astragalus polysaccharides can regulate cytokine and P-glycoprotein expression in H22 tumor-bearing mice

    PubMed Central

    Tian, Qing-E; Li, Huan-De; Yan, Miao; Cai, Hua-Lin; Tan, Qin-You; Zhang, Wen-Yuan

    2012-01-01

    AIM: To investigate the adjunct anticancer effect of Astragalus polysaccharides in H22 tumor-bearing mice. METHODS: To establish a solid tumor model, 5.0 × 106/mL H22 hepatoma cells were inoculated subcutaneously into the right armpit region of Kunming mice (6-12 wk old, 18-22 g). When the tumors reached a size of 100 mm3, the animals were treated as indicated, and the mice were randomly assigned to seven groups (n = 10 each). After ten days of treatment, blood samples were collected from mouse eyes, and serum was harvested by centrifugation. Mice were sacrificed, and the whole body, tumor, spleen and thymus were weighed immediately. The rate of tumor inhibition and organ indexes were calculated. The expression levels of serum cytokines, P-glycoprotein (P-GP) and multidrug resistance (MDR) 1 mRNA in tumor tissues were detected using enzyme-linked immunosorbent assay, Western blotting, and quantitative myeloid-derived suppressor cells reverse transcription-polymerase chain reaction, respectively. RESULTS: The tumor inhibition rates in the treatment groups of Adriamycin (ADM) + Astragalus polysaccharides (APS) (50 mg/kg), ADM + APS (100 mg/kg), and ADM + APS (200 mg/kg) were significantly higher than in the ADM group (72.88% vs 60.36%, P = 0.013; 73.40% vs 60.36%, P = 0.010; 77.57% vs 60.36%, P = 0.001). The spleen indexes of the above groups were also significantly higher than in the ADM group (0.65 ± 0.22 vs 0.39 ± 0.17, P = 0.023; 0.62 ± 0.34 vs 0.39 ± 0.17, P = 0.022; 0.67 ± 0.20 vs 0.39 ± 0.17, P = 0.012), and the thymus indexes of the ADM + APS (100 mg/kg) and ADM + APS (200 mg/kg) groups were significantly higher than in the ADM group (0.20 ± 0.06 vs 0.13 ± 0.04, P = 0.029; 0.47 ± 0.12 vs 0.13 ± 0.04, P = 0.000). APS was found to exert a synergistic anti-tumor effect with ADM and to alleviate the decrease in the sizes of the spleen and thymus induced by AMD. The expression of interleukin-1α (IL-1α), IL-2, IL-6, and tumor necrosis factor-α (TNF

  8. Future prospects for SPECT imaging using the radiolanthanide terbium-155 - production and preclinical evaluation in tumor-bearing mice.

    PubMed

    Müller, Cristina; Fischer, Eliane; Behe, Martin; Köster, Ulli; Dorrer, Holger; Reber, Josefine; Haller, Stephanie; Cohrs, Susan; Blanc, Alain; Grünberg, Jürgen; Bunka, Maruta; Zhernosekov, Konstantin; van der Meulen, Nicholas; Johnston, Karl; Türler, Andreas; Schibli, Roger

    2014-05-01

    We assessed the suitability of the radiolanthanide (155)Tb (t1/2=5.32 days, Eγ=87 keV (32%), 105keV (25%)) in combination with variable tumor targeted biomolecules using preclinical SPECT imaging. (155)Tb was produced at ISOLDE (CERN, Geneva, Switzerland) by high-energy (~1.4 GeV) proton irradiation of a tantalum target followed by ionization and on-line mass separation. (155)Tb was separated from isobar and pseudo-isobar impurities by cation exchange chromatography. Four tumor targeting molecules - a somatostatin analog (DOTATATE), a minigastrin analog (MD), a folate derivative (cm09) and an anti-L1-CAM antibody (chCE7) - were radiolabeled with (155)Tb. Imaging studies were performed in nude mice bearing AR42J, cholecystokinin-2 receptor expressing A431, KB, IGROV-1 and SKOV-3ip tumor xenografts using a dedicated small-animal SPECT/CT scanner. The total yield of the two-step separation process of (155)Tb was 86%. (155)Tb was obtained in a physiological l-lactate solution suitable for direct labeling processes. The (155)Tb-labeled tumor targeted biomolecules were obtained at a reasonable specific activity and high purity (>95%). (155)Tb gave high quality, high resolution tomographic images. SPECT/CT experiments allowed excellent visualization of AR42J and CCK-2 receptor-expressing A431 tumors xenografts in mice after injection of (155)Tb-DOTATATE and (155)Tb-MD, respectively. The relatively long physical half-life of (155)Tb matched in particular the biological half-lives of (155)Tb-cm09 and (155)Tb-DTPA-chCE7 allowing SPECT imaging of KB tumors, IGROV-1 and SKOV-3ip tumors even several days after administration. The radiolanthanide (155)Tb may be of particular interest for low-dose SPECT prior to therapy with a therapeutic match such as the β(-)-emitting radiolanthanides (177)Lu, (161)Tb, (166)Ho, and the pseudo-radiolanthanide (90)Y. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Combination treatment with oncolytic Vaccinia virus and cyclophosphamide results in synergistic antitumor effects in human lung adenocarcinoma bearing mice

    PubMed Central

    2014-01-01

    Background The capacity of the recombinant Vaccinia virus GLV-1h68 as a single agent to efficiently treat different human or canine cancers has been shown in several preclinical studies. Currently, its human safety and efficacy are investigated in phase I/II clinical trials. In this study we set out to evaluate the oncolytic activity of GLV-1h68 in the human lung adenocarcinoma cell line PC14PE6-RFP in cell cultures and analyzed the antitumor potency of a combined treatment strategy consisting of GLV-1h68 and cyclophosphamide (CPA) in a mouse model of PC14PE6-RFP lung adenocarcinoma. Methods PC14PE6-RFP cells were treated in cell culture with GLV-1h68. Viral replication and cell survival were determined by plaque assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, respectively. Subcutaneously implanted PC14PE6-RFP xenografts were treated by systemic injection of GLV-1h68, CPA or a combination of both. Tumor growth and viral biodistribution were monitored and immune-related antigen profiling of tumor lysates was performed. Results GLV-1h68 efficiently infected, replicated in and lysed human PC14PE6-RFP cells in cell cultures. PC14PE6-RFP tumors were efficiently colonized by GLV-1h68 leading to much delayed tumor growth in PC14PE6-RFP tumor-bearing nude mice. Combination treatment with GLV-1h68 and CPA significantly improved the antitumor efficacy of GLV-1h68 and led to an increased viral distribution within the tumors. Pro-inflammatory cytokines and chemokines were distinctly elevated in tumors of GLV-1h68-treated mice. Factors expressed by endothelial cells or present in the blood were decreased after combination treatment. A complete loss in the hemorrhagic phenotype of the PC14PE6-RFP tumors and a decrease in the number of blood vessels after combination treatment could be observed. Conclusions CPA and GLV-1h68 have synergistic antitumor effects on PC14PE6-RFP xenografts. We strongly suppose that in the PC14PE6-RFP model the

  10. Internal radiotherapy and dosimetric study for 111In/ 177Lu-pegylated liposomes conjugates in tumor-bearing mice

    NASA Astrophysics Data System (ADS)

    Wang, Hsin-Ell; Yu, Hung-Man; Lu, Yi-Ching; Heish, Ning-Ning; Tseng, Yun-Long; Huang, Kuang-Liang; Chuang, Kuo-Tang; Chen, Chin-Hsiung; Hwang, Jeng-Jong; Lin, Wuu-Jyh; Wang, Shyh-Jen; Ting, Gann; Whang-Peng, Jacqueline; Deng, Win-Ping

    2006-12-01

    In vivo characterization and dosimetric analysis has been performed to evaluate the potential of pegylated liposomes as carriers of radionuclides in tumor internal radiotherapy. MethodsThe DTPA/PEG-liposomes were synthesized with a medium size of 110 nm, conjugated with 111In/ 177Lu-(oxine) 3 to afford 111In/ 177Lu-liposome. The stability of 111In/ 177Lu-liposome in serum was investigated. The biodistribution, scintigraphic imaging and pharmacokinetics of 111In/ 177Lu-liposomes after intravenous(i.v.) injection into C-26 tumor-bearing BALB/cByJ mice were studied. Radiation dose was estimated by MIRD-III program. ResultsThe incorporation efficiency of 111In/ 177Lu into liposomes was 95%. After incubation at 37 °C for 72 h in serum, more than 83% of radioactivity was still retained in the intact 111In/ 177Lu-liposomes. The biodistribution of 111In-liposomes showed that the radioactivity in the blood decreased from 23.14±8.16%ID/g at 1 h to 0.02±0.00%ID/g at 72 h post-injection (p.i.), while reaching its maximum accumulation in tumors at 48 h p.i., with half-life in blood of 10.2 h. The results were supported by that of 177Lu-liposomes. Scintigraphic imaging with 111In-liposomes showed unambiguous tumor images at 48 h p.i. Dose estimation showed that the absorbed dose in tumor from 177Lu-liposomes was 5.74×10 -5 Gy/MBq. ConclusionsThis study provides an in vivo characterization and dosimetric evaluation for the use of liposome systems as carriers in targeted radionuclide therapy. The results suggest that adequate tumor targeting as well as dose delivered to tumors could be achieved by the use of radionuclide targeted liposomes.

  11. Antitumor activity and systemic effects of PVM/MA-shelled selol nanocapsules in lung adenocarcinoma-bearing mice

    NASA Astrophysics Data System (ADS)

    de Souza, Ludmilla Regina; Alexandre Muehlmann, Luis; Carneiro Matos, Lívia; Simón-Vázquez, Rosana; Guerreiro Marques Lacava, Zulmira; Maurício Batista De-Paula, Alfredo; Mosiniewicz-Szablewska, Ewa; Suchocki, Piotr; César Morais, Paulo; González-Fernández, África; Nair Báo, Sônia; Bentes Azevedo, Ricardo

    2015-12-01

    Selol is a semi-synthetic compound containing selenite that is effective against cancerous cells and safer for clinical applications in comparison with other inorganic forms of selenite. Recently, we have developed a formulation of poly(methyl vinyl ether-co-maleic anhydride)-shelled selol nanocapsules (SPN), which reduced the proliferative activity of lung adenocarcinoma cells and presented little deleterious effects on normal cells in in vitro studies. In this study, we report on the antitumor activity and systemic effects induced by this formulation in chemically induced lung adenocarcinoma-bearing mice. The in vivo antitumor activity of the SPN was verified by macroscopic quantification, immunohistochemistry and morphological analyses. Toxicity analyses were performed by evaluations of the kidney, liver, and spleen; analyses of hemogram and plasma levels of alanine aminotransferase, aspartate transaminase, urea, and creatinine; and DNA fragmentation and cell cycle activity of the bone marrow cells. Furthermore, we investigated the potential of the SPN formulation to cause hemolysis, activate the complement system, provoke an inflammatory response and change the conformation of the plasma proteins. Our results showed that the SPN reduced the area of the surface tumor nodules but not the total number of tumor nodules. The biochemical and hematological findings were suggestive of the low systemic toxicity of the SPN formulation. The surface properties of the selol nanocapsules point to characteristics that are consistent with the treatment of the tumors in vivo: low hemolytic activity, weak inflammatory reaction with no activation of the complement system, and mild or absent conformational changes of the plasma proteins. In conclusion, this report suggests that the SPN formulation investigated herein exhibits anti-tumoral effects against lung adenocarcinoma in vivo and is associated with low systemic toxicity and high biocompatibility.

  12. [Pharmacokinetics and distribution of 5-Fu magnetic albumin deuto-microsphere in normal and tumor-bearing mice].

    PubMed

    Xu, Rong; Shi, Shao-Jun; Zhou, Shun-Chang; Zheng, Jian-Wei; Chen, Hui; Zou, Sheng-Quan; Zeng, Fan-Dian

    2007-01-01

    To observe the pharmacokinetic and tissue-distribution characters of 5-flourouracil magnetic albumin deuto-microsphere (5-Fu-MAD) in normal and tumor-bearing mice, HPLC method for the determination of 5-Fu in plasma and tissues was established and applied to determine 5-Fu in mouse plasma and tissue samples. A Flame atomic absorption spectrometer was used to detect the iron concentration in mouse tissue. Plasma concentration-time curves of free 5-Fu, 5-Fu-MAD and 5-Fu-MAD plus the magnetic frame (MF) conformed to two compartment model of first order absorption and they had C(max) of 34.9, 7.95 and 5.97 mg x L(-1); T1/2 (Ke) of 22.26, 76.0 and 124.6 min, V(d) of 3.28, 30.7 and 66.1 L x kg; AUC(0-t), of 233.9, 78.3 and 50.2 mg x min x L(-1); AUC(0-infinity) of 237.2, 89.3 and 68.1 mg x min x L(-1), respectively. The distribution of 5-Fu and iron was the highest in the plenty blood perfusion organs like the liver, tumor, spleen and lung, while lower in the kidney and heart and lowest in brain and muscle. The tissue distribution of muscle and tumor increased significantly when a magnetic frame was inserted there. The pharmacokinetics and tissue distribution of 5-Fu-MAD exhibited sustained-release and target characteristics.

  13. Modulation of antineoplastic activity of cyclophosphamide by Alstonia scholaris in the Ehrlich ascites carcinoma-bearing mice.

    PubMed

    Jagetia, Ganesh Chandra; Baliga, Manjeshwar Shrinath

    2003-01-01

    Alterations in the neoplastic activity of cyclophosphamide (CPA) by the extract of Alstonia scholaris(ASE) were studied in mice transplanted with Ehrlich ascites carcinoma (EAC). The tumor-bearing animals were injected with various doses of ASE and 25 mg/kg of CPA (1/10th of the LD50 dose). The combination of 120 mg/kg of ASE with 25 mg/kg of CPA was most effective, as it caused the highest tumor regression and enhanced the mean survival time (MST) and the average survival time (AST) up to 42 and 40.7, as against the 29 and 27.5 of CPA alone, respectively. Similarly, when 120 mg/kg of ASE was combined with different doses of CPA (3.125 to 50 mg/kg), a dose-dependent increase in the anticancer activity was observed up to 25 mg/kg of CPA. However, a further increase in the CPA dose up to 37.5 or 50 mg/kg resulted in toxic side effects and death. The best effect was observed when 120 mg/kg of ASE was combined with 25 mg/kg followed by 12.5 mg/kg of CPA, as evident by the greater tumor remission, when compared with the concurrent doses of either drug alone. The administration of 120 mg/kg of ASE 6 h before the administration of 25 mg/kg of CPA resulted in a drastic decline in the glutathione levels and increased the lipid peroxidation considerably when compared with either drug alone.

  14. Intracerebral Distribution of the Oncometabolite d-2-Hydroxyglutarate in Mice Bearing Mutant Isocitrate Dehydrogenase Brain Tumors: Implications for Tumorigenesis

    PubMed Central

    Pickard, Amanda J.; Sohn, Albert S. W.; Bartenstein, Thomas F.; He, Shan; Zhang, Yi; Gallo, James M.

    2016-01-01

    The prevalence of mutant isocitrate dehydrogenase 1 (IDH1) brain tumors has generated significant efforts to understand the role of the mutated enzyme product d-2-hydroxyglutarate (D2HG), an oncometabolite, in tumorigenesis, as well as means to eliminate it. Glymphatic clearance was proposed as a pathway that could be manipulated to accelerate D2HG clearance and dictated the study design that consisted of two cohorts of mice bearing U87/mutant IDH1 intracerebral tumors that underwent two microdialysis – providing D2HG interstitial fluid concentrations – sampling periods of awake and asleep (activate glymphatic clearance) in a crossover manner. Glymphatic clearance was found not to have a significant effect on D2HG brain tumor interstitial fluid concentrations that were 126.9 ± 74.8 μM awake and 117.6 ± 98.6 μM asleep. These concentrations, although low relative to total brain tumor concentrations of 6.8 ± 3.6 mM, were considered sufficient to be transported by interstitial fluid and taken up into normal cells to cause deleterious effects. A model of D2HG CNS distribution supported this contention and was further supported by in vitro studies that showed D2HG could interfere with immune cell function. The study provides insight into the compartmental distribution of D2HG in the brain, wherein the interstitial fluid serves as a dynamic pathway for D2HG to enter normal cells and contribute to tumorigenesis. PMID:27781195

  15. Serum inhibits the immunosuppressive function of myeloid-derived suppressor cells isolated from 4T1 tumor-bearing mice.

    PubMed

    Hamilton, Melisa J; Banáth, Judit P; Lam, Vivian; Lepard, Nancy E; Krystal, Gerald; Bennewith, Kevin L

    2012-05-01

    As more groups investigate the role of myeloid-derived suppressor cells (MDSCs) in promoting the growth of primary tumors and distant tumor metastases, it is imperative to ensure the accurate detection and quantification of MDSC immunosuppression ex vivo. MDSCs are defined by their ability to suppress immune responses. Although different in vitro culture conditions have been used to study MDSCs, the effect of different culture conditions on MDSC immunosuppression is unknown. We therefore isolated MDSCs from the lungs and spleens of 4T1 murine mammary tumor-bearing mice and assayed MDSC-mediated suppression of T cell responses under different culture conditions. We found that 4T1-induced MDSCs effectively suppressed T cell proliferation under serum-free conditions, but not when fetal calf serum (FCS) was present. FCS neither altered the immunosuppressive activities of other myeloid cell types (i.e., peritoneal or tumor-associated macrophages) nor modified the susceptibility of T cells to myeloid cell-mediated suppression, but instead acted directly on 4T1-induced MDSCs to significantly reduce their immunosuppressive function. Importantly, we found that bovine serum albumin was a major contributor to the antagonistic effects of FCS on 4T1-induced MDSC immunosuppression by inhibiting reactive oxygen species production from MDSCs. This work reveals that in vitro culture conditions influence the immunosuppressive properties of MDSCs and highlights the importance of testing different culture conditions on MDSC phenotype to ensure that MDSC immunosuppression is not being masked. These data have important implications for the accurate detection and identification of MDSCs, as well as for determining the influence of MDSC-mediated immunosuppression on primary and metastatic tumor growth.

  16. Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor.

    PubMed

    Yamamoto, N; Naraparaju, V R

    1997-06-01

    Vitamin D3-binding protein (DBP; human DBP is known as Gc protein) is the precursor of macrophage activating factor (MAF). Treatment of mouse DBP with immobilized beta-galactosidase or treatment of human Gc protein with immobilized beta-galactosidase and sialidase generated a remarkably potent MAF, termed DBPMAF or GcMAF, respectively. The domain of Gc protein responsible for macrophage activation was cloned and enzymatically converted to the cloned MAF, designated CdMAF. In Ehrlich ascites tumor-bearing mice, tumor-specific serum alpha-N-acetylgalactosaminidase (NaGalase) activity increased linearly with time as the transplanted tumor cells grew in the peritoneal cavity. Therapeutic effects of DBPMAF, GcMAF, and CdMAF on mice bearing Ehrlich ascites tumor were assessed by survival time, the total tumor cell count in the peritoneal cavity, and serum NaGalase activity. Mice that received a single administration of DBPMAF or GcMAF (100 pg/mouse) on the same day after transplantation of tumor (1 x 10(5) cells) showed a mean survival time of 35 +/- 4 days, whereas tumor-bearing controls had a mean survival time of 16 +/- 2 days. When mice received the second DBPMAF or GcMAF administration at day 4, they survived more than 50 days. Mice that received two DBPMAF administrations, at days 4 and 8 after transplantation of 1 x 10(5) tumor cells, survived up to 32 +/- 4 days. At day 4 posttransplantation, the total tumor cell count in the peritoneal cavity was approximately 5 x 10(5) cells. Mice that received two DBPMAF administrations, at days 0 and 4 after transplantation of 5 x 10(5) tumor cells, also survived up to 32 +/- 4 days, while control mice that received the 5 x 10(5) ascites tumor cells only survived for 14 +/- 2 days. Four DBPMAF, GcMAF, or CdMAF administrations to mice transplanted with 5 x 10(5) Ehrlich ascites tumor cells with 4-day intervals showed an extended survival of at least 90 days and an insignificantly low serum NaGalase level between days 30 and 90.

  17. Targeting a mimotope vaccine to activating Fcgamma receptors empowers dendritic cells to prime specific CD8+ T cell responses in tumor-bearing mice.

    PubMed

    Gil, Margaret; Bieniasz, Magdalena; Wierzbicki, Andrzej; Bambach, Barbara J; Rokita, Hanna; Kozbor, Danuta

    2009-11-15

    A major challenge for inducing antitumor immune responses with native or modified tumor/self-Ags in tumor-bearing hosts relates to achieving efficient uptake and processing by dendritic cells (DCs) to activate immune effector cells and limit the generation of regulatory T cell activity. We analyzed the ability of therapeutic DC vaccines expressing a CD166 cross-reactive mimotope of the GD2 ganglioside, 47-LDA, to selectively expand adoptively transferred, tumor-specific T cells in NXS2 neuroblastoma tumor-bearing syngeneic mice. Before the adoptive cell transfer and DC vaccination, the tumor-bearing mice were lymphodepleted by nonmyeloablative total body irradiation or a myeloablative regimen that required bone marrow transplantation. The 47-LDA mimotope was presented to DCs either as a linear polypeptide in conjunction with universal Th epitopes or as a fusion protein with the murine IgG2a Fc fragment (47-LDA-Fcgamma2a) to deliver the antigenic cassette to the activating Fcgamma receptors. We demonstrate that immunization of adoptively transferred T cells in tumor-bearing mice with the 47-LDA mimotope expressed in the context of the activating Fc fusion protein induced higher levels of antitumor immune responses and protection than the 47-LDA polypeptide-DC vaccine. The antitumor efficacy of the therapeutic 47-LDA-Fcgamma2a-DC vaccine was comparable to that achieved by a virotherapy-associated cancer vaccine using a recombinant oncolytic vaccinia virus expressing the 47-LDA-Fcgamma2a fusion protein. The latter treatment, however, did not require total body irradiation or adoptive cell transfer and resulted in induction of antitumor immune responses in the setting of established tolerance, paving the way for testing novel anticancer treatment strategies.

  18. Insulin-tumour interrelationships in EL4-lymphoma or thymoma-bearing mice. II. Effects of dietary omega-3 and omega-6 polyunsaturated fatty acids.

    PubMed Central

    Yam, D.; Fink, A.; Nir, I.; Budowski, P.

    1990-01-01

    Male C57BL/65 mice received a basal diet supplemented with 4% soya-bean oil, linseed oil or fish oil, in which the major polyunsaturated fatty acids were linoleic acid, alpha-linolenic acid and long chain omega-3 fatty acids, respectively. Groups of animals were injected into the right flank with EL4-lymphoma cells, others with thymoma cells. Tumour implantation caused a gradual decrease in food consumption with both types of tumour, while body weight increased, especially in the EL4-bearing animals receiving the soya-bean diet. The weight gain was due to body water accumulation and was accompanied by decreases in body fat and minor changes in carcass protein and ash contents. The dietary treatments did not produce significant differences in tumour incidence and mortality, but tumour size was decreased by diets supplying omega-3 fatty acids: in the EL4 mice tumour weight was markedly depressed by linseed oil, compared to soya-bean oil, whereas thymoma tumour weight was lowest in mice receiving fish oil and highest in the soya-bean oil group. Both types of tumour caused pronounced hypoglycaemia and hyperinsulinaemia in the hosts, and the effect was modulated by the diets in the EL4 but not in the thymoma animals: the plasma glucose level was especially low in the linseed oil group and relatively highest in the soya-bean oil treatment. The degree of hyperinsulinaemia depended on the diet only in the thymoma-bearing mice, with linseed and fish oils producing higher insulin levels than soya-bean oil. A slight hyperinsulinaemia was also observed in linseed and fish oil-fed control mice. Serum triglycerides were elevated in tumour-bearing animals, without consistent differences between dietary treatments. Although no clear pattern emerged concerning total cholesterol and LDL levels, HDL values were strongly affected by the type of oil: in the control animals linseed oil caused an increase in HDL-cholesterol compared to the other two oils. The thymoma-bearing mice

  19. Antitumor resistance induced by zinostatin stimalamer (ZSS), a polymer-conjugated neocarzinostatin (NCS) derivative. I. Meth A tumor eradication and tumor-neutralizing activity in mice pretreated with ZSS or NCS.

    PubMed

    Masuda, E; Maeda, H

    1995-05-01

    Zinostatin stimalamer (ZSS) is a new anticancer agent derived from neocarzinostatin (NCS), which is synthesized by conjugation of one molecule of NCS and two molecules of poly(styrene-co-maleic acid). ZSS exhibited potent in vitro and in vivo antitumor activity in preclinical experiments, and a clinical trial of the intra-arterial administration of ZSS with iodized oil on hepatocellular carcinoma showed potent antitumor activity. We investigated the effect of ZSS and NCS on antitumor resistance and found that pretreatment with either drug suppressed the growth of MethA tumors in Balb/c mice and induced tumor eradication when given separately by single administration at therapeutic doses between 1 day and 4 weeks before tumor transplantation. The findings that the cytocidal activity of these drugs was not detected in vivo at the time of tumor transplantation and that tumor regression was preceded by a period of transient growth suggested that tumor regression was due to host-mediated antitumor activity induced by these drugs. Pretreatment with ZSS or NCS also suppressed the growth of Colon 26 carcinoma and Sarcoma 180. The finding that NCS showed the same effect as ZSS suggests that poly(styrene-comaleic acid) is not essential for the induction of host-mediated antitumor activity. Furthermore, apo-ZSS, which lacks cytocidal activity, did not induce antitumor activity. From this, it is suggested that the cytocidal effect of ZSS involves the induction of host-mediated antitumor resistance. In athymic Balb/c nu/nu mice, pretreatment with ZSS or NCS did not induce tumor eradication, suggesting that mature T lymphocytes play an important role in tumor eradication. Challenging MethA was rejected without transient growth in mice that had been cured of MethA, but challenging Colon 26 was not, showing that anti-MethA resistance was augmented selectively in the MethA-eradicated mice. Splenocytes from MethA-bearing mice pretreated with the drug showed tumor

  20. Hindlimb Skeletal Muscle Function and Skeletal Quality and Strength in +/G610C Mice With and Without Weight-Bearing Exercise.

    PubMed

    Jeong, Youngjae; Carleton, Stephanie M; Gentry, Bettina A; Yao, Xiaomei; Ferreira, J Andries; Salamango, Daniel J; Weis, MaryAnn; Oestreich, Arin K; Williams, Ashlee M; McCray, Marcus G; Eyre, David R; Brown, Marybeth; Wang, Yong; Phillips, Charlotte L

    2015-10-01

    Osteogenesis imperfecta (OI) is a heterogeneous heritable connective tissue disorder associated with reduced bone mineral density and skeletal fragility. Bone is inherently mechanosensitive, with bone strength being proportional to muscle mass and strength. Physically active healthy children accrue more bone than inactive children. Children with type I OI exhibit decreased exercise capacity and muscle strength compared with healthy peers. It is unknown whether this muscle weakness reflects decreased physical activity or a muscle pathology. In this study, we used heterozygous G610C OI model mice (+/G610C), which model both the genotype and phenotype of a large Amish OI kindred, to evaluate hindlimb muscle function and physical activity levels before evaluating the ability of +/G610C mice to undergo a treadmill exercise regimen. We found +/G610C mice hindlimb muscles do not exhibit compromised muscle function, and their activity levels were not reduced relative to wild-type mice. The +/G610C mice were also able to complete an 8-week treadmill regimen. Biomechanical integrity of control and exercised wild-type and +/G610C femora were analyzed by torsional loading to failure. The greatest skeletal gains in response to exercise were observed in stiffness and the shear modulus of elasticity with alterations in collagen content. Analysis of tibial cortical bone by Raman spectroscopy demonstrated similar crystallinity and mineral/matrix ratios regardless of sex, exercise, and genotype. Together, these findings demonstrate +/G610C OI mice have equivalent muscle function, activity levels, and ability to complete a weight-bearing exercise regimen as wild-type mice. The +/G610C mice exhibited increased femoral stiffness and decreased hydroxyproline with exercise, whereas other biomechanical parameters remain unaffected, suggesting a more rigorous exercise regimen or another exercise modality may be required to improve bone quality of OI mice.

  1. Expansion of CD11b(+)Ly6G (+)Ly6C (int) cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions.

    PubMed

    Spallanzani, Raúl Germán; Dalotto-Moreno, Tomás; Raffo Iraolagoitia, Ximena Lucía; Ziblat, Andrea; Domaica, Carolina Inés; Avila, Damián Ezequiel; Rossi, Lucas Ezequiel; Fuertes, Mercedes Beatriz; Battistone, María Agustina; Rabinovich, Gabriel Adrián; Salatino, Mariana; Zwirner, Norberto Walter

    2013-12-01

    The progesterone analog medroxyprogesterone acetate (MPA) is widely used as a hormone replacement therapy in postmenopausal women and as contraceptive. However, prolonged administration of MPA is associated with increased incidence of breast cancer through ill-defined mechanisms. Here, we explored whether exposure to MPA during mammary tumor growth affects myeloid-derived suppressor cells (MDSCs; CD11b(+)Gr-1(+), mostly CD11b(+)Ly6G(+)Ly6C(int) and CD11b(+)Ly6G(-)Ly6C(high) cells) and natural killer (NK) cells, potentially restraining tumor immunosurveillance. We used the highly metastatic 4T1 breast tumor (which does not express the classical progesterone receptor and expands MDSCs) to challenge BALB/c mice in the absence or in the presence of MPA. We observed that MPA promoted the accumulation of NK cells in spleens of tumor-bearing mice, but with reduced degranulation ability and in vivo cytotoxic activity. Simultaneously, MPA induced a preferential expansion of CD11b(+)Ly6G(+)Ly6C(int) cells in spleen and bone marrow of 4T1 tumor-bearing mice. In vitro, MPA promoted nuclear mobilization of the glucocorticoid receptor (GR) in 4T1 cells and endowed these cells with the ability to promote a preferential differentiation of bone marrow cells into CD11b(+)Ly6G(+)Ly6C(int) cells that displayed suppressive activity on NK cell degranulation. Sorted CD11b(+)Gr-1(+) cells from MPA-treated tumor-bearing mice exhibited higher suppressive activity on NK cell degranulation than CD11b(+)Gr-1(+) cells from vehicle-treated tumor-bearing mice. Thus, MPA, acting through the GR, endows tumor cells with an enhanced capacity to expand CD11b(+)Ly6G(+)Ly6C(int) cells that subsequently display a stronger suppression of NK cell-mediated anti-tumor immunity. Our results describe an alternative mechanism by which MPA may affect immunosurveillance and have potential implication in breast cancer incidence.

  2. Compartment Model Predicts VEGF Secretion and Investigates the Effects of VEGF Trap in Tumor-Bearing Mice

    PubMed Central

    Finley, Stacey D.; Dhar, Manjima; Popel, Aleksander S.

    2013-01-01

    Angiogenesis, the formation of new blood vessels from existing vasculature, is important in tumor growth and metastasis. A key regulator of angiogenesis is vascular endothelial growth factor (VEGF), which has been targeted in numerous anti-angiogenic therapies aimed at inhibiting tumor angiogenesis. Systems biology approaches, including computational modeling, are useful for understanding this complex biological process and can aid in the development of novel and effective therapeutics that target the VEGF family of proteins and receptors. We have developed a computational model of VEGF transport and kinetics in the tumor-bearing mouse, which includes three-compartments: normal tissue, blood, and tumor. The model simulates human tumor xenografts and includes human (VEGF121 and VEGF165) and mouse (VEGF120 and VEGF164) isoforms. The model incorporates molecular interactions between these VEGF isoforms and receptors (VEGFR1 and VEGFR2), as well as co-receptors (NRP1 and NRP2). We also include important soluble factors: soluble VEGFR1 (sFlt-1) and α-2-macroglobulin. The model accounts for transport via macromolecular transendothelial permeability, lymphatic flow, and plasma clearance. We have fit the model to available in vivo experimental data on the plasma concentration of free VEGF Trap and VEGF Trap bound to mouse and human VEGF in order to estimate the rates at which parenchymal cells (myocytes and tumor cells) and endothelial cells secrete VEGF. Interestingly, the predicted tumor VEGF secretion rates are significantly lower (0.007–0.023 molecules/cell/s, depending on the tumor microenvironment) than most reported in vitro measurements (0.03–2.65 molecules/cell/s). The optimized model is used to investigate the interstitial and plasma VEGF concentrations and the effect of the VEGF-neutralizing agent, VEGF Trap (aflibercept). This work complements experimental studies performed in mice and provides a framework with which to examine the effects of anti

  3. A 5-fluorouracil-loaded floating gastroretentive hollow microsphere: development, pharmacokinetic in rabbits, and biodistribution in tumor-bearing mice

    PubMed Central

    Huang, Yu; Wei, Yumeng; Yang, Hongru; Pi, Chao; Liu, Hao; Ye, Yun; Zhao, Ling

    2016-01-01

    5-Fluorouracil (5-FU) was loaded in hollow microspheres to improve its oral bioavailability. 5-FU hollow microspheres were developed by a solvent diffusion–evaporation method. The effect of Span 80 concentration, ether/ethanol volume ratio, and polyvinyl pyrrolidone/ethyl cellulose weight ratio on physicochemical characteristics, floating, and in vitro release behaviors of 5-FU hollow microspheres was investigated and optimized. The formulation and technology composed of Span 80 (1.5%, w/v), ether/ethanol (1.0:10.0, v/v), and polyvinyl pyrrolidone/ethyl cellulose (1.0:10.0, w/w) were employed to develop three batch samples, which showed an excellent reproducibility. The microspheres were spherical with a hollow structure with high drug loading amount (28.4%±0.5%) and production yield (74.2%±0.6%); they exhibited excellent floating and sustained release characteristics in simulated gastric and intestinal fluid. Pharmacokinetic studies demonstrated that 5-FU hollow microspheres significantly enhanced oral bioavailability (area under curve, [AUC](0−t): 12.53±1.65 mg/L*h vs 7.80±0.83 and 5.82±0.83 mg/L*h) with longer elimination half-life (t1/2) (15.43±2.12 hours vs 2.25±0.22 and 1.43±0.18 hours) and mean residence time (7.65±0.97 hours vs 3.61±0.41 and 2.34±0.35 hours), in comparison with its solid microspheres and powder. In vivo distribution results from tumor-bearing nude mice demonstrated that the animals administered with 5-FU hollow microspheres had much higher drug content in tumor, plasma, and stomach at 1 and 8 hours except for 0.5 hours sample collection time point in comparison with those administered with 5-FU solid microspheres and its powder. These results suggested that the hollow microspheres would be a promising controlled drug delivery system for an oral chemotherapy agent like 5-FU. PMID:27042001

  4. A 5-fluorouracil-loaded floating gastroretentive hollow microsphere: development, pharmacokinetic in rabbits, and biodistribution in tumor-bearing mice.

    PubMed

    Huang, Yu; Wei, Yumeng; Yang, Hongru; Pi, Chao; Liu, Hao; Ye, Yun; Zhao, Ling

    2016-01-01

    5-Fluorouracil (5-FU) was loaded in hollow microspheres to improve its oral bioavailability. 5-FU hollow microspheres were developed by a solvent diffusion-evaporation method. The effect of Span 80 concentration, ether/ethanol volume ratio, and polyvinyl pyrrolidone/ethyl cellulose weight ratio on physicochemical characteristics, floating, and in vitro release behaviors of 5-FU hollow microspheres was investigated and optimized. The formulation and technology composed of Span 80 (1.5%, w/v), ether/ethanol (1.0:10.0, v/v), and polyvinyl pyrrolidone/ethyl cellulose (1.0:10.0, w/w) were employed to develop three batch samples, which showed an excellent reproducibility. The microspheres were spherical with a hollow structure with high drug loading amount (28.4%±0.5%) and production yield (74.2%±0.6%); they exhibited excellent floating and sustained release characteristics in simulated gastric and intestinal fluid. Pharmacokinetic studies demonstrated that 5-FU hollow microspheres significantly enhanced oral bioavailability (area under curve, [AUC](0-t): 12.53±1.65 mg/L(*)h vs 7.80±0.83 and 5.82±0.83 mg/L(*)h) with longer elimination half-life (t1/2) (15.43±2.12 hours vs 2.25±0.22 and 1.43±0.18 hours) and mean residence time (7.65±0.97 hours vs 3.61±0.41 and 2.34±0.35 hours), in comparison with its solid microspheres and powder. In vivo distribution results from tumor-bearing nude mice demonstrated that the animals administered with 5-FU hollow microspheres had much higher drug content in tumor, plasma, and stomach at 1 and 8 hours except for 0.5 hours sample collection time point in comparison with those administered with 5-FU solid microspheres and its powder. These results suggested that the hollow microspheres would be a promising controlled drug delivery system for an oral chemotherapy agent like 5-FU.

  5. Preparation of myeloid derived suppressor cells (MDSC) from naive and pancreatic tumor-bearing mice using flow cytometry and automated magnetic activated cell sorting (AutoMACS).

    PubMed

    Nelson, Nadine; Szekeres, Karoly; Cooper, Denise; Ghansah, Tomar

    2012-06-18

    MDSC are a heterogeneous population of immature macrophages, dendritic cells and granulocytes that accumulate in lymphoid organs in pathological conditions including parasitic infection, inflammation, traumatic stress, graft-versus-host disease, diabetes and cancer. In mice, MDSC express Mac-1 (CD11b) and Gr-1 (Ly6G and Ly6C) surface antigens. It is important to note that MDSC are well studied in various tumor-bearing hosts where they are significantly expanded and suppress anti-tumor immune responses compared to naïve counterparts. However, depending on the pathological condition, there are different subpopulations of MDSC with distinct mechanisms and targets of suppression. Therefore, effective methods to isolate viable MDSC populations are important in elucidating their different molecular mechanisms of suppression in vitro and in vivo. Recently, the Ghansah group has reported the expansion of MDSC in a murine pancreatic cancer model. Our tumor-bearing MDSC display a loss of homeostasis and increased suppressive function compared to naïve MDSC. MDSC percentages are significantly less in lymphoid compartments of naïve vs. tumor-bearing mice. This is a major caveat, which often hinders accurate comparative analyses of these MDSC. Therefore, enriching Gr-1(+) leukocytes from naïve mice prior to Fluorescence Activated Cell Sorting (FACS) enhances purity, viability and significantly reduces sort time. However, enrichment of Gr-1(+) leukocytes from tumor-bearing mice is optional as these are in abundance for quick FACS sorting. Therefore, in this protocol, we describe a highly efficient method of immunophenotyping MDSC and enriching Gr-1(+) leukocytes from spleens of naïve mice for sorting MDSC in a timely manner. Immunocompetent C57BL/6 mice are inoculated with murine Panc02 cells subcutaneously whereas naïve mice receive 1XPBS. Approximately 30 days post inoculation; spleens are harvested and processed into single-cell suspensions using a cell dissociation

  6. Preparation of Myeloid Derived Suppressor Cells (MDSC) from Naive and Pancreatic Tumor-bearing Mice using Flow Cytometry and Automated Magnetic Activated Cell Sorting (AutoMACS)

    PubMed Central

    Nelson, Nadine; Szekeres, Karoly; Cooper, Denise; Ghansah, Tomar

    2012-01-01

    MDSC are a heterogeneous population of immature macrophages, dendritic cells and granulocytes that accumulate in lymphoid organs in pathological conditions including parasitic infection, inflammation, traumatic stress, graft-versus-host disease, diabetes and cancer1-7. In mice, MDSC express Mac-1 (CD11b) and Gr-1 (Ly6G and Ly6C) surface antigens7. It is important to note that MDSC are well studied in various tumor-bearing hosts where they are significantly expanded and suppress anti-tumor immune responses compared to naïve counterparts7-10. However, depending on the pathological condition, there are different subpopulations of MDSC with distinct mechanisms and targets of suppression11,12. Therefore, effective methods to isolate viable MDSC populations are important in elucidating their different molecular mechanisms of suppression in vitro and in vivo. Recently, the Ghansah group has reported the expansion of MDSC in a murine pancreatic cancer model. Our tumor-bearing MDSC display a loss of homeostasis and increased suppressive function compared to naïve MDSC 13. MDSC percentages are significantly less in lymphoid compartments of naïve vs. tumor-bearing mice. This is a major caveat, which often hinders accurate comparative analyses of these MDSC. Therefore, enriching Gr-1+ leukocytes from naïve mice prior to Fluorescence Activated Cell Sorting (FACS) enhances purity, viability and significantly reduces sort time. However, enrichment of Gr-1+ leukocytes from tumor-bearing mice is optional as these are in abundance for quick FACS sorting. Therefore, in this protocol, we describe a highly efficient method of immunophenotyping MDSC and enriching Gr-1+ leukocytes from spleens of naïve mice for sorting MDSC in a timely manner. Immunocompetent C57BL/6 mice are inoculated with murine Panc02 cells subcutaneously whereas naïve mice receive 1XPBS. Approximately 30 days post inoculation; spleens are harvested and processed into single-cell suspensions using a cell

  7. Effect of cisplatin and cobalt chloride on antioxidant enzymes in the livers of Lewis lung carcinoma-bearing mice: protective role of heme oxygenase.

    PubMed

    Christova, Tania Y; Gorneva, Galina A; Taxirov, Svetoslav I; Duridanova, Dessislava B; Setchenska, Milka S

    2003-03-03

    Changes in the activities of antioxidant enzymes superoxide dismutase, catalase (CAT), glutathione peroxidase and heme oxygenase (HO) and changes in lipid peroxidation and reduced glutathione (GSH) levels were measured in the livers of control and Lewis lung carcinoma (LLC)-bearing mice 24 h after a single injection of cisplatin or CoCl(2). Treatment with cisplatin induced the same degree of lipid peroxidation and GSH depletion as did CoCl(2) but the antioxidant enzymes were differently involved in cisplatin- and cobalt-induced oxidative stress responses. In cobalt-treated mice the activities of these enzymes were either inhibited or not changed significantly and only the HO activity was increased (5-fold) as a main protective enzyme. In cisplatin-treated animals the antioxidant enzymes were activated but the enhancement of HO and CAT was greater in LLC-inoculated mice. It is suggested that these two enzymes represent the protective response against cisplatin toxicity in the livers of tumor-bearing animals.

  8. Antioxidants selenomethionine and D-pantethine decrease the negative side effects of doxorubicin in NL/Ly lymphoma-bearing mice

    PubMed Central

    Panchuk, Rostyslav R.; Skorokhyd, Nadia R.; Kozak, Yuliya S.; Lehka, Liliya V.; Chumak, Vira V.; Omelyanchik, Sofya N.; Gurinovich, Valery A.; Moiseenok, Andrey G.; Stoika, Rostyslav S.

    2016-01-01

    Aim To investigate the potential tissue-protective effects of antioxidants selenomethionine and D-pantethine applied together with doxorubicin (Dx) on NK/Ly lymphoma-bearing mice. The impact of this chemotherapy scheme on animal survival, blood cell profile, hepatotoxicity, glutathione level, and activity of glutathione-converting enzymes in the liver was compared with the action of Dx applied alone. Methods The hematological profile of animals was studied by the analysis of blood smears under light microscopy. Hepatotoxicity of studied drugs was evaluated measuring the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes, De Ritis ratio, and coenzyme A fractions by McDougal assay. Glutathione level in animal tissues was measured with Ellman reagent, and the activity of glutathione reductase, transferase, and peroxidase was measured using standard biochemical assays. Results D-pantethine (500 mg/kg) and, to a lower extent, selenomethionine (600 µg/kg) partially reduced the negative side effects (leukocytopenia and erythropenia) of Dx (5 mg/kg) in NK/Ly lymphoma bearing animals on the 14th day of their treatment. This increased animal survival time from 47-48 to 60+ days and improved the quality of their life. This ability of D-pantethine and selenomethionine was realized via hepatoprotective and immunomodulating activities. D-pantethine also restored the levels of acid-soluble and free CoA in the liver of tumor-bearing animals, while selenomethionine caused the recovery of glutathione peroxidase levels in the liver, which was significantly diminished under Dx treatment. Both compounds decreased glutathione level in the liver, which was considerably induced by Dx. Conclusions Antioxidants selenomethionine and D-pantethine partially reversed the negative side effects of Dx in NK/Ly lymphoma-bearing mice and significantly increased the therapeutic efficiency of this drug in tumor treatment. PMID:27106359

  9. Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice

    PubMed Central

    Yang, Hong-Mei; Sun, Chao-Yue; Liang, Jia-Li; Xu, Lie-Qiang; Zhang, Zhen-Biao; Luo, Dan-Dan; Chen, Han-Bin; Huang, Yong-Zhong; Wang, Qi; Lee, David Yue-Wei; Yuan, Jie; Li, Yu-Cui

    2017-01-01

    Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future. PMID:28245556

  10. Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice.

    PubMed

    Yang, Hong-Mei; Sun, Chao-Yue; Liang, Jia-Li; Xu, Lie-Qiang; Zhang, Zhen-Biao; Luo, Dan-Dan; Chen, Han-Bin; Huang, Yong-Zhong; Wang, Qi; Lee, David Yue-Wei; Yuan, Jie; Li, Yu-Cui

    2017-02-24

    Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.

  11. Intraoral Mitochondrial-Targeted GS-Nitroxide, JP4-039, Radioprotects Normal Tissue in Tumor-Bearing Radiosensitive Fancd2(-/-) (C57BL/6) Mice.

    PubMed

    Shinde, Ashwin; Berhane, Hebist; Rhieu, Byung Han; Kalash, Ronny; Xu, Karen; Goff, Julie; Epperly, Michael W; Franicola, Darcy; Zhang, Xichen; Dixon, Tracy; Shields, Donna; Wang, Hong; Wipf, Peter; Parmar, Kalindi; Guinan, Eva; Kagan, Valerian; Tyurin, Vladimir; Ferris, Robert L; Zhang, Xiaolan; Li, Song; Greenberger, Joel S

    2016-02-01

    We evaluated normal tissue specific radioprotection of the oral cavity in radiosensitive Fanconi Anemia (FA) Fancd2(-/-) mice with orally established tumors using mitochondrial-targeted GS-nitroxide (JP4-039). Adult (10-12 weeks old) Fancd2(+/+), Fancd2(+/-) and Fancd2(-/-) mice (C57BL/6 background) and subgroups with orally established TC-1 epithelial cell tumors received a single fraction of 28 Gy or four daily fractions of 8 Gy to the head and neck. Subgroups received JP4-039 in F15 emulsion (F15/JP4-039; 0.4 mg/mouse), 4-amino-Tempo in F15 emulsion (F15/4-amino-Tempo; 0.2 mg/mouse) or F15 emulsion alone prior to each irradiation. Oral mucosa of Fancd2(-/-) mice showed baseline elevated RNA transcripts for Sod2, p53, p21 and Rad51 (all P < 0.0012) and suppressed levels of Nfkb and Tgfb, (all P < 0.0020) compared with Fancd2(+/+) mice. The oral mucosa in tumor-bearing mice of all genotypes showed decreased levels of p53 and elevated Tgfb and Gadd45a (P ≤ 0.0001 for all three genotypes). Intraoral F15/JP4-039, but not F15/4-amino-Tempo, modulated radiation-induced normal tissue transcript elevation, ameliorated mucosal ulceration and reduced the depletion of antioxidant stores in oral cavity tissue of all genotypes, but did not radioprotect tumors. Mitochondrial targeting makes F15/JP4-039 an effective normal tissue radioprotector for Fancd2(-/-) mice, as well as wild-type mice.

  12. Effects of 7.5cGy heavy ion irradiation on tumor growth in tumor-bearing male and female mice

    NASA Astrophysics Data System (ADS)

    Bing, T.; Dang, B.; Xie, Y.; Hu, X.; Li, W.

    Purpose The data on heavy ions causing tumor is few In the study the effects of low dose with heavy ion radiation in tumor-bearing mice were investigated Methods and Materials Six hours before the implantation of S180 sarcoma cells the BALB c mice groups were irradiated in whole body with 7 5cGy by the 12 C 6 beam 73 74MeV u at the HIRFL Lanzhou China From the fifth day the sizes of tumor were measured 16 days after irradiation spleen thymus and tumor were sampled immediately upon sacrifice and were weighed Results The S180 sarcoma sizes of the 7 5cGy irradiation group grew bigger than those of the sham-irradiation and the sizes of male grew bigger than those of female The spleen index of tumor-bearing mice is bigger than the normal control group in male and female mice while thymus index of female 7 5cGy irradiation group is bigger than other groups Conclusions This study indicates LDR low dose radiation of heavy ions can cause different biological effect to the different strain and gender animals and LDR of heavy ion may be still hazard to some people whose immunity are low especially If the carbon treatment volume includes normal tissues they are also risky for the appearance of both enhanced acute and late radiation effects The mechanisms involved remain to be elucidated This question is of importance because this late reaction could be one of the parameters limiting the long-term space missions and object-oriented biological hadrontherapy

  13. Effects of Combined Treatment with Branched-Chain Amino Acids, Citric Acid, L-Carnitine, Coenzyme Q10, Zinc, and Various Vitamins in Tumor-Bearing Mice.

    PubMed

    Awa, Hiroko; Futamura, Akihiko; Higashiguchi, Takashi; Ito, Akihiro; Mori, Naoharu; Murai, Miyo; Ohara, Hiroshi; Chihara, Takeshi; Kaneko, Takaaki

    2017-03-01

    A functional dietary supplement (FDS) containing Coenzyme Q10, branched-chain amino acids and L-carnitine was administered to tumor-bearing mice, investigating its effects on tumor and muscle tissues. Experiment (A): B16 melanoma cells were implanted subcutaneously into the right side of the abdomen of 8- to 9-week-old C57BL/6J mice. The mice were divided into two groups: a FDS group that received oral administration of FDS (n=10), and a control group that received oral administration of glucose (n=10). The moribund condition was used as the endpoint, and median survival time was determined. Experiment (B): On day 21 after tumor implantation, tumors, soleus muscle, gastrocnemius muscle, and suprahyoid muscles were collected. Tumor and muscle weight and other aspects were evaluated in each group: FDS group (n=15) and control group (n=15). The median survival time was comparable (21 d in the FDS group vs. 18 d in the control group, p=0.30). However, cumulative food intake was significantly higher in the FDS group than the control group (p=0.011). Metastasis of melanoma to the lung was observed in the control group but not in the FDS group (p=0.043). The weight of the suprahyoid muscles was significantly higher in the FDS group than in the control group (p=0.0045). The weight of the tumor was significantly lower in the FDS group than in the control group (p=0.013). The results possibly suggest oral administration of FDS in tumor-bearing mice enhances the maintenance of suprahyoid muscles, resulting in an extended feeding period and suppression of tumor growth and metastasis.

  14. A dual radiologic contrast agent protocol for 18F-FDG and 18F-FLT PET/CT imaging of mice bearing abdominal tumors.

    PubMed

    Aide, Nicolas; Kinross, Kathryn; Beauregard, Jean-Mathieu; Neels, Oliver; Potdevin, Titaina; Roselt, Peter; Dorow, Donna; Cullinane, Carleen; Hicks, Rodney J

    2011-06-01

    The aim of the study was to improve abdominal tumor detection by use of a dual radiologic contrast protocol. eXia160® (Benitio international) was mixed with 2-deoxy-2-[¹⁸F]fluoro-D: -glucose or 3'-[¹⁸F]fluoro-3'-deoxythymidine for intravenous (IV) injections. Omnipaque® 300 (GE healthcare) was used for intraperitoneal (IP) injections. Positron emission tomography/computed tomography (PET/CT) scans were acquired on a Siemens Biograph® equipped with point spread function reconstruction. The optimal concentration and injection schedule of IP contrast agent was studied in 12 mice. The impact of IP contrast media on PET quantitative accuracy was investigated by phantom studies and by imaging six mice before and after IP injection of Omnipaque®. The impact of a dual contrast media protocol on tumor delineation and quantitation was evaluated in 15 tumor-bearing mice using ex vivo counting as the reference. The optimal sequence was a mixture of tracer plus IV contrast agent followed by 1 mL of IP contrast agent (20 mg iodine/mL) administered 10 min before PET/CT acquisition. Phantom studies showed that the use of a 20-mg iodine/mL concentration of Omnipaque® led to a 4.8% overestimation of radioactivity concentration, as compared to saline. This was confirmed by animal studies that demonstrated a 4.3% overestimation. Tumor detection was excellent and correlation between PET/CT quantitative data and ex vivo counting was good (r² = 0.91, slope = 0.7). A dual radiologic contrast protocol is useful in PET/CT scanning of mice bearing abdominal tumors. Contrast agents used in this manner lead to a small but acceptable overestimation of quantitative PET data.

  15. Beta-Adrenergic Blockade Decreases the Neuroimmune Changes in Mice Induced by Cohabitation with an Ehrlich Tumor-Bearing Cage Mate.

    PubMed

    Margatho, Rafael O; Massoco, Cristina de O; Calefi, Atilio S; Cruz, Daniel S G; Sandini, Thaisa M; Alves, Glaucie Jussilane; Florio, Jorge C; Palermo-Neto, João

    2017-01-01

    Cohabitation with Ehrlich tumor-bearing (ETB) mice induced behavioral, neurochemical, hormonal, and immune effects in the conspecifics as a consequence of stress-induced activation of the sympathetic nervous system (SNS) with catecholamine release. In the current study, the nonspecific β-AR blocker d,l-propranolol and the specific β2-AR blocker ICI-118.551 were employed as pharmacological tools to assess the extent to which catecholamines participated in the effects induced by cohabitation with ETB mice. Two experiments were performed, 1 with d,l-propranolol treatment and the other with ICI-118.551. One mouse in the experimental group was called the "companion of the sick partner" (CSP) since it was forced to live in the same cage with 2 (experiment 1) or 1 (experiment 2) cage mate that had been i.p. injected with 5 × 106 Ehrlich tumor cells. The d,l-propranolol treatment, but not the ICI-118.551 treatment, attenuated the effects of cohabitation with 2 ETB mice on both open-field behavior and the hypothalamic levels and turnover rate of norepinephrine. The 2 β-AR blockers were unable to change the serum corticosterone levels and adrenal weights of the CSP mice; however, these drugs abrogated the effects of cohabitation on neutrophil oxidative burst and phagocytosis. Finally, an increase in the 5-HT turnover rate was observed in the olfactory bulb of CSP mice compared to their respective controls, an effect that was not modified by β-AR blockade. These results confirm and strengthen our hypothesis that the SNS is involved in the effects induced by cohabitation with ETB mice and point towards β2-AR participation in the immune effects analyzed. © 2017 S. Karger AG, Basel.

  16. UPLC-MS method for quantification of pterostilbene and its application to comparative study of bioavailability and tissue distribution in normal and Lewis lung carcinoma bearing mice.

    PubMed

    Deng, Li; Li, Yongzhi; Zhang, Xinshi; Chen, Bo; Deng, Yulin; Li, Yujuan

    2015-10-10

    A UPLC-MS method was developed for determination of pterostilbene (PTS) in plasma and tissues of mice. PTS was separated on Agilent Zorbax XDB-C18 column (50 × 2.1 mm, 1.8 μm) with gradient mobile phase at the flow rate of 0.2 ml/min. The detection was performed by negative ion electrospray ionization in multiple reaction monitoring mode. The linear calibration curve of PTS in mouse plasma and tissues ranged from 1.0 to 5000 and 0.50 to 500 ng/ml (r(2)>0.9979), respectively, with lowest limits of quantification (LLOQ) were between 0.5 and 2.0 ng/ml, respectively. The accuracy and precision of the assay were satisfactory. The validated method was applied to the study of bioavailability and tissue distribution of PTS in normal and Lewis lung carcinoma (LLC) bearing mice. The bioavailability of PTS (dose 14, 28 and 56 mg/kg) in normal mice were 11.9%, 13.9% and 26.4%, respectively; and the maximum level (82.1 ± 14.2 μg/g) was found in stomach (dose 28 mg/kg). The bioavailability, peak concentration (Cmax), time to peak concentration (Tmax) of PTS in LLC mice was increased compared with normal mice. The results indicated the UPLC-MS method is reliable and bioavailability and tissue distribution of PTS in normal and LLC mice were dramatically different. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Intermedin A, a New Labdane Diterpene Isolated from Alpinia intermedia, Prolonged the Survival Time of P-388D1 Tumor-Bearing CDF1 Mice.

    PubMed

    Chen, Lih-Geeng; Su, Pei-Jung; Tsai, Po-Wei; Yang, Ling-Ling; Wang, Ching-Chiung

    2017-01-01

    Eight ethanolic extracts of indigenous Taiwanese plants of the genus Alpinia were tested for tumor cytotoxicity against AGS, Hep G2, HeLa, KB, and HL-60 cells. Among the 50 % and 95 % EtOH extracts of eight Alpinia species, the cytotoxic effects of Alpinia intermedia leaves were the strongest. When the leaf extract of A. intermedia was partitioned using n-hexane and aqueous solvents, the n-hexane layer showed a greater cytotoxic effect and could prolong the survival time of P-388D1 tumor-bearing CDF1 mice. Two new labdane diterpene derivatives, intermedin A (1) and intermedin B (2), and coronarin E (3) were isolated from the n-hexane layer of A. intermedia. Intermedin A induced apoptosis in HL-60 cells at 30 µg/mL and significantly prolonged the survival time of P-388D1 tumor-bearing CDF1 mice by 48.7 % at 20 mg/kg of body weight. We suggest that intermedin A is a major compound of A. intermedia and has a cytotoxic effect on HL-60 and P-388D1 cells. Georg Thieme Verlag KG Stuttgart · New York.

  18. Anticancer potential of Amaryllidaceae alkaloids evaluated by screening with a panel of human cells, real-time cellular analysis and Ehrlich tumor-bearing mice.

    PubMed

    Havelek, Radim; Muthna, Darina; Tomsik, Pavel; Kralovec, Karel; Seifrtova, Martina; Cahlikova, Lucie; Hostalkova, Anna; Safratova, Marcela; Perwein, Maria; Cermakova, Eva; Rezacova, Martina

    2017-09-25

    In this study, twenty-two Amaryllidaceae alkaloids were screened for their anticancer potential. All isolates were evaluated for antiproliferative activities on a panel of 17 human cell types of different tissue origin using WST-1 assay. In addition, we determined the antiproliferative effect with a real-time cell analysis xCELLigence system. Thereafter, to evaluate the barely known in vivo anticancer potential of the most potent molecule haemanthamine, a preliminary study was performed using an Ehrlich tumor-bearing mice model. The results showed that haemanthamine, lycorine and haemanthidine exerted the highest antiproliferative activity. The mean growth percent (GP) value after a single-dose 10 μM treatment was for haemanthamine 21%, for lycorine 21% and for haemanthidine 27% that of untreated control cells (100%). Furthermore, haemanthamine, lycorine and haemanthidine exhibited significant cytotoxicities against all the tested cell lines with individual IC50 values in the micromolar range. Dynamic real-time measures of impedance by xCELLigence indicated that these three compounds suppress cell proliferation after 10 h of treatment at a concentration of 10 μM or higher. Regrettably, in a follow-up in vivo antitumor activity study, haemanthamine showed no statistically significant reduction in the tumor size with no prolongation of survival time of Ehrlich tumor-bearing mice. Taken together, these results provide a new clue and guidance for exploiting Amaryllidaceae alkaloids as anticancer agents. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. RA-XII inhibits tumour growth and metastasis in breast tumour-bearing mice via reducing cell adhesion and invasion and promoting matrix degradation

    PubMed Central

    Leung, Hoi-Wing; Zhao, Si-Meng; Yue, Grace Gar-Lee; Lee, Julia Kin-Ming; Fung, Kwok-Pui; Leung, Ping-Chung; Tan, Ning-Hua; Lau, Clara Bik-San

    2015-01-01

    Cancer cells acquire invasive ability to degrade and adhere to extracellular matrix (ECM) and migrate to adjacent tissues. This ultimately results metastasis. Hence, the present study investigated the in vitro effects of cyclopeptide glycoside, RA-XII on cell adhesion, invasion, proliferation and matrix degradation, and its underlying mechanism in murine breast tumour cells, 4T1. The effect of RA-XII on tumour growth and metastasis in 4T1-bearing mice was also investigated. Our results showed that RA-XII inhibited tumour cell adhesion to collagen, fibronectin and laminin, RA-XII also reduced the expressions of vascular cell adhesion molecule, intracellular adhesion molecule and integrins, and integrin binding. In addition, RA-XII significantly inhibited breast tumour cell migration via interfering cofilin signaling and chemokine receptors. The activities of matrix metalloproteinase-9 and urokinase-type of plasminogen activator, and the expressions of ECM-associated proteinases were attenuated significantly by RA-XII. Furthermore, RA-XII induced G1 phase arrest and inhibited the expressions of cyclins and cyclin-dependent kinases. RA-XII inhibited the expressions of molecules in PI3K/AKT, NF-kappaB, FAK/pSRC, MAPK and EGFR signaling. RA-XII was also shown to have anti-tumour, anti-angiogenic and anti-metastatic activities in metastatic breast tumour-bearing mice. These findings strongly suggested that RA-XII is a potential anti-metastatic agent for breast cancer. PMID:26592552

  20. RA-XII inhibits tumour growth and metastasis in breast tumour-bearing mice via reducing cell adhesion and invasion and promoting matrix degradation.

    PubMed

    Leung, Hoi-Wing; Zhao, Si-Meng; Yue, Grace Gar-Lee; Lee, Julia Kin-Ming; Fung, Kwok-Pui; Leung, Ping-Chung; Tan, Ning-Hua; Lau, Clara Bik-San

    2015-11-23

    Cancer cells acquire invasive ability to degrade and adhere to extracellular matrix (ECM) and migrate to adjacent tissues. This ultimately results metastasis. Hence, the present study investigated the in vitro effects of cyclopeptide glycoside, RA-XII on cell adhesion, invasion, proliferation and matrix degradation, and its underlying mechanism in murine breast tumour cells, 4T1. The effect of RA-XII on tumour growth and metastasis in 4T1-bearing mice was also investigated. Our results showed that RA-XII inhibited tumour cell adhesion to collagen, fibronectin and laminin, RA-XII also reduced the expressions of vascular cell adhesion molecule, intracellular adhesion molecule and integrins, and integrin binding. In addition, RA-XII significantly inhibited breast tumour cell migration via interfering cofilin signaling and chemokine receptors. The activities of matrix metalloproteinase-9 and urokinase-type of plasminogen activator, and the expressions of ECM-associated proteinases were attenuated significantly by RA-XII. Furthermore, RA-XII induced G1 phase arrest and inhibited the expressions of cyclins and cyclin-dependent kinases. RA-XII inhibited the expressions of molecules in PI3K/AKT, NF-kappaB, FAK/pSRC, MAPK and EGFR signaling. RA-XII was also shown to have anti-tumour, anti-angiogenic and anti-metastatic activities in metastatic breast tumour-bearing mice. These findings strongly suggested that RA-XII is a potential anti-metastatic agent for breast cancer.

  1. Pharmacokinetic studies of mouse monoclonal antibodies to a rat colon carcinoma: I. Comparison of biodistribution in normal rats, syngeneic tumor-bearing rats, or tumor-bearing nude mice

    SciTech Connect

    Laborda, J.; Douillard, J.Y.; Burg, C.; Lizzio, E.F.; Ridge, J.; Levenbook, I.; Hoffman, T. )

    1990-06-01

    The pharmacokinetics of two iodine-131-({sup 131}I) labeled murine anti-rat colon carcinoma monoclonal antibodies (D3 and E4) were compared in normal Sprague Dawley rats, syngeneic BDIX rats, or nude mice bearing that tumor. Results of antibody uptake after i.v. administration were analyzed in terms of accumulation and localization indices for normal tissues and tumor. Statistically significant differences between rat and mouse tissue biodistribution were found. D3, which reacts in vitro with the tumor and several normal rat tissues, cleared quickly from the blood of rats and was specifically targeted to several normal tissues, notably the lung. Virtually no targeting to the tumor was observed. Nude mice, however, showed a slower blood clearance and specific antibody targeting only in the tumor. Similar results were seen after injection of another antibody, E4, which is tumor-specific in vitro. Data suggest that studies on the xenogeneic nude mouse model may not necessarily be relevant to the choice of monoclonal antibodies for clinical diagnostic imaging or therapy.

  2. Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation.

    PubMed

    Kusmartsev, S A; Li, Y; Chen, S H

    2000-07-15

    Activation of T cells is a necessary step in the development of a specific antitumor immune response. In the present study, we evaluated the ability of Gr-1+ myeloid cells, derived from the bone marrow or spleen of tumor-bearing mice, to inhibit CD3/CD28-mediated T cell activation. Using flow cytometry, we found that growth of a murine colon carcinoma (MCA-26) induces a significant increase in the number of Gr-1+ and Gr-1+/Mac-1+ myeloid cells in both bone marrow and spleen of the tumor host. The proliferative response of T cells was dramatically decreased when naive T cells were activated by anti-CD3 and anti-CD28 Abs in the presence of a myeloid-enriched cell fraction derived from spleen or bone marrow of tumor-bearing mice vs the bone marrow of naive mice. Reversal of the inhibitory effect could be achieved by adding a combination of MnTBAP (manganese [III] tetrakis [4-benzoic acid]) porphyrin and l -NMMA (NG-monomethyl-l -arginine), a superoxide dismutase mimetic and inducible NO synthase inhibitor, respectively, or by depletion of the Gr-1-positive cells. IFN-gamma, which is endogenously produced by CD3/CD28-stimulated naive T cells, is involved in induction of the inhibitory activity of myeloid cells. Importantly, when T cells pre-activated with anti-CD3 Abs were used as responder cells, the bone marrow- or spleen-derived Gr-1+ myeloid cells were unable to suppress CD3/CD28-induced T cell proliferation. Our findings suggest that one mechanism by which an increased number of immune suppressive Gr-1+ cells can induce T cell unresponsiveness or immune tolerance in tumor hosts could be through peroxynitrite production upon primary T cell activation.

  3. Improved antiangiogenic and antitumour activity of the combination of the natural flavonoid fisetin and cyclophosphamide in Lewis lung carcinoma-bearing mice

    PubMed Central

    Touil, Yasmine S.; Seguin, Johanne; Scherman, Daniel; Chabot, Guy G.

    2011-01-01

    Purpose The natural flavonoid fisetin was recently identified as a lead compound that stabilizes endothelial cell microtubules. In this study we investigated the antiproliferative and antiangiogenic properties of fisetin in vitro and in vivo. Methods Fisetin cytotoxicity was evaluated using Lewis lung carcinoma cells (LLC), endothelial cells and NIH 3T3 cells. Endothelial cell (EC) migration and capillary-like structure formation were evaluated using EAhy 926 cells. In vivo tumour growth inhibition studies were performed using LLC bearing mice treated with fisetin and/or cyclophosphamide (CPA). Results The fisetin IC50 was 59 μM for LLC and 77 μM for EC cells, compared to 210 μM for normal NIH 3T3 cells (24 h). Fisetin inhibited EC migration and capillary-like structure formation at non-cytotoxic concentrations (22–44 μM). In mice, fisetin inhibited angiogenesis assessed using the Matrigel plug assay. In LLC bearing mice, fisetin produced a 67% tumour growth inhibition (223 mg/kg, intraperitoneal), similar to the 66% produced by low dose CPA (30 mg/kg, subcutaneous). When fisetin and CPA were combined, however, a marked improvement in antitumour activity was observed (92% tumour growth inhibition), with low systemic toxicity. Tumour histology showed decreased microvessel density with either fisetin or CPA alone, and a dramatic decrease after the fisetin/CPA combination. Conclusions We have shown that fisetin not only displays in vitro and in vivo antiangiogenic properties, but that it can also markedly improve the in vivo antitumour effect of CPA. We propose that this drug combination associating a non-toxic dietary flavonoid with a cytotoxic agent could advantageously be used in the treatment of solid tumours. PMID:21069336

  4. Differential effects of BCNU on T cell, macrophage, natural killer and lymphokine-activated killer cell activities in mice bearing a syngeneic tumor.

    PubMed

    Nagarkatti, M; Nagarkatti, P S; Kaplan, A M

    1988-01-01

    Chloroethylnitrosoureas have been used widely to treat human and experimental animal tumors. We have earlier observed that greater than 90% of the mice transplanted with syngeneic tumors survive following treatment with nitrosoureas such as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and furthermore, they resist subsequent challenge with the same tumor. The present investigation was initiated to determine the mechanism by which BCNU brings about this effect. Treatment of tumor cell targets in vivo or in vitro with BCNU, increased their susceptibility to macrophage (M luminal diameter)-mediated cytotoxicity as measured in a direct cytotoxicity assay or in an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. In contrast, the antitumor cytotoxicity caused by cytotoxic T lymphocytes (CTL), natural killer (NK) cells, or lymphokine-activated killer (LAK) cells, was not altered following BCNU treatment of tumor targets. Studies were also conducted to investigate the direct effect of BCNU in vivo on various cytotoxic effector cells. For this purpose, M luminal diameter, NK, LAK, and CTL activities from BCNU-treated-tumor-bearing mice were screened for cytotoxicity against untreated tumor targets in vitro. It was observed that tumor-specific CTL and LAK cell activity increased in BCNU-treated tumor-bearing mice when compared to untreated controls while the cytotoxic potential of NK cells and M luminal diameters was not altered. The present study suggests that antitumor drugs such as BCNU are not only tumoricidal but also selectively act in a variety of ways at both the effector and target cell level, leading to overall enhanced antitumor immunity and high rate of cures from the syngeneic tumor challenge.

  5. Interleukin-15-transferred cytokine-induced killer cells elevated anti-tumor activity in a gastric tumor-bearing nude mice model.

    PubMed

    Peng, Zheng; Liang, Wentao; Li, Zexue; Xu, Yingxin; Chen, Lin

    2016-02-01

    Gastric cancer is the second leading cause of cancer-related mortality worldwide. Adoptive cell therapy (ACT) for gastric cancer is a novel therapy modality. However, the therapeutic effectiveness in vivo is still limited. The objective of this study was to assess the value of interleukin-15 (IL-15)-transferred cytokine-induced killer (CIK) cells in ACT for gastric cancer. IL-15-IRES-TK retroviral vector was constructed and transferred into the CIK cells. A gastric tumor-bearing nude mice model was constructed by subcutaneously injecting gastric cancer cells, BGC-823. Gastric tumor-bearing nude mice were randomly divided into three groups (five mice each group) and injected with physiological saline, CIK cells, and IL-15-IRES-TK-transfected CIK cells for 2 weeks, respectively. IL-15-IRES-TK-transferred CIK cells were prepared successfully and flow cytometry (FCM) analysis indicated that the transfection rate reached 85.7% after 5 days culture. In vivo experiment, we found that CIK cells retarded tumor growth by reducing tumor volume and tumor weight, as well as increasing tumor inhibition rate. Furthermore, IL-15-IRES-TK-transferred CIK cells showed a much stronger inhibition on tumor growth than CIK cells alone. Tumor morphology observation and growth indexes also showed that IL-15-transfected CIK cells had stronger cytotoxicity to tumor tissue than CIK cells. IL-15-IRES-TK transfection could elevate the effects of CIK cells to gastric carcinoma. The engineered CIK cells carrying IL-15-IRES-TK may be used in the ACT for gastric carcinoma, but prudent clinical trial is still indispensable.

  6. Natural killer cell activity, lymphocyte proliferation, and cytokine profile in tumor-bearing mice treated with MAPA, a magnesium aggregated polymer from Aspergillus oryzae.

    PubMed

    Justo, G Z; Durán, N; Queiroz, M L S

    2003-08-01

    The present study examined the effects of MAPA, an antitumor aggregated polymer of protein magnesium ammonium phospholinoleate-palmitoleate anhydride, isolated from Aspergillus oryzae, on concanavalin A (Con A)-induced spleen cell proliferation, cytokine production and on natural killer (NK) cell activity in Ehrlich ascites tumor-bearing mice. The Ehrlich ascites tumor (EAT) growth led to diminished mitogen-induced expansion of spleen cell populations and total NK activity. This was accompanied by striking spleen enlargement, with a marked increase in total cell counts. Moreover, a substantial enhancement in IL-10 levels, paralleled by a significant decrease in IL-2 was observed, while production of IL-4 and interferon-gamma (IFN-gamma) was not altered. Treatment of mice with 5 mg/kg MAPA for 7 days promoted spleen cell proliferation, IL-2 production and NK cell activity regardless of tumor outgrowth. In addition, MAPA treatment markedly enhanced IFN-gamma levels and reduced IL-10 production relative to EAT mice. A 35% reduction in splenomegaly with normal number of nucleated cells was also found. Altogether, our results suggest that MAPA directly and/or indirectly modulates immune cell activity, and probably disengages tumor-induced suppression of these responses. Clearly, MAPA has an impact and may delay tumor outgrowth through immunotherapeutic mechanisms.

  7. Antitumor and immunomodulatory effects of recombinant fusion protein rMBP-NAP through TLR-2 dependent mechanism in tumor bearing mice.

    PubMed

    Wang, Ting; Liu, Xilong; Ji, Zhenyu; Men, Yingli; Du, Mingxuan; Ding, Cong; Wu, Yahong; Liu, Xin; Kang, Qiaozhen

    2015-12-01

    The pro-inflammatory and immunomodulatory properties of Helicobacter pylori neutrophil activating protein (Hp-NAP) not only make it to play an important role in disease pathogenesis but also make it to be a potential candidate for therapeutic applications, including vaccine and drug development. Our previous work demonstrated that the recombinant Hp-NAP fused with the maltose binding protein of Escherichia coli (rMBP-NAP) play an important role in regulating the differentiation of Th1 cells. In this study, we investigated the ability of rMBP-NAP to induce antitumor immunity using two murine models of hepatoma H22 and sarcoma S180. Subcutaneous administration of mice with rMBP-NAP resulted in an about 40%-50% decrease of tumor growth compared with that of the control mice. Splenocytes from the tumor-bearing mice treated with rMBP-NAP showed a significant accumulation of CD4(+) IFN-γ-secreting cells, which is a cytokine profile of Th1 cells. Furthermore, intravenous injection of T2.5, toll like receptor (TLR) 2 blocking antibody, significantly recede the antitumor effect of rMBP-NAP and the production of IFN-γ induced by rMBP-NAP. Our findings indicate that potentiality of rMBP-NAP to be a candidate for the development of immunomodulatory antitumoral drugs.

  8. Prophylactic Administration of Fucoidan Represses Cancer Metastasis by Inhibiting Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinases (MMPs) in Lewis Tumor-Bearing Mice

    PubMed Central

    Huang, Tse-Hung; Chiu, Yi-Han; Chan, Yi-Lin; Chiu, Ya-Huang; Wang, Hang; Huang, Kuo-Chin; Li, Tsung-Lin; Hsu, Kuang-Hung; Wu, Chang-Jer

    2015-01-01

    Fucoidan, a heparin-like sulfated polysaccharide, is rich in brown algae. It has a wide assortment of protective activities against cancer, for example, induction of hepatocellular carcinoma senescence, induction of human breast and colon carcinoma apoptosis, and impediment of lung cancer cells migration and invasion. However, the anti-metastatic mechanism that fucoidan exploits remains elusive. In this report, we explored the effects of fucoidan on cachectic symptoms, tumor development, lung carcinoma cell spreading and proliferation, as well as expression of metastasis-associated proteins in the Lewis lung carcinoma (LLC) cells-inoculated mice model. We discovered that administration of fucoidan has prophylactic effects on mitigation of cachectic body weight loss and improvement of lung masses in tumor-inoculated mice. These desired effects are attributed to inhibition of LLC spreading and proliferation in lung tissues. Fucoidan also down-regulates expression of matrix metalloproteinases (MMPs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and vascular endothelial growth factor (VEGF). Moreover, the tumor-bearing mice supplemented with fucoidan indeed benefit from an ensemble of the chemo-phylacticity. The fact is that fucoidan significantly decreases viability, migration, invasion, and MMPs activities of LLC cells. In summary, fucoidan is suitable to act as a chemo-preventative agent for minimizing cachectic symptoms as well as inhibiting lung carcinoma metastasis through down-regulating metastatic factors VEGF and MMPs. PMID:25854641

  9. Studies of methyl 2-nitroimidazole-1-acetohydroxamate (KIN-804) 1: effect on free radical scavenging system in mice bearing Ehrlich ascites carcinoma.

    PubMed

    Abu-Zeid, M; Hori, H; Nagasawa, H; Uto, Y; Inayama, S

    2000-02-01

    Methyl 2-nitroimidazole-1-acetohydroxamate (KIN-804) is a 2-nitroimidazole derivative containing a hydroxamate side chain designed to enhance the radiosensitization response of hypoxic cells. The possible sensitization of tumor tissue by KIN-804 can be evaluated through investigation of the levels of the free radical scavengers; namely, glutathione (GSH) and its complex enzyme system including glutathione reductase (GR) and glutathione peroxidase (GSH-Px), as well as glucose-6-phosphate dehydrogenase (G-6-PD). Female albino mice were inoculated with Ehrlich carcinoma in the thigh. Administration of KIN-804 (i.p. 80 mg/kg body weight) was carried out 20 min before localized irradiation of 10 Gy. The data revealed that KIN-804 administration, followed or not by gamma irradiation, resulted in a significant decrease in GSH content in tumor tissues associated with inhibition in GR and G-6-PD activities. Blood GSH-Px was enhanced in tumor inoculated mice and the administration of KIN-804 returned it to the normal value. These changes were more noticeable in tumor bearing mice exposed to both KIN-804 and irradiation.

  10. Prophylactic administration of fucoidan represses cancer metastasis by inhibiting vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in Lewis tumor-bearing mice.

    PubMed

    Huang, Tse-Hung; Chiu, Yi-Han; Chan, Yi-Lin; Chiu, Ya-Huang; Wang, Hang; Huang, Kuo-Chin; Li, Tsung-Lin; Hsu, Kuang-Hung; Wu, Chang-Jer

    2015-04-03

    Fucoidan, a heparin-like sulfated polysaccharide, is rich in brown algae. It has a wide assortment of protective activities against cancer, for example, induction of hepatocellular carcinoma senescence, induction of human breast and colon carcinoma apoptosis, and impediment of lung cancer cells migration and invasion. However, the anti-metastatic mechanism that fucoidan exploits remains elusive. In this report, we explored the effects of fucoidan on cachectic symptoms, tumor development, lung carcinoma cell spreading and proliferation, as well as expression of metastasis-associated proteins in the Lewis lung carcinoma (LLC) cells-inoculated mice model. We discovered that administration of fucoidan has prophylactic effects on mitigation of cachectic body weight loss and improvement of lung masses in tumor-inoculated mice. These desired effects are attributed to inhibition of LLC spreading and proliferation in lung tissues. Fucoidan also down-regulates expression of matrix metalloproteinases (MMPs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and vascular endothelial growth factor (VEGF). Moreover, the tumor-bearing mice supplemented with fucoidan indeed benefit from an ensemble of the chemo-phylacticity. The fact is that fucoidan significantly decreases viability, migration, invasion, and MMPs activities of LLC cells. In summary, fucoidan is suitable to act as a chemo-preventative agent for minimizing cachectic symptoms as well as inhibiting lung carcinoma metastasis through down-regulating metastatic factors VEGF and MMPs.

  11. Anti-tumor effects of (1→3)-β-d-glucan from Saccharomyces cerevisiae in S180 tumor-bearing mice.

    PubMed

    Mo, Li; Chen, Yafei; Li, Wenjian; Guo, Shuai; Wang, Xuzhao; An, Hailong; Zhan, Yong

    2017-02-01

    (1→3)-β-d-Glucan from Saccharomyces cerevisiae is a typical polysaccharide with various biological effects and is considered a candidate for the prevention and treatment of cancer in vitro. Research into the function of (1→3)-β-d-glucan in tumor-bearing animals in vivo, however, is limited. Here, we investigated the effects of (1→3)-β-d-glucan from S. cerevisiae on S180 tumor-bearing mice and on the immunity of the tumor-bearing host. The molecular mechanisms underlying the observed effects were investigated. (1→3)-β-d-Glucan was shown to exert anti-tumor effects without toxicity in normal mouse cells. The volume and weight of S180 tumors decreased dramatically following treatment with (1→3)-β-d-glucan, and treatment with the polysaccharide was furthermore shown to increase the tumor inhibition rate in a dose-dependent manner. Spleen index, T lymphocyte subsets (CD4 and CD8), as well as interleukins (IL)-2, (IL-2, IL-6), and tumor necrosis factor-α were assayed to detect the immunoregulatory and anti-tumor effects after (1→3)-β-d-glucan intragastrical administration. (1→3)-β-d-Glucan was shown to significantly potentiate the mouse immune responses by, among other effects, decreasing the ratio of CD4 to CD8. The expression levels of IL-2, IL-6, and TNF-α were also significantly increased by (1→3)-β-d-glucan. These results suggest that (1→3)-β-d-glucan enhances the host's immune function during the tumor inhibition process. S180 tumor cells treated with (1→3)-β-d-glucan also exhibited significant apoptotic characteristics. (1→3)-β-d-glucan increased the ratio of Bax to Bcl-2 at the translation level by up-regulating Bax expression and down-regulating Bcl-2 expression, resulting in the initiation of cell apoptosis in S180 tumor-bearing mice. Taken together, these results indicate that the anti-tumor effects exerted by (1→3)-β-d-glucan may be attributed to the polysaccharide's immunostimulating properties and apoptosis

  12. Bone loss and aggravated autoimmune arthritis in HLA-DRβ1-bearing humanized mice following oral challenge with Porphyromonas gingivalis.

    PubMed

    Sandal, Indra; Karydis, Anastasios; Luo, Jiwen; Prislovsky, Amanda; Whittington, Karen B; Rosloniec, Edward F; Dong, Chen; Novack, Deborah V; Mydel, Piotr; Zheng, Song Guo; Radic, Marko Z; Brand, David D

    2016-10-26

    The linkage between periodontal disease and rheumatoid arthritis is well established. Commonalities among the two are that both are chronic inflammatory diseases characterized by bone loss, an association with the shared epitope susceptibility allele, and anti-citrullinated protein antibodies. To explore immune mechanisms that may connect the two seemingly disparate disorders, we measured host immune responses including T-cell phenotype and anti-citrullinated protein antibody production in human leukocyte antigen (HLA)-DR1 humanized C57BL/6 mice following exposure to the Gram-negative anaerobic periodontal disease pathogen Porphyromonas gingivalis. We measured autoimmune arthritis disease expression in mice exposed to P. gingivalis, and also in arthritis-resistant mice by flow cytometry and multiplex cytokine-linked and enzyme-linked immunosorbent assays. We also measured femoral bone density by microcomputed tomography and systemic cytokine production. Exposure of the gingiva of DR1 mice to P. gingivalis results in a transient increase in the percentage of Th17 cells, both in peripheral blood and cervical lymph nodes, a burst of systemic cytokine activity, a loss in femoral bone density, and the generation of anti-citrullinated protein antibodies. Importantly, these antibodies are not produced in response to P. gingivalis treatment of wild-type C57BL/6 mice, and P. gingivalis exposure triggered expression of arthritis in arthritis-resistant mice. Exposure of gingival tissues to P. gingivalis has systemic effects that can result in disease pathology in tissues that are spatially removed from the initial site of infection, providing evidence for systemic effects of this periodontal pathogen. The elicitation of anti-citrullinated protein antibodies in an HLA-DR1-restricted fashion by mice exposed to P. gingivalis provides support for the role of the shared epitope in both periodontal disease and rheumatoid arthritis. The ability of P. gingivalis to induce disease

  13. Determination of the in vivo pharmacokinetics of palladium-bacteriopheophorbide (WST09) in EMT6 tumour-bearing Balb/c mice using graphite furnace atomic absorption spectroscopy.

    PubMed

    Brun, Pierre Hervé; DeGroot, Jennifer L; Dickson, Eva F Gudgin; Farahani, Mohsen; Pottier, Roy H

    2004-01-01

    Palladium-bacteriopheophorbide (WST09), a novel bacteriochlorophyll derivative, is currently being investigated for use as a photodynamic therapy (PDT) drug due to its strong absorption in the near-infrared region and its ability to efficiently generate singlet oxygen when irradiated. In this study, we determined the pharmacokinetics and tissue distribution of WST09 in female EMT6 tumour-bearing Balb/c mice in order to determine if selective accumulation of this drug occurs in tumour tissue. A total of 41 mice were administered WST09 by bolus injection into the tail vein at a dose level of 5.0 +/- 0.8 mg kg(-1). Three to six mice were sacrificed at each of 0.08, 0.25, 0.5, 1.0, 3.0, 6.0, 9.0, 12, 24, 48, 72, and 96 h post injection, and an additional three control mice were sacrificed without having been administered WST09. Terminal blood samples as well as liver, skin, muscle, kidney and tumour samples were obtained from each mouse and analyzed for palladium content (from WST09) using graphite furnace atomic absorption spectroscopy (GFAAS). The representative concentration of WST09 in the plasma and tissues was then calculated. Biphasic kinetics were observed in the plasma, kidney, and liver with clearance from each of these tissues being relatively rapid. Skin, muscle and tumour did not show any significant accumulation at all time points investigated. No selective drug accumulation was seen in the tumour and normal tissues, relative to plasma. Thus the results of this study indicate that vascular targeting resulting from WST09 in the circulation, as opposed to selective WST09 accumulation in tumour tissues, may be responsible for PDT effects in tumours that have been observed in other WST09 studies.

  14. Levels of Murine, but Not Human, CXCL13 Are Greatly Elevated in NOD-SCID Mice Bearing the AIDS-Associated Burkitt Lymphoma Cell Line, 2F7

    PubMed Central

    Widney, Daniel P.; Olafsen, Tove; Wu, Anna M.; Kitchen, Christina M. R.; Said, Jonathan W.; Smith, Jeffrey B.; Peña, Guadalupe; Magpantay, Larry I.; Penichet, Manuel L.; Martinez-Maza, Otoniel

    2013-01-01

    Currently, few rodent models of AIDS-associated non-Hodgkin’s lymphoma (AIDS-NHL) exist. In these studies, a novel mouse/human xenograft model of AIDS-associated Burkitt lymphoma (AIDS-BL) was created by injecting cells of the human AIDS-BL cell line, 2F7, intraperitoneally into NOD-SCID mice. Mice developed tumors in the peritoneal cavity, with metastases to the spleen, thymus, and mesenteric lymph nodes. Expression of the chemokine receptor, CXCR5, was greatly elevated in vivo on BL tumor cells in this model, as shown by flow cytometry. CXCL13 is the ligand for CXCR5, and serum and ascites levels of murine, but not human, CXCL13 showed a striking elevation in tumor-bearing mice, with levels as high as 200,000 pg/ml in ascites, as measured by ELISA. As shown by immunohistochemistry, murine CXCL13 was associated with macrophage-like tumor-infiltrating cells that appeared to be histiocytes. Blocking CXCR5 on 2F7 cells with neutralizing antibodies prior to injection into the mice substantially delayed tumor formation. The marked elevations in tumor cell CXCR5 expression and in murine CXCL13 levels seen in the model may potentially identify an important link between tumor-interacting histiocytes and tumor cells in AIDS-BL. These results also identify CXCL13 as a potential biomarker for this disease, which is consistent with previous studies showing that serum levels of CXCL13 were elevated in human subjects who developed AIDS-lymphoma. This mouse model may be useful for future studies on the interactions of the innate immune system and AIDS-BL tumor cells, as well as for the assessment of potential tumor biomarkers for this disease. PMID:23936541

  15. Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer.

    PubMed

    Carneiro, Marcella Lemos Brettas; Peixoto, Raphael C A; Joanitti, Graziela A; Oliveira, Ricardo G S; Telles, Luis A M; Miranda-Vilela, Ana L; Bocca, Anamélia L; Vianna, Leonora M S; da Silva, Izabel C R; de Souza, Aparecido R; Lacava, Zulmira G M; Báo, Sônia N

    2013-02-16

    Magnetic fluids containing superparamagnetic iron oxide nanoparticles represent an attractive platform as nanocarriers in chemotherapy. Recently, we developed a formulation of maghemite nanoparticles coated with rhodium (II) citrate, which resulted in in vitro cytotoxicity enhanced up to 4.6 times when compared to free rhodium (II) citrate formulation on breast carcinoma cells. In this work, we evaluate the antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Mice were evaluated with regard to the treatments' toxicity through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine; DNA fragmentation and cell cycle of bone marrow cells; and liver, kidney and lung histology. In addition, the antitumor activity of rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate was verified by tumor volume reduction, histology and immunohistochemistry. Regarding the treatments' toxicity, no experimental groups had alterations in levels of serum ALT or creatinine, and this suggestion was corroborated by the histopathologic examination of liver and kidney of mice. Moreover, DNA fragmentation frequency of bone marrow cells was lower than 15% in all experimental groups. On the other hand, the complexes rhodium (II) citrate-functionalized maghemite and free rhodium (II) citrate led to a marked growth inhibition of tumor and decrease in CD31 and Ki-67 staining. In summary, we demonstrated that both rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate formulations exhibited antitumor effects against 4T1 metastatic breast cancer cell line following intratumoral administration. This antitumor effect was followed by inhibition of both cell proliferation and microvascularization and by tumor tissue injury characterized as necrosis and fibrosis. Remarkably, this is the first published report demonstrating the therapeutic efficacy of maghemite

  16. Enhanced anticancer effect and reduced toxicity of doxorubicin in combination with thymoquinone released from poly-N-acetyl glucosamine nanomatrix in mice bearing solid Ehrlish carcinoma.

    PubMed

    El-Ashmawy, Nahla E; Khedr, Eman G; Ebeid, El-Zeiny M; Salem, Mohamed L; Zidan, Abdel-Aziz A; Mosalam, Esraa M

    2017-09-07

    The incidence of breast cancer remarkably increases all over the world. Therefore, there is a great demand to introduce new approaches into cancer treatment field. The current study was designated to evaluate the role of doxorubicin (DOX) and/or thymoquinone (TQ) nanomatrix in potentiating the cytotoxicity of either drug, and to investigate the ability of TQ to reduce cardiotoxicity of DOX in solid Ehrlich carcinoma (SEC)-bearing mice. DOX and TQ were loaded into F2 gel, which is a fully-acetylated poly-N-acetyl glucosamine nanofiber. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into eight groups (n=10): normal control, tumor control, F2 gel, free DOX, DOX+F2 gel, free TQ, TQ+F2 gel, and DOX+TQ+F2 gel. On day 28th from tumor inoculation, mice were sacrificed and blood samples were collected for measurement of the cardiac markers; lactate dehydrogenase (LDH) and creatine kinase (CK-MB). In addition, cardiac tissue was utilized for determination of lipid peroxide, and tumor tissue was used for measurement of anti-apoptotic protein Bcl-2 as well as gene expression of the tumor suppressor gene P53. DOX and/or TQ showed a significant reduction in tumor volume, cardiac markers, tumor Bcl-2, and P53 upregulation compared to free conventional therapies. Co-treatment with DOX+TQ+F2 gel was superior to all other groups in exerting beneficial effects. Use of TQ as an adjuvant therapy with DOX could improve its cytotoxic effects and limit its cardiac toxicity. Furthermore, loading of DOX and/or TQ into F2 gel showed a remarkable anti-cancer activity. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer

    PubMed Central

    2013-01-01

    Background Magnetic fluids containing superparamagnetic iron oxide nanoparticles represent an attractive platform as nanocarriers in chemotherapy. Recently, we developed a formulation of maghemite nanoparticles coated with rhodium (II) citrate, which resulted in in vitro cytotoxicity enhanced up to 4.6 times when compared to free rhodium (II) citrate formulation on breast carcinoma cells. In this work, we evaluate the antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Methods Mice were evaluated with regard to the treatments’ toxicity through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine; DNA fragmentation and cell cycle of bone marrow cells; and liver, kidney and lung histology. In addition, the antitumor activity of rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate was verified by tumor volume reduction, histology and immunohistochemistry. Results Regarding the treatments’ toxicity, no experimental groups had alterations in levels of serum ALT or creatinine, and this suggestion was corroborated by the histopathologic examination of liver and kidney of mice. Moreover, DNA fragmentation frequency of bone marrow cells was lower than 15% in all experimental groups. On the other hand, the complexes rhodium (II) citrate-functionalized maghemite and free rhodium (II) citrate led to a marked growth inhibition of tumor and decrease in CD31 and Ki-67 staining. Conclusions In summary, we demonstrated that both rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate formulations exhibited antitumor effects against 4T1 metastatic breast cancer cell line following intratumoral administration. This antitumor effect was followed by inhibition of both cell proliferation and microvascularization and by tumor tissue injury characterized as necrosis and fibrosis. Remarkably, this is the first published report

  18. Curcumol induces apoptosis in SPC-A-1 human lung adenocarcinoma cells and displays anti-neoplastic effects in tumor bearing mice.

    PubMed

    Tang, Qi-Ling; Guo, Ji-Quan; Wang, Qi-You; Lin, Hai-Shu; Yang, Zhou-Ping; Peng, Tong; Pan, Xue-Diao; Liu, Bing; Wang, Su-Jun; Zang, Lin-Quan

    2015-01-01

    Curcumol is a sesquiterpene originally isolated from curcuma rhizomes, a component of herbal remedies commonly used in oriental medicine. Its beneficial pharmacological activities have attract significant interest recently. In this study, anti-cancer activity of curcumol was examined with both in vitro and in vivo models. It was found that curcumol exhibited time- and concentration-dependent anti-proliferative effects in SPC-A-1 human lung adenocarcinoma cells with cell cycle arrest in the G0/G1 phase while apoptosis-induction was also confirmed with flow cytometry and morphological analyses. Interestingly, curcumol did not display growth inhibition in MRC-5 human embryonic lung fibroblasts, suggesting the anti-proliferative effects of curcumol were specific to cancer cells. Anti-neoplastic effects of curcumol were also confirmed in tumor bearing mice. Curcumol (60 mg/kg daily) significantly reduced tumor size without causing notable toxicity. In conclusion, curcumol appears a favorable anti-cancer candidate for further development.

  19. Application of 67Cu Produced by 68Zn(n,n'p+d)67Cu to Biodistribution Study in Tumor-Bearing Mice

    NASA Astrophysics Data System (ADS)

    Sugo, Yumi; Hashimoto, Kazuyuki; Kawabata, Masako; Saeki, Hideya; Sato, Shunichi; Tsukada, Kazuaki; Nagai, Yasuki

    2017-02-01

    67Cu produced by the 68Zn(n,n'p+d)67Cu reaction was used for the first time to determine the biodistribution of 67CuCl2 in colorectal tumor-bearing mice. A high uptake of 67Cu was observed in the tumor as well as in the liver and kidney, which are the major organs for copper metabolism. The result showing 67Cu accumulation in the tumor suggests that 67CuCl2 can be a potential radionuclide agent for cancer radiotherapy. It should also encourage further studies on the therapeutic effect on small animals using an increased dose of 67Cu produced by the 68Zn(n,n'p+d)67Cu reaction using presently available intense neutrons.

  20. Study of action of cyclophosphamide and extract of mycelium of Pleurotus ostreatus in vivo on mice, bearing melanoma B16-F0-GFP

    NASA Astrophysics Data System (ADS)

    Meerovich, Irina G.; Yang, Meng; Jiang, Ping; Hoffman, Robert M.; Gerasimenya, Valery P.; Orlov, Alexander E.; Savitsky, Alexander P.; Popov, Vladimir O.

    2005-04-01

    In this work we studied in vivo the combined action of cyclophosphamide and the extract of mycelium of Pleurotus ostreatus on mice bearing melanoma B16-F0, expressing green fluorescent protein (GFP). This model allows to recognize small-size tumors and metastases, unrecognizable by other methods. It was found that combined administration of cyclophosphamide (300 mg/kg) and the extract of mycelium of Pleurotus ostreatus (100 mg/kg), administered for 10 days after cyclophosphamide injection, as well administration of cyclophosphamide alone, cause inhibition of tumor growth about 97%. It was shown that administration of the extract of mycelium of Pleurotus ostreatus alone leads to inhibition of tumor growth of 61%. It was found that in case of combined administration of cyclophosphamide and the extract of mycelium of Pleurotus ostreatus, leucopenia was less expressed than in case of administration of cyclophosphamide alone.

  1. The influence of EDTMP-concentration on the biodistribution of radio-lanthanides and 225-Ac in tumor-bearing mice. The ISOLDE Collaboration.

    PubMed

    Beyer, G J; Offord, R; Künzi, G; Aleksandrova, Y; Ravn, U; Jahn, S; Barker, J; Tengblad, O; Lindroos, M

    1997-07-01

    High-resolution gamma spectroscopy was applied to measure simultaneously the biodistribution of carrier-free radionuclides of several lanthanides (141Ce, 145Sm, 149Gd, 167Tm) and 225Ac in tumor-bearing nude mice. Mixtures of the radiotracers were injected in solutions containing different concentrations of EDTMP (ethylenediaminetetramethylenephosphonic acid). The strong dependence of liver uptake on the ionic radius of the radio-lanthanides was confirmed for all tracers used. The ratios of radioactivity concentrated in tumour that concentrated in liver are strongly influenced by the EDTMP concentration, reaching values close to 10 for Tm, 3 for Sm, and 1 for Ac. The optimal EDTMP concentrations, giving highest tumor-to-liver ratios of enrichment, were between 1 and 10 mM for 100 microL injected volume for the animal model used in this experiment. In radionuclide therapy using EDTMP as ligands, close control of ligand concentration will be necessary.

  2. Composition and mechanism of anti-tumor effects of Hericium erinaceus mushroom extracts in tumor-bearing mice

    USDA-ARS?s Scientific Manuscript database

    We investigated anti-tumor effects of the following four extracts of freeze-dried Hericium erinaceus mushrooms in Balb/c mice intracutaneously transplanted on the backs with CT-26 colon cancer cells: HWE, hot-water extraction by boiling in water for 3 h; MWE, microwaving in 50% ethanol/water at 60 W...

  3. Total syntheses of three copper (II) tetracarboranylphenylporphyrins containing 40 or 80 boron atoms and their biological properties in EMT-6 tumor-bearing mice.

    PubMed

    Wu, Haitao; Micca, Peggy L; Makar, Michael S; Miura, Michiko

    2006-08-01

    Three carboranyltetraphenylporphyrins containing 40 or 80 boron atoms were synthesized and evaluated for their biodistribution and toxicity in EMT-6 tumor-bearing mice. Copper (II) meso-5,10,15,20-tetrakis[3-methoxy-4-(o-carboranylmethoxy)phenyl]porphyrin, 6, and copper (II) meso-5,10,15,20-tetrakis[3-hydroxy-4-(o-carboranylmethoxy)phenyl]porphyrin, 8, are B40 congeners with different lipophilicities, each less than their B80 congener, copper (II) meso-5,10,15,20-tetrakis[m-(3,5-di-o-carboranylmethoxybenzyloxy)phenyl]porphyrin, 18. Two days after the last of a series of i.p. injections in BALB/c mice bearing EMT-6 mammary tumors, a dose of 185 mg/kg 6 (54 mg/kg B) delivered over 3.5 times the concentration of boron to tumor (169 microg/g B) than did 118 mg/kg 8 (36 mg/kg B), which delivered 35 microg/g B, or 87 mg/kg 18 (30 mg/kg B), which delivered 46 microg/g B. The tumor-to-blood and tumor-to-brain boron concentration ratios at that time for all three porphyrins exceeded 80:1. Two days after the last injection, there resulted moderate thrombocytopenia that essentially disappeared two days later from 6 and 18, and mild leukocytosis from 6, 8, and 18, all of which were clinically inconsequential. Thus, 6 may rank among the most clinically promising carboranyl porphyrins ever made to deliver 10B to tumors for boron neutron-capture therapy (BNCT) that has also been tested for its toxicity in vivo.

  4. 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice

    DOE PAGES

    Jeanbart, Laura; Kourtis, Iraklis C.; van der Vlies, André J.; ...

    2015-05-16

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress effector T cell responses and can reduce the efficacy of cancer immunotherapies. We previously showed that ultra-small polymer nanoparticles efficiently drain to the lymphatics after intradermal injection and target antigen-presenting cells, including Ly6chi Ly6g₋monocytic MDSCs (Mo-MDSCs), in skin-draining lymph nodes (LNs) and spleen. Here, we developed ultra-small polymer micelles loaded with 6-thioguanine (MC-TG), a cytotoxic drug used in the treatment of myelogenous leukemia, with the aim of killing Mo-MDSCs in tumor-bearing mice and thus enhancing T cell-mediated anti-tumor responses. We found that 2 days post-injection inmore » tumor-bearing mice (B16-F10 melanoma or E.G7-OVA thymoma), MC-TG depleted Mo-MDSCs in the spleen, Ly6clo Ly6g+ granulocytic MDSCs (G-MDSCs) in the draining LNs, and Gr1int Mo-MDSCs in the tumor. In both tumor models, MC-TG decreased the numbers of circulating Mo- and G-MDSCs, as well as of Ly6chi macrophages, for up to 7 days following a single administration. MDSC depletion was dose dependent and more effective with MC-TG than with equal doses of free TG. Finally, we tested whether this MDSC-depleting strategy might enhance cancer immunotherapies in the B16-F10 melanoma model. We found that MC-TG significantly improved the efficacy of adoptively transferred, OVA-specific CD8+ T cells in melanoma cells expressing OVA. Ultimately, these findings highlight the capacity of MC-TG in depleting MDSCs in the tumor microenvironment and show promise in promoting anti-tumor immunity when used in combination with T cell immunotherapies.« less

  5. Role of isothiocyanate conjugate of pterostilbene on the inhibition of MCF-7 cell proliferation and tumor growth in Ehrlich ascitic cell induced tumor bearing mice

    SciTech Connect

    Nikhil, Kumar; Sharan, Shruti; Chakraborty, Ajanta; Bodipati, Naganjaneyulu; Krishna Peddinti, Rama; Roy, Partha

    2014-01-15

    Naturally occurring pterostilbene (PTER) and isothiocyanate (ITC) attract great attention due to their wide range of biological properties, including anti-cancer, anti-leukemic, anti-bacterial and anti-inflammatory activities. A novel class of hybrid compound synthesized by introducing an ITC moiety on PTER backbone was evaluated for its anti-cancer efficacy in hormone-dependent breast cancer cell line (MCF-7) in vitro and Ehrlich ascitic tumor bearing mice model in vivo. The novel hybrid molecule showed significant in vitro anti-cancer activity (IC{sub 50}=25±0.38) when compared to reference compound PTER (IC{sub 50}=65±0.42). The conjugate molecule induced both S and G2/M phase cell cycle arrest as indicated by flow cytometry analysis. In addition, the conjugate induced cell death was characterized by changes in cell morphology, DNA fragmentation, activation of caspase-9, release of cytochrome-c into cytosol and increased Bax: Bcl-2 ratio. The conjugate also suppressed the phosphorylation of Akt and ERK. The conjugate induced cell death was significantly increased in presence of A6730 (a potent Akt1/2 kinase inhibitor) and PD98059 (a specific ERK inhibitor). Moreover, the conjugated PTER inhibited tumor growth in Ehrlich ascitic cell induced tumor bearing mice as observed by reduction in tumor volume compared to untreated animals. Collectively, the pro-apoptotic effect of conjugate is mediated through the activation of caspases, and is correlated with the blockade of the Akt and ERK signaling pathways in MCF-7 cells. - Highlights: • Conjugate was prepared by appending isothiocyanate moiety on pterostilbene backbone. • Conjugate showed anticancer effects at comparatively lower dose than pterostilbene. • Conjugate caused blockage of the Akt and ERK signaling pathways in MCF-7 cells. • Conjugate significantly reduced solid tumor volume as compared to pterostilbene.

  6. The altered tumoricidal capacity of macrophages isolated from tumor- bearing mice is related to reduce expression of the inducible nitric oxide synthase gene

    PubMed Central

    1996-01-01

    Nitric oxide (NO) is a major effector molecule in the destruction of tumor cells by activated macrophages. However, in many cases, developing neoplasms appear to be capable of impairing steps in the complex process leading to NO production as a means of avoiding immune destruction. After activation with lipopolysaccharide (LPS), peritoneal- elicited macrophages (PEM) from mice bearing mammary tumors display alterations in their ability to lyse tumor cells due to reduced production of NO. In contrast, when these same cells are stimulated with LPS in combination with interferon gamma (IFN-gamma), they are able to produce NO and lyse targets at normal levels. Since tumor- associated macrophages are intimately associated with the cells of the developing tumor, their ability to produce NO and lyse tumor targets is likely to be more relevant to controlling tumor growth. This population of macrophages exhibited a more profound inability to produce NO and lyse targets and, unlike the PEM, was not able to upregulate these functions even when treated with combinations of LPS and IFN-gamma. Northern and Western blots revealed that inducible nitric oxide synthase (iNOS) mRNA and protein levels correlated directly with the ability of each macrophage population to produce NO, and the levels of these macromolecules were altered sufficiently in tumor bearers' macrophages to account for the diminished NO production described. These results indicate that a spatial gradient of suppression of macrophage cytolytic activity and iNOS expression exists in mammary tumor-bearing mice, whereby macrophages from within the tumor exhibit a more pronounced suppression than the more distally located PEM. This suppression may be due to proximity of the macrophages to the developing tumor, macrophage maturational state, or both. PMID:8666890

  7. Bearing system

    DOEpatents

    Kapich, Davorin D.

    1987-01-01

    A bearing system includes backup bearings for supporting a rotating shaft upon failure of primary bearings. In the preferred embodiment, the backup bearings are rolling element bearings having their rolling elements disposed out of contact with their associated respective inner races during normal functioning of the primary bearings. Displacement detection sensors are provided for detecting displacement of the shaft upon failure of the primary bearings. Upon detection of the failure of the primary bearings, the rolling elements and inner races of the backup bearings are brought into mutual contact by axial displacement of the shaft.

  8. Systemic injection of TLR1/2 agonist improves adoptive antigen-specific T cell therapy in glioma-bearing mice.

    PubMed

    Zhang, Yufei; Luo, Feifei; Li, Anning; Qian, Jiawen; Yao, Zhenwei; Feng, Xiaoyuan; Chu, Yiwei

    2014-09-01

    Adoptive immunotherapy is an attractive strategy for glioma treatment. However, some obstacles still need be overcome. In this study, GL261-bearing mice treated with adoptively transferred antigen-specific T cells and systemic injection of bacterial lipoprotein (BLP), a TLR1/2 agonist, got a long-term survival and even immune protection. By analyzing adoptive T cells, it was found that BLP maintained T cell survival, proliferation and anti-tumor efficacy in the brains of tumor-bearing hosts. Moreover, tumor microenvironment was modified by up-regulating IFN-γ-secreting CD8+ T cells and down-regulating MDSC, which might be related with high CXCL10 and low CCL2 expression. In addition, TLR2 deficiency abrogated therapeutic effect with increased MDSC accumulation and decreased IFN-γ-secreting CD8+ T cells in the brains. Thus, the systemic injection of BLP could improve the adoptive T cell therapy by maintaining T cell persistence, modifying the tumor microenvironment and even inducing systemic anti-tumor immunity, which might offer a clinically promising immunotherapeutic strategy for glioma.

  9. Phloroglucinol Inhibits the Bioactivities of Endothelial Progenitor Cells and Suppresses Tumor Angiogenesis in LLC-Tumor-Bearing Mice

    PubMed Central

    Kwon, Yi-Hong; Jung, Seok-Yun; Kim, Jae-Won; Lee, Sang-Hun; Lee, Jun-Hee; Lee, Boo-Yong; Kwon, Sang-Mo

    2012-01-01

    Background There is increasing evidence that phloroglucinol, a compound from Ecklonia cava, induces the apoptosis of cancer cells, eventually suppressing tumor angiogenesis. Methodology/Principal Findings This is the first report on phloroglucinol's ability to potentially inhibit the functional bioactivities of endothelial progenitor cells (EPCs) and thereby attenuate tumor growth and angiogenesis in the Lewis lung carcinoma (LLC)-tumor-bearing mouse model. Although Phloroglucinol did not affect their cell toxicity, it specifically inhibited vascular endothelial growth factor (VEGF) dependent migration and capillary-like tube formation of EPCs. Our matrigel plug assay clearly indicated that orally injected phloroglucinol effectively disrupts VEGF-induced neovessel formation. Moreover, we demonstrated that when phloroglucinol is orally administered, it significantly inhibits tumor growth and angiogenesis as well as CD45−/CD34+ progenitor mobilization into peripheral blood in vivo in the LLC-tumor-bearing mouse model. Conclusions/Significance These results suggest a novel role for phloroglucinol: Phloroglucinol might be a modulator of circulating EPC bioactivities, eventually suppressing tumorigenesis. Therefore, phloroglucinol might be a candidate compound for biosafe drugs that target tumor angiogenesis. PMID:22496756

  10. Isolation from individual A/J mice of anti-rho-azophenylarsonate antibodies bearing a cross-reactive idiotype.

    PubMed

    Tung, A S; Nisonoff, A

    1975-01-01

    Immuization of A/J mice with a KLH-p-azophenylarsonate conjugate induces the formation of antihapten antibodies, some of which share idiotypic specificity common to all recipients. The subpopulation carrying the idiotype generally comprises 20-70% of the total antibody content. Large quantities of antihapten antibody (occasionally over 100 mg) were obtained from individual mice through the induction of an ascites fluid. This facilitated isolation of antibodies with the cross-reactive idiotype by isoelectric focusing. Most of this subpopulation has pI values between 6.65 and 6.95 and essentially all is of the IgG1 subclass. Two peaks, near pI 6.7 and 6.9, were frequently observed. Upon refocusing, the protein artifact of the procedure, but indicates microheterogeneity. The antibodies in the two peaks were found to be idiotypically identical by measurements of cross-inhibition. Preliminary studies have indicated that it is feasible to initiate investigations of primary structure with antibodies from individual inbred mice.

  11. Isolation from individual A/J mice of anti-rho-azophenylarsonate antibodies bearing a cross-reactive idiotype

    PubMed Central

    1975-01-01

    Immuization of A/J mice with a KLH-p-azophenylarsonate conjugate induces the formation of antihapten antibodies, some of which share idiotypic specificity common to all recipients. The subpopulation carrying the idiotype generally comprises 20-70% of the total antibody content. Large quantities of antihapten antibody (occasionally over 100 mg) were obtained from individual mice through the induction of an ascites fluid. This facilitated isolation of antibodies with the cross- reactive idiotype by isoelectric focusing. Most of this subpopulation has pI values between 6.65 and 6.95 and essentially all is of the IgG1 subclass. Two peaks, near pI 6.7 and 6.9, were frequently observed. Upon refocusing, the protein artifact of the procedure, but indicates microheterogeneity. The antibodies in the two peaks were found to be idiotypically identical by measurements of cross-inhibition. Preliminary studies have indicated that it is feasible to initiate investigations of primary structure with antibodies from individual inbred mice. PMID:46907

  12. Analysis of volatile organic compounds released from human lung cancer cells and from the urine of tumor-bearing mice

    PubMed Central

    2012-01-01

    Backgrounds A potential strategy for the diagnosis of lung cancer is to exploit the distinct metabolic signature of this disease by way of biomarkers found in different sample types. In this study, we investigated whether specific volatile organic compounds (VOCs) could be detected in the culture medium of the lung cancer cell line A549 in addition to the urine of mice implanted with A549 cells. Results Several VOCs were found at significantly increased or decreased concentrations in the headspace of the A549 cell culture medium as compared with the culture medium of two normal lung cell lines. We also analyzed the urine of mice implanted with A549 cells and several VOCs were also found to be significantly increased or decreased relative to urine obtained from control mice. It was also revealed that seven VOCs were found at increased concentrations in both sample types. These compounds were found to be dimethyl succinate, 2-pentanone, phenol, 2-methylpyrazine, 2-hexanone, 2-butanone and acetophenone. Conclusions Both sample types produce distinct biomarker profiles, and VOCs have potential to distinguish between true- and false-positive screens for lung cancer. PMID:22364569

  13. Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis.

    PubMed

    Lawrence, H J; Helgason, C D; Sauvageau, G; Fong, S; Izon, D J; Humphries, R K; Largman, C

    1997-03-15

    Several homeobox genes of the HOXA and HOXB clusters are expressed in primitive blood cells, suggesting a role for HOX genes in normal hematopoiesis. The HOXA9 gene is expressed in CD34+ marrow cells and in developing lymphocytes. We examined blood-forming organs of mice homozygous for an interrupted HOXA9 allele to determine if loss of HOX gene function is deleterious to hematopoiesis. HOXA9-/- mice have approximately 30% to 40% reductions in total leukocytes and lymphocytes (P < .001) and a blunted granulocytic response to granulocyte colony-stimulating factor (G-CSF). Homozygous mice have significantly smaller spleens and thymuses. Myeloid/erythroid and pre-B progenitors in the marrow are significantly reduced, but no significant decreases are noted in mixed colonies, day 12 colony-forming units-spleen (CFU-S), or long-term culture-initiating cells (LTC-IC), suggesting little or no perturbation in earlier progenitors. Heterozygous animals display no hematopoietic defects. The abnormalities in leukocyte production are transplantable, indicating that the defect resides in the hematopoietic cells. These studies demonstrate a physiologic role for a HOX gene in blood cell differentiation, with the greatest apparent influence of HOXA9 at the level of the committed progenitor.

  14. Improvement in the drug delivery and anti-tumor efficacy of PEGylated liposomal doxorubicin by targeting RNA aptamers in mice bearing breast tumor model.

    PubMed

    Moosavian, Seyedeh Alia; Abnous, Khalil; Badiee, Ali; Jaafari, Mahmoud Reza

    2016-03-01

    Targeted delivery by ligands such as aptamers, is a promising method to increase the efficiency of PEGylated-liposomal doxorubicin (PL-Dox). In this study, we have successfully conjugated our recently developed anti-breast cancer RNA aptamer (TSA14) to the surface of PL-Dox and characterized for their size, zeta potential, Dox percent encapsulation and release properties in the presence of fetal bovine serum. In vitro experiments showed that aptamer could improve cellular uptake and cytotoxicity of PL-Dox in TUBO breast cell line. In mice bearing TUBO breast tumor, although, the doxorubicin plasma level of liposomal doxorubicin did not significantly change after modification of nanoparticles with aptamer, however, much higher tumor accumulation of Dox as compared with non-targeted liposomes proved the tumor-targeting capability of aptamers. In the same way, aptamer-PL-Dox improved anti-tumor efficiency of liposomes in TUBO breast tumor in mice compared to non-targeted liposomes. Overall, the results showed that aptamer decoration of PL-Dox could significantly improve selectivity and the therapeutic efficacy of liposomal DOX and merits further investigation. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Development and evaluation of magnetic microemulsion: tool for targeted delivery of camptothecin to BALB/c mice-bearing breast cancer.

    PubMed

    Natesan, Subramanian; Sugumaran, Abimanyu; Ponnusamy, Chandrasekar; Jeevanesan, Vinoth; Girija, Gangarani; Palanichamy, Rajaguru

    2014-12-01

    Development and evaluation of camptothecin-loaded-microemulsion (ME) and -magnetic microemulsion (MME) for passive/active-targeted delivery to BALB/c mice-bearing breast cancer. Based on the pseudo-ternary phase diagrams camptothecin-loaded-MEs and -MMEs were developed using benzyl alcohol:Captex 300 (3:1), TPGS:Tween 80 (2:1) and water. Furthermore, characterized for their droplet size distribution, magnetic susceptibility and effect of droplet size in plasma and evaluated for in vitro and in vivo targeting potential, drug release, haemolytic potential, cytotoxicity, genotoxicity, in vivo biodistribution and lactone ring stability. Drug-loaded MEs showed uniform droplet distribution, extended drug release (76.07 ± 4.30% at 24 h), acceptable level of haemolytic activity (<20%), significant cytotoxicity (129 ± 3.9 ng/mL) against MCF-7 cancer cells and low DNA damage in lymphocytes. Targeting potential of MMEs was documented in 4T1 breast cancer-induced BALB/c mice. MMEs were concentrated more at the target tissue on introduction of external magnetic field. In vivo biodistribution study documented the active targeting of 5067.56 ± 354.72 ng/gm and passive targeting of 1677.58 ± 134.20 ng/gm camptothecin to breast cancer from MME and ME, respectively. Lactone stability study shows around 80% of the lactone stable at 24 h. Developed ME and MME may act as a promising nanocarrier for efficient targeting of breast cancer tissues.

  16. Biodistribution, pharmacokinetics, and nuclear imaging studies of 111In-labeled rGel/BLyS fusion toxin in SCID mice bearing B cell lymphoma.

    PubMed

    Wen, Xiaoxia; Lyu, Mi-Ae; Zhang, Rui; Lu, Wei; Huang, Qian; Liang, Dong; Rosenblum, Michael G; Li, Chun

    2011-08-01

    We examined the biodistribution and pharmacokinetics of (111)In-labeled rGel/BLyS, a gelonin toxin (rGel)-B lymphocyte stimulator (BLyS) fusion protein. rGel/BLyS was labeled with In-111 through DTPA with a labeling efficiency >95%. Biodistribution/imaging studies were obtained in severe-combined immunodeficiency mice bearing diffuse large B cell lymphoma OCI-Ly10. Pharmacokinetic studies were performed in BALB/c mice. In vitro, DTPA-conjugated rGel/BLyS displayed selective cytotoxicity against OCI-Ly10 cells and mantle cell lymphoma JeKo cells. In vivo, rGel/BLyS exhibited a tri-exponential disposition with a rapid initial mean distribution followed by an extensive mean distribution and a long terminal elimination phase. At 48 h after injection, uptake of the radiotracer in tumors was 1.25 %ID/g, with a tumor-to-blood ratio of 13. Tumors were clearly visualized at 24-72 h post-injection. Micro-SPECT-CT images and ex vivo analyses confirmed the accumulation of rGel/BLyS in OCI-Ly10 tumors. (111)In-DTPA-rGel/BLyS are distributed to B cell tumors and induce apoptosis in tumors. Preclinical antitumor studies using rGel/BLyS should use a twice-per-week treatment schedule.

  17. Preclinical Evaluation of an Anti-Nectin-4 ImmunoPET Reagent in Tumor-Bearing Mice and Biodistribution Studies in Cynomolgus Monkeys.

    PubMed

    Campbell, Dean O; Noda, Akihiro; Verlinsky, Alla; Snyder, Josh; Fujita, Yuji; Murakami, Yoshihiro; Fushiki, Hiroshi; Miyoshi, Sosuke; Lacayo, Sergio; Cabral, Edward; Yang, Peng; Stover, David R; Joseph, Ingrid B J K

    2016-10-01

    Nectin-4 is selectively overexpressed in a variety of cancers and is currently under clinical investigation as a therapeutic target. A monoclonal antibody against nectin-4 (AGS-22M6) was evaluated as an Immuno-positron emission tomography (ImmunoPET) reagent. Its ability to assay nectin-4 expression as well as detect nectin-4 positive tumors in the liver and bone was evaluated using mouse models. The biodistribution of [(89)Zr]AGS-22M6 was evaluated in mice bearing tumors with varying levels of nectin-4 expression. An isogenic breast cancer tumor line was used to model metastatic liver and bone disease in mice. The biodistribution of [(18)F]AGS-22M6 in cynomolgus monkeys was evaluated. A positive correlation was demonstrated between tumor nectin-4 expression and [(89)Zr]AGS-22M6 uptake. Tumors in the liver and bone were detected and differentiated based on nectin-4 expression. [(18)F]AGS-22M6 showed limited uptake in cynomolgus monkey tissues. [(89)Zr]AGS-22M6 is a promising ImmunoPET reagent that can assay nectin-4 expression in both primary and metastatic lesions.

  18. PET imaging of apoptosis in tumor-bearing mice and rabbits after paclitaxel treatment with 18F-Labeled recombinant human His10-annexin V

    PubMed Central

    Qin, Haidong; Zhang, Ming-Rong; Xie, Lin; Hou, Yanjie; Hua, Zichun; Hu, Minjin; Wang, Zizheng; Wang, Feng

    2015-01-01

    Monitoring response to chemo- or radiotherapy is of great importance in clinical practice. Apoptosis imaging serves as a very useful tool for the early evaluation of tumor response. The goal of this study was PET imaging of apoptosis with 18F-labeled recombinant human annexin V linked with 10 histidine tag (18F-rh-His10-annexin V) in nude mice bearing an A549 tumor and rabbits bearing a VX2 lung cancer after paclitaxel therapy. 18F-rh-His10-annexin V was prepared by conjugation of rh-His10-annexin V with N-succinimidyl 4-[18F]fluorobenzoate. Biodistribution was determined in mice by the dissection method and small-animal PET. Single-dose paclitaxel (175 mg/m2) was used to induce apoptosis in A549 and VX2 tumor models. 18F-rh-His10-annexin V was injected into A549 mice and VX rabbits to acquire dynamic and static PET images 72 h after paclitaxel treatment. The uptake of 18F-rh-His10-annexin V in apoptotic cells 4 h after induction was 6.45±0.52 fold higher than that in non-induced cells. High focal uptake of 18F-rh-His10-annexin V was visualized in A549 (SUVmax: 0.35±0.13) and VX2 (0.41±0.23) tumor models after paclitaxel treatment, whereas lower uptake was found in the corresponding tumors before treatment (A549 SUVmax: 0.04±0.02; VX2: 0.009±0.002). The apoptotic index was 75.61±11.56% in the treated VX2 cancer, much higher than that in the untreated VX2 (8.03±2.81%). This study demonstrated the feasibility of 18F-rh-His10-annexin V for the detection of apoptosis after chemotherapy in A549 and VX2 tumor models. PMID:25625024

  19. Negligible Colon Cancer Risk from Food-Borne Acrylamide Exposure in Male F344 Rats and Nude (nu/nu) Mice-Bearing Human Colon Tumor Xenografts

    PubMed Central

    Raju, Jayadev; Roberts, Jennifer; Sondagar, Chandni; Kapal, Kamla; Aziz, Syed A.; Caldwell, Don; Mehta, Rekha

    2013-01-01

    Acrylamide, a possible human carcinogen, is formed in certain carbohydrate-rich foods processed at high temperature. We evaluated if dietary acrylamide, at doses (0.5, 1.0 or 2.0 mg/kg diet) reflecting upper levels found in human foods, modulated colon tumorigenesis in two rodent models. Male F344 rats were randomized to receive diets without (control) or with acrylamide. 2-weeks later, rats in each group received two weekly subcutaneous injections of either azoxymethane (AOM) or saline, and were killed 20 weeks post-injections; colons were assessed for tumors. Male athymic nude (nu/nu) mice bearing HT-29 human colon adenocarcinoma cells-derived tumor xenografts received diets without (control) or with acrylamide; tumor growth was monitored and mice were killed 4 weeks later. In the F344 rat study, no tumors were found in the colons of the saline-injected rats. However, the colon tumor incidence was 54.2% and 66.7% in the control and the 2 mg/kg acrylamide-treated AOM-injected groups, respectively. While tumor multiplicity was similar across all diet groups, tumor size and burden were higher in the 2 mg/kg acrylamide group compared to the AOM control. These results suggest that acrylamide by itself is not a “complete carcinogen”, but acts as a “co-carcinogen” by exacerbating the effects of AOM. The nude mouse study indicated no differences in the growth of human colon tumor xenografts between acrylamide-treated and control mice, suggesting that acrylamide does not aid in the progression of established tumors. Hence, food-borne acrylamide at levels comparable to those found in human foods is neither an independent carcinogen nor a tumor promoter in the colon. However, our results characterize a potential hazard of acrylamide as a colon co-carcinogen in association with known and possibly other environmental tumor initiators/promoters. PMID:24040114

  20. The influence of active hexose correlated compound (AHCC) on cisplatin-evoked chemotherapeutic and side effects in tumor-bearing mice

    SciTech Connect

    Hirose, Aya; Sato, Eri; Fujii, Hajime; Sun Buxiang; Nishioka, Hiroshi . E-mail: nishioka@aminoup.co.jp; Aruoma, Okezie I. . E-mail: okezie.aruoma@touro.edu

    2007-07-15

    Cisplatin (cis-diaminedichloroplatinum (II) or CDDP) (a widely used platinum-containing anticancer drug) is nephrotoxic and has a low percentage of tolerance in patients during chemotherapy. The active hexose correlated compound (AHCC) is an extract of Basidiomycotina marketed as a supplement for cancer patients due to its nutrients and fibre content and its ability to strengthen and optimize the capacity of the immune system. The possibility that AHCC could reduce the side effects of cisplatin was assessed in the tumor-bearing BALB/cA mice on the basis of the ability to ameliorate the cisplatin-induced body weight loss, anorexia, nephrotoxicity and hematopoietic toxicity. Although cisplatin (8 mg/kg body weight) reduced the size and weight of the solid tumors, supplementation with AHCC significantly enhanced cisplatin-induced antitumor effect in both the size (p < 0.05) and weight (p < 0.05). Food intake in the cisplatin-treated mice were decreased following commencement of treatment and this remained low compared with the cisplatin-untreated group (control) throughout the experiment period. Supplementation with AHCC increased the food intake in the cisplatin-treated mice. The blood urea nitrogen and serum creatinine concentrations, and the ratio of blood urea nitrogen to serum creatinine were significantly increased in the cisplatin alone treated group compared to the control group. Their increased levels were mitigated by supplementation with AHCC (100 mg/kg body weight) in the cisplatin-treated group. AHCC was also able to modulate the suppression of bone marrow due to cisplatin and the improvement was statistically significant. The histopathological examination of the kidney revealed the presence of cisplatin-induced damage and this was modulated by AHCC treatment. The potential for AHCC to ameliorate the cisplatin-evoked toxicity as well as the chemotherapeutic effect could have beneficial economic implications for patients undergoing chemotherapy with

  1. Chlorambucil and ascorbic acid-mediated anticancer activity and hematological toxicity in Dalton's ascites lymphoma-bearing mice.

    PubMed

    Kalita, Suravi; Verma, Akalesh Kumar; Prasad, Surya Bali

    2014-02-01

    Chlorambucil is an anticancer drug with alkylating and immunosuppressive activities. Considering various reports on the possible antioxidant/protective functions of ascorbic acid (vitamin C), it was aimed at to explore the modulatory effect of ascorbic acid on therapeutic efficacy and toxicity induced by chlorambucil. Dalton's ascites lymphoma tumor serially maintained in Swiss albino mice were used for the present experiments. The result of antitumor activity showed that combination treatment with ascorbic acid and chlorambucil exhibited enhanced antitumor activity with 170% increase in life span (ILS), which is significantly higher as compared to chlorambucil alone (ILS 140%). Analysis of apoptosis in Dalton's lymphoma tumor cells revealed a significantly higher apoptotic index after combination treatment as compared to chlorambucil alone. Blood hemoglobin content, erythrocytes and leukocytes counts were decreased after chlorambucil treatment, however, overall recovery in these hematological values was noted after combination treatment. Chlorambucil treatment also caused morphological abnormalities in red blood cells, majority of which include acanthocytes, burr and microcystis. Combination treatment of mice with ascorbic acid plus chlorambucil showed less histopathological changes in kidney as compared to chlorambucil treatment alone, thus, ascorbic acid is effective in reducing chlorambucil-induced renal toxicity in the hosts. Based on the results, for further development, hopefully into the clinical usage, the administration of ascorbic acid in combination with chlorambucil may be recommended.

  2. Results from screening over 9000 mutation-bearing mice for defects in the electroretinogram and appearance of the fundus

    PubMed Central

    Pinto, Lawrence H.; Vitaterna, Martha Hotz; Siepka, Sanda M.; Shimomura, Kazuhiro; Lumayag, Stephen; Baker, Matthew; Fenner, Deborah; Mullins, Robert F.; Sheffield, Val C.; Stone, Edwin M.; Heffron, Edward; Takahashi, Joseph S.

    2013-01-01

    Random mutagenesis combined with phenotypic screening using carefully crafted functional tests has successfully led to the discovery of genes that are essential for a number of functions. This approach does not require prior knowledge of the identity of the genes that are involved and is a way to ascribe function to the nearly 6000 genes for which knowledge of the DNA sequence has been inadequate to determine the function of the gene product. In an effort to identify genes involved in the visual system via this approach, we have tested over 9000 first and third generation offspring of mice treated with the mutagen N-ethyl-N-nitrosourea (ENU) for visual defects, as evidenced by abnormalities in the electroretinogram and appearance of the fundus. We identified 61 putative mutations with this procedure and outline the steps needed to identify the affected genes. PMID:15536001

  3. Results from screening over 9000 mutation-bearing mice for defects in the electroretinogram and appearance of the fundus.

    PubMed

    Pinto, Lawrence H; Vitaterna, Martha Hotz; Siepka, Sanda M; Shimomura, Kazuhiro; Lumayag, Stephen; Baker, Matthew; Fenner, Deborah; Mullins, Robert F; Sheffield, Val C; Stone, Edwin M; Heffron, Edward; Takahashi, Joseph S

    2004-12-01

    Random mutagenesis combined with phenotypic screening using carefully crafted functional tests has successfully led to the discovery of genes that are essential for a number of functions. This approach does not require prior knowledge of the identity of the genes that are involved and is a way to ascribe function to the nearly 6000 genes for which knowledge of the DNA sequence has been inadequate to determine the function of the gene product. In an effort to identify genes involved in the visual system via this approach, we have tested over 9000 first and third generation offspring of mice treated with the mutagen N-ethyl-N-nitrosourea (ENU) for visual defects, as evidenced by abnormalities in the electroretinogram and appearance of the fundus. We identified 61 putative mutations with this procedure and outline the steps needed to identify the affected genes.

  4. Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice.

    PubMed

    Kim, Joong Sun; Son, Yeonghoon; Bae, Min Ji; Lee, Minyoung; Lee, Chang Geun; Jo, Wol Soon; Kim, Sung Dae; Yang, Kwangmo

    2015-07-01

    Although granulocyte-colony stimulating factor (G-CSF) is commonly used to support recovery from radiation-induced side-effects, the precise effects of G-CSF on colon cancer under radiotherapy remain poorly understood. In the present study, to investigate the effects of tumor growth following radiotherapy and G-CSF administration in a murine xenograft model of colon cancer, female BALB/c mice were injected with cells of a colon carcinoma cell line (CT26) with irradiation and G-CSF, alone or in combination. Mice received 2 Gy of focal radiation daily for 5 days and intraperitoneal injection of G-CSF (100 µg/kg/day) after irradiation for 7 days. Changes in the levels of myeloperoxidase (MPO), vascular endothelial growth factor (VEGF), matrix metalloproteinase type 9 (MMP-9) and CD31 were assessed in the mouse cancer induced by injection of colon cancer cells. We observed that G-CSF increased the number of circulating neutrophils, but facilitated tumor growth. However, G-CSF treatment did not affect radiation-induced cytotoxicity and cell viability in CT26 cells in vitro. Increased levels of myeloperoxidase, a neutrophil marker and those of vascular endothelial growth factor were observed in tumors with G-CSF supplementation. In addition, we found that increased levels of CD31 and matrix metalloproteinase-9 were correlated with the enhanced tumor growth after G-CSF treatment. Therefore, these data suggest that G-CSF may contribute to tumor growth and decrease the antitumor effect of radiotherapy, possibly by promoting vascularization in cancer lesions.

  5. Exosomes Isolated from Ascites of T-Cell Lymphoma-Bearing Mice Expressing Surface CD24 and HSP-90 Induce a Tumor-Specific Immune Response

    PubMed Central

    Menay, Florencia; Herschlik, Leticia; De Toro, Julieta; Cocozza, Federico; Tsacalian, Rodrigo; Gravisaco, María José; Di Sciullo, María Paula; Vendrell, Alejandrina; Waldner, Claudia I.; Mongini, Claudia

    2017-01-01

    Extracellular vesicles (EVs), including endosome-derived nanovesicles (exosomes), are involved in cell–cell communication. Through transfer of their molecular contents, extracellular nanovesicles can alter the function of recipient cells. Due to these characteristics, EVs have shown potential as a new alternative for cancer immunotherapy. Tumor exosomes isolated from malignant ascites can activate dendritic cells, thereby priming the immune system to recognize and kill cancer cells. However, a suppressive role on tumor immune response has also been reported, suggesting that the neoplastic stage of carcinogenesis and the microenvironment where tumor cells grow may influence the amount of EVs released by the cell. This neoplastic stage and microenvironment may also impact EVs’ components such as proteins and miRNA, determining their biological behavior. Most T-cell lymphomas have an aggressive clinical course and poor prognosis. Consequently, complementary alternative therapies are needed to improve the survival rates achieved with conventional treatments. In this work, we have characterized EVs isolated from ascites of mice bearing a very aggressive murine T-cell lymphoma and have studied their immunogenic properties. Small EVs were isolated by differential centrifugation, ultrafiltration, and ultracentrifugation at 100,000 × g on a sucrose cushion. The EVs were defined as exosomes by their morphology and size analyzed by electron microscopy, their floating density on a sucrose gradient, as well as their expression of endosome marker proteins ALIX, TSG-101; the tetraspanins CD63, CD9, and CD81. In addition, they contain tumor antigens, the marker for malignancy CD24, the heat shock protein HSP-70, and an unusual surface expression of HSP-90 was demonstrated. The administration of EVs isolated from ascites (EVs A) into naïve-syngeneic mice induced both humoral and cellular immune responses that allowed the rejection of subsequent tumor challenges. However

  6. Biodistribution, pharmacokinetic, and imaging studies with sup 186 Re-labeled NR-LU-10 whole antibody in LS174T colonic tumor-bearing mice

    SciTech Connect

    Goldrosen, M.H.; Biddle, W.C.; Pancook, J.; Bakshi, S.; Vanderheyden, J.L.; Fritzberg, A.R.; Morgan, A.C. Jr.; Foon, K.A. )

    1990-12-15

    Biodistribution, pharmacokinetic, and radioimaging studies were performed with 186Re-labeled NR-LU-10 whole antibody in athymic nude mice bearing the LS174T tumor growing either s.c. or in an experimental hepatic metastasis model. NR-LU-10 is an IgG2b murine monoclonal antibody (MAb) that reacts with virtually all human tumors of epithelial origin. NR-BC-1, a IgG2b murine MAb that reacts with normal human B-cell and B malignancies, was used as an isotype-matched control. These MAbs were radiolabeled with 186Re by a preformed chelate approach by using the triamide thiolate ligand system. 186Re-labeled NR-LU-10 (50 microCi) was injected into nude mice bearing LS174T tumors growing s.c. Biodistribution studies revealed that the LS174T tumor retained the highest concentration of 186Re-labeled NR-LU-10 at day 6. The tumor:blood ratio ranged from 0.1:1 to 10.8:1 by day 6, the last day of analysis. In contrast the tumor:blood ratio of 186Re-labeled NR-BC-1, the isotype-matched MAb control, was 1:1 on day 6. Pharmacokinetic analysis indicated that the t1/2 beta of NR-LU-10 for blood and other tissues ranged from 21 to 25 h, while the t1/2 beta for the LS174T tumor averaged 52 h. The area under the curve for tumor compared to blood was 2.8- to 5.7-fold higher than the area under the curve for all other tissues and organs. The mean residence time for NR-LU-10 in blood and all other organs ranged from 23 to 26 h, while the mean residence time for NR-LU-10 in the LS174T tumor was 72 h. Scintigraphic images revealed selective uptake of the 186Re-labeled NR-LU-10, but not of the 186Re-labeled NR-BC-1, at the LS174T tumor site. Studies in an experimental model of hepatic metastasis revealed a similar selective pattern of 186Re-labeled NR-LU-10 accumulation. Scintigraphic images of the LS174T tumor growing within the athymic nude mouse liver were obtained.

  7. 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice

    SciTech Connect

    Jeanbart, Laura; Kourtis, Iraklis C.; van der Vlies, André J.; Swartz, Melody A.; Hubbell, Jeffrey A.

    2015-05-16

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress effector T cell responses and can reduce the efficacy of cancer immunotherapies. We previously showed that ultra-small polymer nanoparticles efficiently drain to the lymphatics after intradermal injection and target antigen-presenting cells, including Ly6chi Ly6gmonocytic MDSCs (Mo-MDSCs), in skin-draining lymph nodes (LNs) and spleen. Here, we developed ultra-small polymer micelles loaded with 6-thioguanine (MC-TG), a cytotoxic drug used in the treatment of myelogenous leukemia, with the aim of killing Mo-MDSCs in tumor-bearing mice and thus enhancing T cell-mediated anti-tumor responses. We found that 2 days post-injection in tumor-bearing mice (B16-F10 melanoma or E.G7-OVA thymoma), MC-TG depleted Mo-MDSCs in the spleen, Ly6clo Ly6g+ granulocytic MDSCs (G-MDSCs) in the draining LNs, and Gr1int Mo-MDSCs in the tumor. In both tumor models, MC-TG decreased the numbers of circulating Mo- and G-MDSCs, as well as of Ly6chi macrophages, for up to 7 days following a single administration. MDSC depletion was dose dependent and more effective with MC-TG than with equal doses of free TG. Finally, we tested whether this MDSC-depleting strategy might enhance cancer immunotherapies in the B16-F10 melanoma model. We found that MC-TG significantly improved the efficacy of adoptively transferred, OVA-specific CD8+ T cells in melanoma cells expressing OVA. Ultimately, these findings highlight the capacity of MC-TG in depleting MDSCs in the tumor microenvironment and show promise in promoting anti-tumor immunity when used in combination with T cell immunotherapies.

  8. Attempted use of zinc in vivo to protect against nitrogen mustard toxicity in tumor-free and in L1210 leukemia-bearing B6D2F sub 1 mice

    SciTech Connect

    Shackelford, M.E.; Tobey, R.A.

    1989-12-01

    The use of alkylating agents in treating cancer is limited by their toxicity to both normal and tumor tissue. Early in vitro and in vivo studies had indicated that zinc could be effective in mitigating this toxicity to normal tissue. The present studies were done to determine the capability of zinc to induce in living tissue a protective response to an alkylating agent, without also contributing to mortality. Tumor-free and leukemia-bearing B6D2F{sub 1} mice were treated with zinc before administration of the alkylating agent nitrogen mustard (HN{sub 2}). Protocols for administration route and frequency and chemical formulation of the zinc were varied. The effect of a phytate-free diet was studied. Two parameters were used to judge the effectiveness of zinc in protecting animals from the toxicity of HN{sub 2}: the number of tumor-free mice who survived and any increase in the median life span of the tumor-bearing mice. Zinc provided a limited degree of protection against HN{sub 2} toxicity in tumor-free mice, but in tumor-bearing animals, the protective response elicited with the protocols examined was too small to provide a significant therapeutic benefit. 6 refs., 3 figs., 2 tabs.

  9. Olmesartan Potentiates the Anti-Angiogenic Effect of Sorafenib in Mice Bearing Ehrlich's Ascites Carcinoma: Role of Angiotensin (1–7)

    PubMed Central

    Abd-Alhaseeb, Mohammad M.; Zaitone, Sawsan A.; Abou-El-Ela, Soad H.; Moustafa, Yasser M.

    2014-01-01

    Local renin-angiotensin systems exist in various malignant tumor tissues; this suggests that the main effector peptide, angiotensin II, could act as a key factor in tumor growth. The underlying mechanisms for the anti-angiogenic effect of angiotensin II type 1 receptor blockers need to be further evaluated. The present study was carried out to investigate the anti-angiogenic effect of olmesartan alone or in combination with sorafenib, an angiotensin (1–7) agonist or an angiotensin (1–7) antagonist in Ehrlich's ascites carcinoma-bearing mice. The tumor was induced by intradermal injection of Ehrlich's ascites carcinoma cells into mice. Tumor discs were used to evaluate the microvessel density; the serum levels of vascular endothelial growth factor (VEGF) and serum insulin-like growth factor I (IGF-I); and their intratumoral receptors, VEGF receptor-2 and IGF-I receptor, respectively. All parameters were determined following the treatment course, which lasted for 21 days post-inoculation. Monotherapy with olmesartan and its combination with sorafenib resulted in a significant reduction in microvessel density and serum levels of VEGF and IGF-I, as well as their intratumoral receptors. In addition, the combination of olmesartan (30 mg/kg) with an angiotensin (1–7) agonist reduced the microvessel density, IGF-I serum levels and the levels of its intratumoral receptor. In conclusion, olmesartan reduced the levels of the angiogenesis markers IGF-I and VEGF and down-regulated the intratumoral expression of their receptors in a dose-dependent manner, and these effects were dependent on the angiotensin (1–7) receptor. These results suggest that olmesartan is a promising adjuvant to sorafenib in the treatment of cancer. PMID:24465768

  10. Anti-carcinogenic action of curcumin by activation of antioxidant defence system and inhibition of NF-κB signalling in lymphoma-bearing mice.

    PubMed

    Das, Laxmidhar; Vinayak, Manjula

    2012-04-01

    NF-κB (nuclear factor κB) plays a significant role in inflammation, immunity, cell proliferation, apoptosis and malignancy. ROS (reactive oxygen species) are among the most important regulating factors of NF-κB. Intracellular ROS are mainly regulated by an endogenous antioxidant defence system. Any disruption of redox balance leads to oxidative stress, which causes a number of pathological conditions including inflammation and malignancy. Increased metabolic activity in cancerous cells leads to oxidative stress, which is further enhanced due to depletion of the endogenous antioxidant defence system. However, the activation and signalling of NF-κB are reported to be inhibited by overexpression and induced activity of antioxidant enzymes. Therefore the present study focuses on the correlation between the endogenous antioxidant defence system, ROS and NF-κB activation during lymphoma growth in mice. The study highlights the anti-carcinogenic role of curcumin by modulation of NF-κB activation and oxidative stress via the endogenous antioxidant defence system. Oxidative stress was monitored by lipid peroxidation, protein carbonylation and antioxidant enzyme activity. NF-κB-mediated signalling was tested by DNA-binding activity. The results reflect that intracellular production of H2O2 in oxidative tumour micro-environment regulates NF-κB activation. Curcumin inhibits oxidative state in the liver of lymphoma-bearing mice by enhancing the transcription and activities of antioxidant enzymes, which in turn modulate activation of NF-κB, leading to a decrease in lymphoma growth. Morphological changes as well as cell proliferation and cell survival assays confirmed reduced lymphoma growth. Thus curcumin contributes to cancer prevention by disrupting the vicious cycle of constant ROS production, responsible for a high oxidative micro-environment for tumour growth.

  11. Positron emission tomographic imaging of iodine 124 anti-prostate stem cell antigen-engineered antibody fragments in LAPC-9 tumor-bearing severe combined immunodeficiency mice.

    PubMed

    Fonge, Humphrey; Leyton, Jeffrey V

    2013-05-01

    The humanized antibody (hu1G8) has been shown to localize to prostate stem cell antigen (PSCA) and image PSCA-positive xenografts. We previously constructed hu1G8 anti-PSCA antibody fragments and tested them for tumor targeting and the ability to image prostate cancer at early and late time points postinjection by positron emission tomography (PET). We now then compare the PET imaging and the radioactivity accumulation properties in prostate cancer tumors and nontarget tissues to determine the superior 124I-labeled hu1G8 antibody format. 124I-labeled diabody, minibody, scFv-Fc, scFv-Fc double mutant (DM), and parental IgG were administered into severe combined immunodeficiency (SCID) mice bearing LAPC-9 xenografts and followed by whole-body PET imaging of mice at preselected time points. Regions of interest were manually drawn around tumor and nontarget tissues and evaluated for radioactivity accumulation. The 124I-hu1G8 IgG has its best time point for tumor high-contrast imaging at 168 hours postinjection. The 124I-hu1G8 minibody at 44 hours postinjection results in superior tumor high-contrast imaging compared to the other antibody formats. The 124I-hu1G8 minibody at 44 hours postinjection also has comparable percent tumor radioactivity compared to 124I-hu1G8 IgG at 168 hours postinjection. The 124I-hu1G8 minibody is the best engineered hu1G8 antibody format for imaging prostate cancer.

  12. PLGA-encapsulated tea polyphenols enhance the chemotherapeutic efficacy of cisplatin against human cancer cells and mice bearing Ehrlich ascites carcinoma

    PubMed Central

    Singh, Madhulika; Bhatnagar, Priyanka; Mishra, Sanjay; Kumar, Pradeep; Shukla, Yogeshwer; Gupta, Kailash Chand

    2015-01-01

    The clinical success of the applicability of tea polyphenols awaits efficient systemic delivery and bioavailability. Herein, following the concept of nanochemoprevention, which uses nanotechnology for enhancing the efficacy of chemotherapeutic drugs, we employed tea polyphenols, namely theaflavin (TF) and epigallocatechin-3-gallate (EGCG) encapsulated in a biodegradable nanoparticulate formulation based on poly(lactide-co-glycolide) (PLGA) with approximately 26% and 18% encapsulation efficiency, respectively. It was observed that TF/EGCG encapsulated PLGA nanoparticles (NPs) offered an up to ~7-fold dose advantage when compared with bulk TF/EGCG in terms of exerting its antiproliferative effects and also enhanced the anticancer potential of cisplatin (CDDP) in A549 (lung carcinoma), HeLa (cervical carcinoma), and THP-1 (acute monocytic leukemia) cells. Cell cycle analysis revealed that TF/EGCG-NPs were more efficient than bulk TF/EGCG in sensitizing A549 cells to CDDP-induced apoptosis, with a dose advantage of up to 20-fold. Further, TF/EGCG-NPs, alone or in combination with CDDP, were more effective in inhibiting NF-κB activation and in suppressing the expression of cyclin D1, matrix metalloproteinase-9, and vascular endothelial growth factor, involved in cell proliferation, metastasis, and angiogenesis, respectively. EGCG and TF-NPs were also found to be more effective than bulk TF/EGCG in inducing the cleavage of caspase-3 and caspase-9 and Bax/Bcl2 ratio in favor of apoptosis. Further, in vivo evaluation of these NPs in combination with CDDP showed an increase in life span (P<0.05) in mice bearing Ehrlich’s ascites carcinoma cells, with apparent regression of tumor volume in comparison with mice treated with bulk doses with CDDP. These results indicate that EGCG and TF-NPs have superior cancer chemosensitization activity when compared with bulk TF/EGCG. PMID:26586942

  13. Direct comparison of a radioiodinated intact chimeric anti-CEA MAb with its F(ab')2 fragment in nude mice bearing different human colon cancer xenografts.

    PubMed Central

    Vogel, C. A.; Bischof-Delaloye, A.; Mach, J. P.; Pèlegrin, A.; Hardman, N.; Delaloye, B.; Buchegger, F.

    1993-01-01

    Tumour localisation and tumour to normal tissue ratios of a chimeric anti-carcinoembryonic antigen (CEA) monoclonal antibody (MAb), in intact form and as an F(ab')2 fragment labelled with 125I and 131I, were compared in groups of nude mice bearing four different colon cancer xenografts, T380, Co112 or LoVo, of human origin, or a rat colon cancer transfected with human CEA cDNA, called '3G7'. For each tumour, three to four mice per time point were analysed 6, 12, 24, 48 and 96 h after MAb injection. In the different tumours, maximal localisation of intact MAb was obtained at 24 to 48 h, and of F(ab')2 fragment 12 to 24 h after injection. Among the different tumours, localisation was highest with colon cancer T380, with 64% of the injected dose per gram (% ID/g) for the intact MAb and 57% for its F(ab')2 fragment, while in the three other tumours, maximal localisation ranged from 14 to 22% ID g-1 for the intact MAb and was about 11% for the F(ab')2. Tumour to normal tissue ratios of intact MAb increased rapidly until 24 h after injection and remained stable or showed only a minor increase thereafter. In contrast, for the F(ab')2 fragment, the tumour to normal tissue ratios increased steadily up to 4 days after injection reaching markedly higher values than those obtained with intact MAb. For the four different xenografts, tumour to blood ratios of F(ab')2 were about 2, 3 and 5 to 16 times higher than those of intact antibodies at 12, 24 and 96 h after injection, respectively. PMID:8398694

  14. Mesenchymal stromal cells primed with Paclitaxel attract and kill leukaemia cells, inhibit angiogenesis and improve survival of leukaemia-bearing mice.

    PubMed

    Pessina, Augusto; Coccè, Valentina; Pascucci, Luisa; Bonomi, Arianna; Cavicchini, Loredana; Sisto, Francesca; Ferrari, Maura; Ciusani, Emilio; Crovace, Antonio; Falchetti, Maria Laura; Zicari, Sonia; Caruso, Arnaldo; Navone, Stefania; Marfia, Giovanni; Benetti, Anna; Ceccarelli, Piero; Parati, Eugenio; Alessandri, Giulio

    2013-03-01

    Current leukaemia therapy focuses on increasing chemotherapy efficacy. Mesenchymal stromal cells (MSCs) have been proposed for carrying and delivery drugs to improve killing of cancer cells. We have shown that MSCs loaded with Paclitaxel (PTX) acquire a potent anti-tumour activity. We investigated the effect of human MSCs (hMSCs) and mouse SR4987 loaded with PTX (hMSCsPTX and SR4987PTX) on MOLT-4 and L1210, two leukaemia cell (LCs) lines of human and mouse origin, respectively. SR4987PTX and hMSCsPTX showed strong anti-LC activity. hMSCsPTX, co-injected with MOLT-4 cells or intra-tumour injected into established subcutaneous MOLT-4 nodules, strongly inhibited growth and angiogenesis. In BDF1-mice-bearing L1210, the intraperitoneal administration of SR4987PTX doubled mouse survival time. In vitro, both hMSCs and hMSCsPTX released chemotactic factors, bound and formed rosettes with LCs. In ultrastructural analysis of rosettes, hMSCsPTX showed no morphological alterations while the attached LCs were apoptotic and necrotic. hMSCs and hMSCsPTX released molecules that reduced LC adhesion to microvascular endothelium (hMECs) and down-modulated ICAM1 and VCAM1 on hMECs. Priming hMSCs with PTX is a simple procedure that does not require any genetic cell manipulation. Once the effectiveness of hMSCsPTX on established cancers in mice is proven, this procedure could be proposed for leukaemia therapy in humans.

  15. Curing tumor-bearing mice by shifting a Th2 to a Th1 anti-tumor response.

    PubMed

    Hellstrom, Karl Erik; Dai, Min; Hellstrom, Ingegerd

    2017-01-01

    Over the past several years remarkable therapeutic responses have been obtained with immunomodulatory monoclonal antibodies (mAbs), both in mice \\cite{10,18,20,48,54,61} and human cancer patients \\cite{1,3,14,28,30,39,80}. However, complete regressions and cures are infrequent and not predictable and some tumor types respond much worse than others. As an attempt to increase curability, we have investigated in mouse models the therapeutic efficacy of several mAb combinations, focusing on anti-PD-1/CTLA-4/CD137 and anti-PD-1/CTLA-4/CD137/CD19, and we have also combined mAbs with the chemotherapeutic drug cisplatin. Our data demonstrate an important contribution of anti-CD19 mAb to therapeutic efficacy, they show that intratumoral delivery of the mAbs is therapeutically more effective than systemic delivery, and that there is synergy when the mAbs are combined with cisplatin. In an attempt to improve predictability, we developed an in vitro model that may also be employed to search for novel immunomodulatory agents and combinations. This article reviews our data and discusses what is known about the underlying mechanisms.

  16. Lipid-associated methylpheophorbide-a (hexyl-ether) as a photodynamic agent in tumor-bearing mice.

    PubMed

    Mayhew, E; Vaughan, L; Panus, A; Murray, M; Henderson, B W

    1993-12-01

    Liposomes are a potential system for more selective delivery of photosensitizers (PS) to tumors. Pheophorbides are one series of new PS under investigation for use in photodynamic therapy. The pharmacokinetics, anti-tumor response and normal tissue effects of methylpheophorbide-a-(hexyl-ether) (MPH) associated with negatively charged phospholipid vesicles composed of high and low transition temperature lipids were determined in mice. In some preparations monosialoganglioside, which is known to impart long circulation time to liposomes was also included. Normally water-insoluble MPH could be quantitatively incorporated in multilamellar liposomes up to at least 20 mol MPH/mol lipid% for most liposome compositions and sonicated to form clear suspensions. Evidence from electron microscopy and entrapment of aqueous space markers indicated that the particles formed by sonication were not standard liposomes. Anti-tumor responses to light treatment (135 J/cm2, 665 nm argon-dye laser) 24 h after MPH (0.4 mumol/kg) administration were slightly but significantly greater (P < 0.05) for lipid associated MPH compared to MPH solubilized in Tween 80. There were no major differences in tumor uptake and tumor cell photosensitization between lipid or Tween 80 formulations of MPH, whereas, dependent on lipid composition and time after MPH administration, the doses of light required to cause occlusive vascular damage were increased for the lipid formulations. Pharmacokinetic studies showed rapid dissociation between lipids and MPH in vivo. Lipid formulations are useful for solubilizing MPH and may improve the therapeutic effects of this PS.

  17. [Effect of solcoseryl and combined therapy of solcoseryl and FT-207 for mice bearing meth-A tumor].

    PubMed

    Iwasa, H; Mimura, K; Ohsaki, Y; Kanabe, S; Hiraide, H; Mizoguchi, O; Tamaki, K; Kurokawa, T; Hatsuse, K; Kadota, T; Ezoe, I; Tsuru, S; Zinnaka, Y

    1983-02-01

    The effects of a combined chemotherapy of solcoseryl and FT-207 on tumor growth, delayed hypersensitivity and cell population of the spleen were studied using inbred BALB/c mice. Meth-A tumor cells (2 X 10(6] were inoculated into the back of 5 to 6 week old BALB/c male mouse. Animals were divided into three groups: Solcoseryl group, in which 0.04 mg of solcoseryl was injected intravenously three times before inoculation and four times after inoculation; Combined group, in which 1.2 mg of FT-207 and 0.04 mg of solcoseryl were injected intravenously four times after inoculation; FT-207 group, in which 1.2 mg of FT-207 was injected four times after inoculation, with out solcoseryl administration. Following results were obtained: Solcoseryl group showed enhanced immunity and tumor suppression; Decreased immunity due to FT-207 was recovered by administration of solcoseryl but no tumor suppression was observed and, Decreased T-cell population of spleen due to FT-207 was recovered by administration of solcoseryl. These facts suggested that solcoseryl was useful because of making recovery possible from decreased immunity due to chemotherapy.

  18. Synthesis of copper octabromotetracarboranylphenylporphyrin for boron neutron capture therapy and its toxicity and biodistribution in tumour-bearing mice.

    PubMed

    Miura, M; Morris, G M; Micca, P L; Nawrocky, M M; Makar, M S; Cook, S P; Slatkin, D N

    2004-07-01

    Copper tetracarboranyltetraphenylporphyrin (CuTCPH) is a minimally toxic carborane-containing porphyrin that has safely delivered high concentrations of boron for experimental boron neutron capture therapy (BNCT). Copper octabromotetracarboranylphenylporphyrin (CuTCPBr), synthesized by bromination of CuTCPH, is one of several new minimally toxic analogues of CuTCPH being studied in our laboratory, which could possess comparable or better tumour-targeting properties with enhanced tumour cytotoxicity. Its biodistribution, biokinetics and toxicity in mice with subcutaneous EMT-6 (mammary) or SCCVII (squamous cell) carcinomas were compared with those of CuTCPH. The administration of approximately 200 mg kg(-1) of either porphyrin in six intraperitoneal injections over 2 days had no apparent effect, but administration of approximately 400 mg kg(-1) slightly lowered body weights, elevated alanine and aspartate transaminase activities in blood plasma, and depressed blood platelet counts for several days. Enzymes and platelets returned to normal within 5 days after those injections and body weights returned to normal within 2 weeks. High average concentrations of boron from either porphyrin were achieved in the two tumour models from a total dose of approximately 200 mg kg(-1). The high tumour boron concentration decreased slowly while concentrations in blood decreased rapidly. Boron concentrations in brain and skin were consistently lower than in tumour by a factor of 10 or more. Although either CuTCPH or CuTCPBr can be labelled with (64)Cu for imaging by positron emission tomography (PET), CuTCPBr can also be labelled by (76)Br, another PET-imageable nuclide.

  19. In vivo pharmacokinetics, biodistribution and the anti-tumor effect of cyclic RGD-modified doxorubicin-loaded polymers in tumor-bearing mice.

    PubMed

    Wang, Chen; Li, Yuan; Chen, Binbin; Zou, Meijuan

    2016-10-01

    In our previous study, we successfully produced and characterized a multifunctional drug delivery system with doxorubicin (RC/GO/DOX), which was based on graphene oxide (GO) and cyclic RGD-modified chitosan (RC). Its characteristics include: pH-responsiveness, active targeting of hepatocarcinoma cells, and efficient loading with controlled drug release. Here, we report the pharmacokinetics, biodistribution, and anti-tumor efficacy of RC/GO/DOX polymers in tumor-bearing nude mice. The objective of this study is to assess its targeting potential for tumors. Pharmacokinetic and biodistribution profiles demonstrated that tumor accumulation of RC/GO/DOX polymers was almost three times higher than the others, highlighting the efficacy of the active targeting strategy. Furthermore, the tumor inhibition rate of RC/GO/DOX polymers was 56.64%, 2.09 and 2.93 times higher than that of CS/GO/DOX polymers (without modification) and the DOX solution, respectively. Anti-tumor efficacy results indicated that the tumor growth was better controlled by RC/GO/DOX polymers than the others. Hematoxylin and eosin (H&E) staining showed remarkable changes in tumor histology. Compared with the saline group, the tumor section from the RC/GO/DOX group revealed a marked increase in the quantity of apoptotic and necrotic cells, and a reduction in the quantity of the blood vessels. Together, these studies show that this new system could be regarded as a suitable form of DOX-based treatment of the hepatocellular carcinoma.

  20. Radioiodination of 2,3-dimethyl-4H-furo[3,2-c]coumarin and biological evaluation in solid tumor bearing mice.

    PubMed

    Abd Elhalim, S M; Ibrahim, I T

    2014-10-22

    Compound 2,3-dimethyl-4H-furo[3,2-c]coumarin is a coumarin derivative that could be labeled with (125)I. The process of labeling was started using 1mg of the compound, 50µg CAT oxidizing agent, 30min as reaction time at pH with a yield about 95%. The (125)I-coumarin derivative was stable for about 48h. Radiochemical purity of the labeled compound was performed by electrophoresis and HPLC. The labeled compound was separated with purity about 95%. Tumor transplantation to produce a solid tumor in the right leg of albino mice was made by intramuscular injection of 2×10(6) EAC (Ehrlish acittes carcinoma cells). Biodistribution study of (125)I-coumarin derivative revealed that the uptake in tumor bearing leg was over 5% at 1h and 4h post-injection. This uptake encourages the use of (123)I-coumarin derivative in imaging of tumor sites.

  1. Biodistribution and pharmacokinetics in rats and antitumor effect in various types of tumor-bearing mice of novel self-assembled gelatin-oleic acid nanoparticles containing paclitaxel.

    PubMed

    Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Lee, Beom-Jin

    2014-01-01

    The aim of this study was to investigate the pharmacokinetics and biodistribution in Sprague-Dawley rats, anti-tumor activity and acute toxicity in different tumor-bearing mice of novel biocompatible nanoparticles. Paclitaxel (PTX) was selected as a model drug and loaded on different tumor types and at various doses. The nanoparticles were prepared using a newly synthesized gelatin-oleic acid conjugate via self-assembly in an aqueous solution. The nanoparticles were further functionalized using folic acid (FA) as a targeting ligand for cancer. The in vivo effects of the nanoparticles were compared with the commercially available Taxol (a solution form of PTX) as a reference dosage form. The in vivo studies confirmed that nanoparticles showed improved therapeutic effects on tumors and significantly reduced the toxic effects associated with Taxol, even at the 50% lethal dose (LD50). The in vivo pharmacokinetic parameters and biodistribution of the nanoparticles containing PTX also indicated slower clearance, longer blood circulation and higher tumor selectivity. Furthermore, the functionalized nanoparticles with FA were more effective than the non-functionalized nanoparticles. Thus, the suitable properties of gelatin-oleic nanoparticles (GON) as a drug carrier and the effective targeting ligand could synergistically maximize the in vivo anti-tumor efficacy resulting in delayed tumor volume growth and hence, providing versatile strategies in cancer therapy and drug delivery.

  2. Tissue distribution of 2-methoxyestradiol nanosuspension in rats and its antitumor activity in C57BL/6 mice bearing lewis lung carcinoma.

    PubMed

    Shen, Guopeng; Wang, Qingyu; Zhang, Qingqing; Sun, Huibin; Zhao, Ya; Zhang, Zhenzhong; Du, Bin

    2012-01-01

    The purpose of the present study was to evaluate the tissue distribution and antitumor activity of 2-methoxyestradiol (2-ME) nanosuspension compared with 2-ME solution both in vitro and in vivo. 2-ME nanosuspension was made by nanoprecipitation-high-frequency ultrasonication method with the particle size of 168.4 ± 3.2 nm and the zeta potential of -29.79 ± 1.89 mV. The overall targeting efficiency (TE(Q)) of 2-ME nanosuspension was improved from 28.71 to 51.95% in the lung of rats. MTT assay showed that 2-ME nanosuspension could significantly enhance the in vitro cytotoxicity against lewis lung carcinoma (LLC) cells compared with the 2-ME solution, the IC(50) at 72 h was reduced from 6.35 µM for 2-ME solution to 3.56 µM for 2-ME nanosuspension. The antitumor activity in vivo was investigated in C57BL/6 mice bearing LLC, and the results indicated that 2-ME nanosuspension not only exhibited significant suppression of the tumor growth when compared with that of positive group or cyclophosphamide group at the same dose, but also enhanced the spleen indices. Overall, 2-ME nanosuspension could mainly deliver the drug to lungs and made the drug accumulate in the lungs, so 2-ME nanosuspension has a possible lung cancer therapeutic potential.

  3. Anti-hepatocarcinoma effects of berberine nanosuspension against human HepG2 and Huh7 cells as well as H22 tumor bearing mice

    NASA Astrophysics Data System (ADS)

    Wang, Zhi-ping; Wu, Jun-biao; Zhou, Qun; Wang, Yi-fei; Chen, Tongsheng

    2014-09-01

    Hepatocarcinoma, a malignant cancer, threaten human life badly. It is a current issue to seek the effective natural remedy from plant to treat cancer due to the resistance of the advanced hepatocarcinoma to chemotherapy. Berberine (Ber), an isoquinoline derivative alkaloid, has a wide range of pharmacological properties and is considered to have anti-hepatocarcinoma effects. However its low oral bioavailability restricts its wide application. In this report, Ber nanosuspension (Ber-NS) composed of Ber and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared by high pressure homogenization technique. Both in vitro and in vivo anti-hepatocarcinoma effects of Ber-NS relative to effcacy of bulk Ber were evaluated. The particle size and zeta potential of Ber-NS were 73.1 +/- 3.7 nm and 6.99 +/- 0.17 mV, respectively. Ber-NS exhibited significant inhibitory effects against human HepG2 and Huh7 cells, and the corresponding IC50 values were 8.1 and 4.7 μg/ml (18.3 and 6.5 μg/ml of Ber solution). In vivo studies also showed higher antitumor efficacy, and inhibition rates was 63.7% (41.4 % of Ber solution) at 100 mg/kg intragastric administration in the H22 solid tumor bearing mice. These results suggest that the delivery of Ber as a nanosuspension is a promising approach for treating hepatocarcinoma.

  4. Plasma, tumor and tissue pharmacokinetics of Docetaxel delivered via nanoparticles of different sizes and shapes in mice bearing SKOV-3 human ovarian carcinoma xenograft

    PubMed Central

    Chu, Kevin S.; Hasan, Warefta; Rawal, Sumit; Walsh, Mark D.; Enlow, Elizabeth M.; Luft, J. Christopher; Bridges, Arlene S.; Kuijer, Jennifer L.; Napier, Mary E.; Zamboni, William C.; DeSimone, Joseph M.

    2013-01-01

    The particle fabrication technique PRINT® was used to fabricate monodisperse size and shape specific poly(lactide-co-glycolide) particles loaded with the chemotherapeutic Docetaxel. The pharmacokinetics of two cylindrical shaped particles with diameter=80nm; height=320nm (PRINT-Doc-80×320) and d=200nm; h=200nm (PRINT-Doc-200×200) were compared to Docetaxel in mice bearing human ovarian carcinoma SKOV-3 flank xenografts. The Docetaxel plasma exposure was ~20-fold higher for both particles compared to docetaxel. Additionally, the volume of distribution (Vd) of Docetaxel in PRINT formulations was ~18-fold (PRINT-Doc-80×320) and ~33-fold (PRINT-Doc-200×200) lower than Docetaxel. The prolonged duration of Docetaxel in plasma when dosed with PRINT formulations subsequently lead to increased tumor exposure of Docetaxel from 0-168 hours (~53% higher for PRINT-Doc-80×320 and ~76% higher for PRINT-Doc-200×200 particles). PRINT-Doc-80×320 had lower exposures in the liver, spleen and lung compared with PRINT-Doc-200×200. Thus, the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system. PMID:23219874

  5. Cell and tissue distribution of synthetic oligonucleotides in healthy and tumor-bearing nude mice. An autoradiographic, immunohistological, and direct fluorescence microscopy study.

    PubMed Central

    Plenat, F.; Klein-Monhoven, N.; Marie, B.; Vignaud, J. M.; Duprez, A.

    1995-01-01

    Antisense oligonucleotides have the ability to inhibit individual gene expression in the potential treatment of cancer and viral diseases. However, the way parenterally administered oligonucleotides distribute themselves into healthy tissues or tumors is poorly understood. In this study, the cell and tissue distribution of two modified or unmodified phosphodiester pentadeca-beta-oligonucleotides intravenously administered to healthy or tumor-bearing nude mice was assessed by autoradiography as well as by direct fluorescence and immunoenzymatic histological methods. Resistance of oligonucleotides to degradation by nuclease activity was previously studied in vitro. Using these methods we were able to show the following: 1) within minutes, oligonucleotides permeate all cells and tissues with the exceptions of erythrocytes and intervertebral discs; 2) cell and tissue distribution does not depend on the sequence of the given oligonucleotide; 3) concentration of oligonucleotides is higher within the connective tissue cells than in the interstitial matrix; 4) after uptake, oligomers partition throughout all of the cellular compartments, including at the highest intracellular concentrations in the nuclei; 5) oligonucleotides penetrate easily the tumor cell compartments, oligonucleotide diffusion being unimpeded by the extracellular matrix. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 PMID:7604874

  6. Evaluation of the angiogenesis inhibitor KR-31831 in SKOV-3 tumor-bearing mice using (64)Cu-DOTA-VEGF(121) and microPET.

    PubMed

    Lee, Iljung; Yoon, Kwang Yup; Kang, Choong Mo; Lin, Xin; Chen, Xiaoyuan; Kim, Jung Young; Kim, Sung-Min; Ryu, Eun Kyoung; Choe, Yearn Seong

    2012-08-01

    KR-31831 ((2R,3R,4S)-6-amino-4-[N-(4-chloropheyl)-N-(1H-imidazol-2ylmethyl)amino]-3-hydroxyl-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran), an angiogenesis inhibitor, was evaluated in tumor-bearing mice using molecular imaging technology. Pre-treatment microPET images were acquired on SKOV-3 cell-implanted nude mice after injection with (64)Cu-DOTA-VEGF(121). KR-31831 (50 mg/kg) was then injected intraperitoneally into the treatment group (n=3), while injection vehicle was injected into the control (n=4) and blocking (n=3) groups. After injections occurred daily for 28 days, all groups of mice underwent post-treatment microPET imaging after injection with (64)Cu-DOTA-VEGF(121). The post-treatment images showed high tumor uptake in the control group and reduced tumor uptake in both the blocking and treatment groups. ROI analysis of the tumor images revealed 6.25%±1.18% ID/g at 1 h, 6.55%±0.69% ID/g at 2 h, and 4.68%±0.63% ID/g at 16 h in the control group; 3.87%±0.45% ID/g at 1 h, 4.50%±0.44% ID/g at 2 h, and 3.63%±0.25% ID/g at 16 h in the blocking group; and 4.03%±0.74% ID/g at 1 h, 4.37%±0.67% ID/g at 2 h, and 3.83%±0.90% ID/g at 16 h in the treatment group. Biodistribution obtained after the post-treatment microPET imaging also demonstrated high tumor uptake (3.74%±0.27% ID/g) in the control group and reduced uptakes in both the blocking group (2.69%±0.73% ID/g, P<.05) and the treatment group (3.11%±0.25% ID/g, P<.05), which correlated well with microPET imaging data. Immunofluorescence analysis showed higher levels of VEGFR2 and CD31 expressions in tumor tissues of the control and blocking groups than in tumor tissues of the treatment group. These results suggest that the antiangiogenic activity of KR-31831 is mediated through VEGFR2 and microPET serves as a useful molecular imaging tool for evaluation of a newly developed angiogenesis inhibitor, KR-31831. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Evaluation of the angiogenesis inhibitor KR-31831 in SKOV-3 tumor-bearing mice using 64Cu-DOTA-VEGF121 and microPET☆

    PubMed Central

    Lee, Iljung; Yoon, Kwang Yup; Kang, Choong Mo; Lin, Xin; Chen, Xiaoyuan; Kim, Jung Young; Kim, Sung-Min; Ryu, Eun Kyoung; Choe, Yearn Seong

    2013-01-01

    KR-31831 ((2R,3R,4S)-6-amino-4-[N-(4-chloropheyl)-N-(1H-imidazol-2ylmethyl)amino]-3-hydroxyl-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran), an angiogenesis inhibitor, was evaluated in tumor-bearing mice using molecular imaging technology. Pre-treatment microPET images were acquired on SKOV-3 cell-implanted nude mice after injection with 64Cu-DOTA-VEGF121. KR-31831 (50 mg/kg) was then injected intraperitoneally into the treatment group (n=3), while injection vehicle was injected into the control (n=4) and blocking (n=3) groups. After injections occurred daily for 28 days, all groups of mice underwent post-treatment microPET imaging after injection with 64Cu-DOTA-VEGF121. The post-treatment images showed high tumor uptake in the control group and reduced tumor uptake in both the blocking and treatment groups. ROI analysis of the tumor images revealed 6.25%±1.18% ID/g at 1 h, 6.55%±0.69% ID/g at 2 h, and 4.68%±0.63% ID/g at 16 h in the control group; 3.87%±0.45% ID/g at 1 h, 4.50%±0.44% ID/g at 2 h, and 3.63%±0.25% ID/g at 16 h in the blocking group; and 4.03%±0.74% ID/g at 1 h, 4.37%±0.67% ID/g at 2 h, and 3.83%±0.90% ID/g at 16 h in the treatment group. Biodistribution obtained after the post-treatment microPET imaging also demonstrated high tumor uptake (3.74%±0.27% ID/g) in the control group and reduced uptakes in both the blocking group (2.69%±0.73% ID/g, P<.05) and the treatment group (3.11%±0.25% ID/g, P<.05), which correlated well with microPET imaging data. Immunofluorescence analysis showed higher levels of VEGFR2 and CD31 expressions in tumor tissues of the control and blocking groups than in tumor tissues of the treatment group. These results suggest that the antiangiogenic activity of KR-31831 is mediated through VEGFR2 and microPET serves as a useful molecular imaging tool for evaluation of a newly developed angiogenesis inhibitor, KR-31831. PMID:22406249

  8. Tissue distribution and metabolism of gamma-linolenoyl-3-eicosapentaenoyl propane diol enterally or intravenously administered to mice bearing human pancreatic carcinomas.

    PubMed

    De Antueno, R; Bai, M; Elliot, M

    1999-01-01

    Synthetic propane diol lipids have been proposed as novel compounds to deliver cytocidal polyunsaturated fatty acids (PUFA) such as gamma-linolenic (GLA) and eicosapentaenoic (EPA) acids. To assess the biodistribution and metabolism of these PUFA in immunodeficient mice bearing human pancreatic carcinomas (AsPC-1), gamma-linolenoyl-3-eicosapentaenoyl propane diol (GE diol) was provided in a fat-free diet (5% w:w) for 6 weeks or parentally administered as 14C-GE diol (1 or 3 consecutive doses of 1.66 g/kg/day) in an innovative non-ionic-digalactosyldiacylglycerol emulsion. In tumor, liver, brain, kidney, plasma and fat tissue of mice fed GE diol, PUFA were increased over 25-fold, except for arachidonic acid (AA) levels, which were reduced or remained constant when compared to mice fed control corn oil diet. GLA and EPA were mainly stored in fat tissue. The recovery of radioactivity from the i.v. infected 14C-GE diol was dose and time dependent. Ten days after the i.v. infusion, GLA was only detected in substantial concentrations in tumor and in fat tissue (21 and 202 micrograms/g, respectively). Overall, these studies showed that: GE diol emulsions provide 640-fold higher doses of both GLA and EPA without causing hemolysis or adverse effects in the host mouse when compared to free PUFA infusions; GE diol is metabolized after oral or i.v. administration; tumor concentrations of GLA and EPA from the enterally administered diol were 4 to 13-fold higher than the in vitro cytotoxic levels; EPA, competes with AA and probably inhibits the activity of delta 5 desaturase without affecting the elongation of GLA in the host and tumor tissue; the change in PUFA profile modifies the substrates for eicosanoid synthesis. In short, a potentially desirable cytotoxic PUFA pattern can be achieved in host tissues and, in particular, in a human pancreatic tumor by providing GLA and EPA in the form GE-diol. These findings guarantee further investigations in oncology with this neutral

  9. Antitumor and antimetastasis effects of carboplatin liposomes with polyethylene glycol-2000 on SGC-7901 gastric cell-bearing nude mice.

    PubMed

    Zhang, Jianzhong; Huang, Changming; Huang, Heguang

    2014-11-01

    The present study aimed to analyze the characteristics of polyethylene glycol (PEG)ylated carboplatin liposomes (PL-CBPs), including size, stability, their release, entrapping and loading efficiencies, and their antitumor and antimetastatic effects on the lymph nodes. The PL-CBPs were prepared using PEG-2000 with the thin film hydration method. The liposome size and release, entrapping and loading efficiencies were detected by ultra-violet/visible spectrophotometry. A nude mouse model was established with the SGC-7901 gastric cell line to evaluate the antitumor effect of the PL-CBP. After 7 days, the mice were randomly divided into three groups (the control, CBP, and PL-CBP groups). CBP and PL-CBP were administered at a dose of 10 mg/kg for two consecutive cycles of treatment, 5 days apart, to their respective groups. In each group, two doses of 5 mg/kg were administered every 48 h. The tumor weight and volume were detected, and the food intake and body weight were measured during the administration. Apoptosis in the tumor cells was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and platinum (Pt) accumulation was detected by atomic absorption spectroscopy. Lastly, lymph node metastasis was evaluated by hematoxylin and eosin staining. The PL-CBPs were more stable when comapred with CBP alone, and the drug release efficiency was 0.7, 22.5, 48.7 and 65.1% at 37°C for 0, 12, 24 and 48 h. The results showed that the encapsulation efficiency was 85% and the loading efficiency was 0.15 mg/mg lipid. After 35 days, PL-CBP induced potent antitumor effects compared with the control and CBP groups (PL-CBP vs. control, P<0.01; PL-CBP vs. CBP, P<0.05). PL-CBP and CBP induced a lower and the lowest body weight and level of food intake, respectively, compared with the control group (CBP vs. control, P<0.05). The apoptosis rate and lymph node metastasis in the PL-CBP group was higher than that in the CBP and control groups (PL-CBP vs. control, P

  10. THRUST BEARING

    DOEpatents

    Heller, P.R.

    1958-09-16

    A thrust bearing suitable for use with a rotor or blower that is to rotate about a vertical axis is descrihed. A centrifagal jack is provided so thnt the device may opernte on one hearing at starting and lower speeds, and transfer the load to another bearing at higher speeds. A low viscosity fluid is used to lubricate the higher speed operation bearing, in connection with broad hearing -surfaces, the ability to withstand great loads, and a relatively high friction loss, as contraated to the lower speed operatio;n bearing which will withstand only light thrust loads but is sufficiently frictionfree to avoid bearing seizure during slow speed or startup operation. An axially aligned shaft pin provides the bearing surface for low rotational speeds, but at higher speed, weights operating against spring tension withdraw nthe shaft pin into the bearing proper and the rotor shaft comes in contact with the large bearing surfaces.

  11. Gear bearings

    NASA Technical Reports Server (NTRS)

    Vranish, John M. (Inventor)

    2003-01-01

    A gear bearing having a first gear and a second gear, each having a plurality of teeth. Each gear operates on two non-parallel surfaces of the opposing gear teeth to perform both gear and bearing functions simultaneously. The gears are moving at substantially the same speed at their contact points. The gears may be roller gear bearings or phase-shifted gear bearings, and may be arranged in a planet/sun system or used as a transmission.

  12. [Investigation on the migration and biologic effects of nano FeOx powders under the exposure of extremely low frequency altering electric magnetic field in human heptoma-bearing nude mice in vivo].

    PubMed

    Ju, Hui-Xiang; Dai, Zhen-Yu; Sun, Ming-Zhong

    2011-08-01

    To investigate the mechanism and biologic effects of 37 nm magnetic nano FeOx powders (MNPs) on human hepatoma-bearing nude mice. 37 nm MNPs were prepared by coprecipitation methods and then injected into human hepatoma (Bel-7402) bearing-nude mice through the tail vein. After injection of MNPs, the mice were first exposed under static magnetic field and then treated under extremely low frequency altering-electric magnetic field directing to the tumor area. The migration and trafficking of MNPs were determined by MMR. Tumor growth was monitored with calipers every 5 days and tumor volume was calculated on the basis of three-dimensioned measurements. The apoptosis of tumor cells was analyzed by flow cytometry analysis. The expressions of apoptosis-associated proteins Bcl-2, Bax and HSP27 were determined using western-blot analysis. Static magnetic field could direct the migration and trafficking of MNPs to the tumor site with a higher ratio of 98.9%. Extremely Low Frequency Electric-Magnetic Field (EMF) treatment could inhibit the proliferation of tumor cells and prolong the survive time of tumor-bearing mice injected with MNPs. In addition, the survival time of tumor-bearing mice and percentages of prohibition on tumor cell growth were 27.4+/-0.7 days and 37.5+/-0.8% (F = 0.005, P is less than to 0.05), respectively. The results of flow cytometry analyses showed that about 18.1+/-0.6% (F = 0.030, P is less than to 0.05) of tumor cells were induced into early apoptosis. Furthermore, expressions of apoptosis-associated proteins Bcl-2 and Bax were significantly induced by MNPs under EMF treatment. The ratio of Bcl/Bax in both MNPs and EMF treatment group was 0.07+/-0.01, which was much lower than that of control group (0.23+/-0.02) (F = 0.016, P is less than to 0.05). Heat shock protein-27 (Hsp-27) was not significantly induced in different treatment groups. Injection of MNPs with EMF exposure on human hepatoma-bearing nude mice could significantly prolong the

  13. Journal bearing

    DOEpatents

    Menke, John R.; Boeker, Gilbert F.

    1976-05-11

    1. An improved journal bearing comprising in combination a non-rotatable cylindrical bearing member having a first bearing surface, a rotatable cylindrical bearing member having a confronting second bearing surface having a plurality of bearing elements, a source of lubricant adjacent said bearing elements for supplying lubricant thereto, each bearing element consisting of a pair of elongated relatively shallowly depressed surfaces lying in a cylindrical surface co-axial with the non-depressed surface and diverging from one another in the direction of rotation and obliquely arranged with respect to the axis of rotation of said rotatable member to cause a flow of lubricant longitudinally along said depressed surfaces from their distal ends toward their proximal ends as said bearing members are rotated relative to one another, each depressed surface subtending a radial angle of less than 360.degree., and means for rotating said rotatable bearing member to cause the lubricant to flow across and along said depressed surfaces, the flow of lubricant being impeded by the non-depressed portions of said second bearing surface to cause an increase in the lubricant pressure.

  14. Biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomal cisplatin administered in Ehrlich tumor-bearing mice.

    PubMed

    Araújo, José Geraldo Coimbra; Mota, Luciene das Graças; Leite, Elaine Amaral; Maroni, Laís de Carvalho; Wainstein, Alberto Julius Alves; Coelho, Luiz Gonzaga Vaz; Savassi-Rocha, Paulo Roberto; Pereira, Márcio Tadeu; de Carvalho, Andréa Teixeira; Cardoso, Valbert Nascimento; De Oliveira, Mônica Cristina

    2011-07-01

    Cisplatin (CDDP) is one of the most active cytotoxic agents and has been widely used in the treatment of peritoneal carcinomatosis by the intraperitoneal (i.p.) route. However, CDDP, a low-molecular-weight compound, is rapidly absorbed by the capillaries in the i.p. serosa and transferred to the bloodstream, inducing the appearance of systemic side-effects, such as nephrotoxicity. Furthermore, the i.p. CDDP chemotherapy is limited to patients whose residual tumor nodules are less than 0.5 cm in diameter after surgical debulking. The failure of i.p. therapy is attributed to the poor penetration of CDDP into larger tumors. One strategy to improve drug delivery in the peritoneal region and reduce toxicity is the use of drug delivery systems. The objective of the present work was to evaluate the biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP), as compared with free CDDP, after their i.p. administration in Ehrlich ascitic tumor-bearing mice. After administering a 6 mg/kg single i.p. bolus injection of either free CDDP or SpHL-CDDP, ascitic fluid (AF), blood and organs (kidneys, liver, spleen and lungs) were collected and analyzed for CDDP content. The area under the CDDP concentration-time curve (AUC) obtained for AF and blood after SpHL-CDDP administration was 3.3-fold larger and 1.3-fold lower, respectively, when compared with free CDDP treatment, thus indicating its high retention within the peritoneal cavity. The determination of the ratio between AUC in each tissue and that in blood (Kp) showed a lower accumulation of CDDP in kidneys after SpHL-CDDP treatment. The SpHL-CDDP treatment demonstrated a significant uptake by the liver and spleen. SpHL-CDDP treatment led to a higher survival rate of mice with initial or disseminated peritoneal carcinomatosis than CDDP treatment. These results indicate that SpHL-CDDP may be useful for i.p. chemotherapy due to their greater concentration in the peritoneal

  15. Lung-targeting drug delivery system of baicalin-loaded nanoliposomes: development, biodistribution in rabbits, and pharmacodynamics in nude mice bearing orthotopic human lung cancer

    PubMed Central

    Wei, Yumeng; Liang, Jing; Zheng, Xiaoli; Pi, Chao; Liu, Hao; Yang, Hongru; Zou, Yonggen; Ye, Yun; Zhao, Ling

    2017-01-01

    The present study aims to develop a kind of novel nanoliposomes for the lung-targeting delivery system of baicalin as a Chinese medicine monomer. Baicalin-loaded nanoliposomes were prepared by the effervescent dispersion and lyophilized techniques. Baicalin-loaded nanoliposomes had an average particle size of 131.7±11.7 nm with 0.19±0.02 polydispersity index, 82.8%±1.24% entrapment efficiency and 90.47%±0.93% of yield and sustaining drug release effect over 24 h and were stable for 12 months at least. In vitro no hemolytic activity was observed for the experimental drug concentration. After intravenous administration of baicalin-loaded nanoliposomes to rabbits, drug concentration in the lungs was the highest among the tested organs at all time points and was significantly higher than that of its solution. For the targeting parameters, the relative intake rate and the ratio of peak concentration of lung were 4.837 and 2.789, respectively. Compared with plasma, liver, spleen, and kidney, the ratios of targeting efficacy (Te)liposomes to (Te)injection of lung were increased by a factor of 14.131, 1.893, 3.357, and 3.470, respectively. Furthermore, the results showed that the baicalin-loaded nanoliposomes did not induce lung injury. Importantly, baicalin-loaded nanoliposomes showed better antitumor therapeutic efficacy in the nude mice bearing orthotopic human lung cancer with the median survival time of blank liposomes (11.40±0.16 days), baicalin solution (17.30±0.47 days), and baicalin-loaded nanoliposomes (25.90±0.53 days). Therefore, the liposome is a promising drug carrier with an excellent lung-targeting property and therapeutic effect for the treatment of lung disease, such as lung cancer. PMID:28096670

  16. Z-505 hydrochloride, an orally active ghrelin agonist, attenuates the progression of cancer cachexia via anabolic hormones in Colon 26 tumor-bearing mice.

    PubMed

    Yoshimura, Makoto; Shiomi, Yoshihiro; Ohira, Yuta; Takei, Mineo; Tanaka, Takao

    2017-09-15

    Cancer cachexia is a progressive wasting syndrome characterized by anorexia and weight loss, specifically muscle wasting and fat depletion. There is no therapeutic agent for treatment of this syndrome. We investigated the anti-cachexia effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, using a mouse model of cancer cachexia. We performed a calcium flux assay in Chinese hamster ovary (CHO-K1) cells stably expressing human GHSR1a to quantify the agonistic activity of Z-505. In Colon 26 tumor-bearing mice, Z-505 (300mg/kg, p.o., twice daily) was administered for 7 days to assess its anti-cachexia effects. Body weight and food intake were monitored during the period, and the skeletal muscle and epididymal fat weights were measured. Serum levels of insulin, insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6), and corticosterone were measured to confirm the mechanism of the anti-cachexia action of Z-505. Z-505 showed strong agonistic activity similar to that of human ghrelin, with a half maximal effective concentration (EC50) value of 0.45nM. Z-505 treatment significantly increased food intake and inhibited the progression of weight loss. Z-505 also significantly attenuated muscle wasting and fat loss, and increased circulating levels of anabolic factors such as insulin and IGF-1, but not catabolic factors such as IL-6 and corticosterone. These findings suggest that Z-505 might be effective in the treatment of cachexia via the increased anabolic hormone levels stimulated by the activation of the ghrelin receptor, GHSR1a. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Boron uptake in normal melanocytes and melanoma cells and boron biodistribution study in mice bearing B16F10 melanoma for boron neutron capture therapy.

    PubMed

    Faião-Flores, Fernanda; Coelho, Paulo Rogério Pinto; Arruda-Neto, João Dias Toledo; Camillo, Maria Aparecida Pires; Maria-Engler, Silvya Stuchi; Rici, Rose Eli Grassi; Sarkis, Jorge Eduardo Souza; Maria, Durvanei Augusto

    2012-08-01

    Information on (10)B distribution in normal tissues is crucial to any further development of boron neutron capture therapy (BNCT). The goal of this study was to investigate the in vitro and in vivo boron biodistribution in B16F10 murine melanoma and normal tissues as a model for human melanoma treatment by a simple and rapid colorimetric method, which was validated by HR-ICP-MS. The B16F10 melanoma cell line showed higher melanin content than human melanocytes, demonstrating a greater potential for boronophenylalanine uptake. The melanocytes showed a moderate viability decrease in the first few minutes after BNCT application, stabilizing after 75 min, whereas the B16F10 melanoma showed the greatest intracellular boron concentration at 150 min after application, indicating a different boron uptake of melanoma cells compared to normal melanocytes. Moreover, at this time, the increase in boron uptake in melanoma cells was approximately 1.6 times higher than that in normal melanocytes. The (10)B concentration in the blood of mice bearing B16F10 melanoma increased until 90 min after BNCT application and then decreased after 120 min, and remained low until the 240th minute. On the other hand, the (10)B concentration in tumors was increased from 90 min and maximal at 150 min after application, thus confirming the in vitro results. Therefore, the present in vitro and in vivo study of (10)B uptake in normal and tumor cells revealed important data that could enable BNCT to be possibly used as a treatment for melanoma, a chemoresistant cancer associated with high mortality.

  18. The effect of 2-methoxyestradiol liposome on growth inhibition, angiogenesis and expression of VEGF and Ki67 in mice bearing H22 hepatocellular carcinoma.

    PubMed

    Du, Bin; Wang, Shu-Yu; Shi, Xiu-Fang; Zhang, Chao-Feng; Zhang, Zhen-Zhong

    2011-01-01

    2-methoxyestradiol (2-ME), an endogenous metabolite of estrogen, has very low water solubility. It is currently in phase II clinical trials as both a chemopreventive and chemotherapeutic agent and has been orally administered to cancer patients. However, the poor oral absorption of the compound is one of the major obstacles for 2-ME development. Based on the molecular features of 2-ME, liposome can be considered an attractive formulation approach. Our purpose in this study is to research the antitumor efficacy of 2-methoxyestradiol liposome (2-ME-L) in mice bearing H 22 tumors. Murine H22 hepatocarcinoma served as an ectopic solid tumor model. The effects of antitumor therapy were evaluated by testing tumor growth, measuring the tumor inhibition rates in terms of weight and volume, and staining the tissues by hematoxylin and eosin. The synergistic mechanism of 2-ME-L therapy was elucidated by detecting changes in the expression of pathognostic factors in the tumor microenvironment. 2-ME-L significantly suppressed tumor growth. The morphological changes in the tumors indicated that the tumors in the treatment groups were effectively confined with little surrounding angiogenesis. Tumor cells of the treatment groups had abundant areas of necrosis with few nuclei in the mitotic phase. It was found that there was less immunohistochemical expression of vascular endothelial growth factor (VEGF), Ki67 and CD31 in the treatment groups and the efficacy of 2-ME-L was better than that of 2-ME solution (2-ME-S). This research demonstrated that 2-ME-L inhibited the growth of H 22 tumors in a concentration-dependent manner and was more effective than 2-ME-S. 2-ME-L can suppress the growth of H22 solid tumors and has antiproliferative, proapoptotic and antiangiogenic activity. 2-ME-L could be of potential use in the treatment of hepatocellular carcinoma.

  19. Lung-targeting drug delivery system of baicalin-loaded nanoliposomes: development, biodistribution in rabbits, and pharmacodynamics in nude mice bearing orthotopic human lung cancer.

    PubMed

    Wei, Yumeng; Liang, Jing; Zheng, Xiaoli; Pi, Chao; Liu, Hao; Yang, Hongru; Zou, Yonggen; Ye, Yun; Zhao, Ling

    2017-01-01

    The present study aims to develop a kind of novel nanoliposomes for the lung-targeting delivery system of baicalin as a Chinese medicine monomer. Baicalin-loaded nanoliposomes were prepared by the effervescent dispersion and lyophilized techniques. Baicalin-loaded nanoliposomes had an average particle size of 131.7±11.7 nm with 0.19±0.02 polydispersity index, 82.8%±1.24% entrapment efficiency and 90.47%±0.93% of yield and sustaining drug release effect over 24 h and were stable for 12 months at least. In vitro no hemolytic activity was observed for the experimental drug concentration. After intravenous administration of baicalin-loaded nanoliposomes to rabbits, drug concentration in the lungs was the highest among the tested organs at all time points and was significantly higher than that of its solution. For the targeting parameters, the relative intake rate and the ratio of peak concentration of lung were 4.837 and 2.789, respectively. Compared with plasma, liver, spleen, and kidney, the ratios of targeting efficacy (Te)liposomes to (Te)injection of lung were increased by a factor of 14.131, 1.893, 3.357, and 3.470, respectively. Furthermore, the results showed that the baicalin-loaded nanoliposomes did not induce lung injury. Importantly, baicalin-loaded nanoliposomes showed better antitumor therapeutic efficacy in the nude mice bearing orthotopic human lung cancer with the median survival time of blank liposomes (11.40±0.16 days), baicalin solution (17.30±0.47 days), and baicalin-loaded nanoliposomes (25.90±0.53 days). Therefore, the liposome is a promising drug carrier with an excellent lung-targeting property and therapeutic effect for the treatment of lung disease, such as lung cancer.

  20. Green Synthesis of Sub-10 nm Gadolinium-Based Nanoparticles for Sparkling Kidneys, Tumor, and Angiogenesis of Tumor-Bearing Mice in Magnetic Resonance Imaging.

    PubMed

    Zhang, Bingbo; Yang, Weitao; Yu, Jiani; Guo, Weisheng; Wang, Jun; Liu, Shiyuan; Xiao, Yi; Shi, Donglu

    2017-02-01

    Gadolinium (Gd)-based nanoparticles are known for their high potential in magnetic resonance imaging (MRI). However, further MRI applications of these nanoparticles are hampered by their relatively large sizes resulting in poor organ/tumor targeting. In this study, ultrafine sub-10 nm and biocompatible Gd-based nanoparticles are synthesized in a bioinspired, environmentally benign, and straightforward fashion. This novel green synthetic strategy is developed for growing dextran-coated Gd-based nanoparticles (GdNPs@Dex). The as-prepared GdNPs@Dex is not only biocompatible but also stable with a sub-10 nm size. It exhibits higher longitudinal and transverse relaxivities in water (r1 and r2 values of 5.43 and 7.502 s(-1) × 10(-3) m(-1) of Gd(3+) , respectively) than those measured for Gd-DTPA solution (r1 and r2 values of 3.42 and 3.86 s(-1) × 10(-3) m(-1) of Gd(3+) , respectively). In vivo dynamic T1 -weighted MRI in tumor-bearing mice shows GdNPs@Dex can selectively target kidneys and tumor, in addition to liver and spleen. GdNPs@Dex is found particularly capable for determining the tumor boundary with clearly enhanced tumor angiogenesis. GdNPs@Dex is also found cleared from body gradually mainly via hepatobiliary and renal processing with no obvious systemic toxicity. With this green synthesis strategy, the sub-10 nm GdNPs@Dex presents promising potentials for translational biomedical imaging applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Hypoxia pathway and hypoxia-mediated extensive extramedullary hematopoiesis are involved in ursolic acid's anti-metastatic effect in 4T1 tumor bearing mice

    PubMed Central

    Gao, Jian-Li; Shui, Yan-Mei; Jiang, Wei; Huang, En-Yi; Shou, Qi-Yang; Ji, Xin; He, Bai-Cheng; Lv, Gui-Yuan; He, Tong-Chuan

    2016-01-01

    Hypoxic in the tumor mass is leading to the myeloproliferative-like disease (leukemoid reaction) and anemia of body, which characterized by strong extensive extramedullary hematopoiesis (EMH) in spleen. As the key transcription factor of hypoxia, hypoxia-inducible factor-1 (HIF-1) activates the expression of genes essential for EMH processes including enhanced blood cell production and angiogenesis. We found ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, inhibited growth of breast cancer both in vivo and in vitro. The suppression was mediated through the inhibition of multiple cell pathways linked to inflammation, proliferation, angiogenesis, and metastasis. UA also suppressed the leukemoid reaction and the EMH phenomenon of the tumor bearing mice without any significant suppression on body weight (i.p. by 20 mg/kg for 28 days). This is associated with the significant decrease in white blood cells (WBC), platelets (PLT) and spleen weight. During this process, we also detected the down-regulation of cell proliferative genes (PCNA, and β-catenin), and metastatic genes (VEGF, and HIF-1α), as well as the depression of nuclear protein intensity of HIF-1α. Furthermore, the expression of E2F1, p53 and MDM2 genes were increased in UA group when the VEGF and HIF-1α was over-expressed. Cancer cells were sensitive to UA treating after the silencing of HIF-1α and the response of Hypoxic pathway reporter to UA was suppressed when HIF-1α was over expressed. Overall, our results from experimental and predictive studies suggest that the anticancer activity of UA may be at least in part caused by suppressing the cancer hypoxia and hypoxia-mediated EMH. PMID:27708244

  2. Dose, timing, schedule, and the choice of targeted epitope alter the efficacy of anti-CD22 immunotherapy in mice bearing human lymphoma xenografts.

    PubMed

    O'Donnell, Robert T; Ma, Yunpeng; McKnight, Hayes C; Pearson, David; Tuscano, Joseph M

    2009-12-01

    CD22 is a cell-surface adhesion molecule on most B-cell NHL, so it is a promising target for immunotherapy. HB22.7 is an anti-CD22 mAb that binds the two NH(2)-terminal immunoglobulin domains and specifically blocks the interaction of CD22 with its ligand. CD22-blocking mAbs induce apoptosis in neoplastic B-cells and are functionally distinguishable from other anti-CD22 mAbs. This study assessed the optimal dose, route, schedule, and the targeted CD22 epitope. Raji NHL-bearing nude mice were studied. A non-blocking anti-CD22 mAb (HB22.27) was used as a control. HB22.27 had minimal effect, whereas HB22.7 improved survival and shrank tumors substantially. HB22.7 doses greater than 1.4 mg/week did not further increase efficacy (or toxicity). Tumors less than 200 mm(3) had a higher response rate than did larger tumors. Various schedules of HB22.7 administration were tested; one dose every other week was more effective than more or less frequent dosing. Pharmacokinetic studies revealed that the half-life of HB22.7 was 28 days; this correlated with the time needed to re-populate cell-surface CD22 after treatment with HB22.7. Immuno-PET showed that NHL was rapidly and specifically targeted by copper-64-labeled-HB22.7. This study provided data as to an optimal dose, route, schedule and interval between doses of HB22.7.

  3. Evaluation of (188)Re-labeled NGR-VEGI protein for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts.

    PubMed

    Ma, Wenhui; Shao, Yahui; Yang, Weidong; Li, Guiyu; Zhang, Yingqi; Zhang, Mingru; Zuo, Changjing; Chen, Kai; Wang, Jing

    2016-07-01

    Vascular endothelial growth inhibitor (VEGI) is an anti-angiogenic protein, which includes three isoforms: VEGI-174, VEGI-192, and VEGI-251. The NGR (asparagine-glycine-arginine)-containing peptides can specifically bind to CD13 (Aminopeptidase N) receptor which is overexpressed in angiogenic blood vessels and tumor cells. In this study, a novel NGR-VEGI fusion protein was prepared and labeled with (188)Re for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts. Single photon emission computerized tomography (SPECT) imaging results revealed that (188)Re-NGR-VEGI exhibits good tumor-to-background contrast in CD13-positive HT-1080 tumor xenografts. The CD13 specificity of (188)Re-NGR-VEGI was further verified by significant reduction of tumor uptake in HT-1080 tumor xenografts with co-injection of the non-radiolabeled NGR-VEGI protein. The biodistribution results demonstrated good tumor-to-muscle ratio (4.98 ± 0.25) of (188)Re-NGR-VEGI at 24 h, which is consistent with the results from SPECT imaging. For radiotherapy, 18.5 MBq of (188)Re-NGR-VEGI showed excellent tumor inhibition effect in HT-1080 tumor xenografts with no observable toxicity, which was confirmed by the tumor size change and hematoxylin and eosin (H&E) staining of major mouse organs. In conclusion, these data demonstrated that (188)Re-NGR-VEGI has the potential as a theranostic agent for CD13-targeted tumor imaging and therapy.

  4. Systemic co-delivery of doxorubicin and siRNA using nanoparticles conjugated with EGFR-specific targeting peptide to enhance chemotherapy in ovarian tumor bearing mice

    NASA Astrophysics Data System (ADS)

    Liu, C. W.; Lin, W. J.

    2013-10-01

    This aim of this study was to develop peptide-conjugated nanoparticles (NPs) for systemic co-delivery of siRNA and doxorubicin to enhance chemotherapy in epidermal growth factor receptor (EGFR) high-expressed ovarian tumor bearing mice. The active targeting NPs were prepared using heptapeptide-conjugated poly( d, l-lactic-co-glycolic acid)-poly(ethylene glycol). The particle sizes of peptide-free and peptide-conjugated NPs were 159.3 ± 32.5 and 184.0 ± 52.9 nm, respectively, with zeta potential -21.3 ± 3.8 and -15.3 ± 2.8 mV. The peptide-conjugated NPs uptake were more efficient in EGFR high-expressed SKOV3 cells than in EGFR low-expressed HepG2 cells due to heptapeptide specificity. The NPs were used to deliver small molecule anticancer drug (e.g., doxorubicin) and large molecule genetic agent (e.g., siRNA). The IC50 of doxorubicin-loaded peptide-conjugated NPs (0.09 ± 0.06 μM) was significantly lower than peptide-free NPs (5.72 ± 2.64 μM). The similar result was observed in siRNA-loaded NPs. The peptide-conjugated NPs not only served as a nanocarrier to efficiently deliver doxorubicin and siRNA to EGFR high-expressed ovarian cancer cells but also increased the intracellular accumulation of the therapeutic agents to induce assured anti-tumor growth effect in vivo.

  5. GAS BEARING

    DOEpatents

    Skarstrom, C.W.

    1960-09-01

    A gas lubricated bearing for a rotating shaft is described. The assembly comprises a stationary collar having an annular member resiliently supported thereon. The collar and annular member are provided with cooperating gas passages arranged for admission of pressurized gas which supports and lubricates a bearing block fixed to the rotatable shaft. The resilient means for the annular member support the latter against movement away from the bearing block when the assembly is in operation.

  6. Grizzly bear

    USGS Publications Warehouse

    Schwartz, C.C.; Miller, S.D.; Haroldson, M.A.; Feldhamer, G.; Thompson, B.; Chapman, J.

    2003-01-01

    The grizzly bear inspires fear, awe, and respect in humans to a degree unmatched by any other North American wild mammal. Like other bear species, it can inflict serious injury and death on humans and sometimes does. Unlike the polar bear (Ursus maritimus) of the sparsely inhabited northern arctic, however, grizzly bears still live in areas visited by crowds of people, where presence of the grizzly remains physically real and emotionally dominant. A hike in the wilderness that includes grizzly bears is different from a stroll in a forest from which grizzly bears have been purged; nighttime conversations around the campfire and dreams in the tent reflect the presence of the great bear. Contributing to the aura of the grizzly bear is the mixture of myth and reality about its ferocity. unpredictable disposition, large size, strength, huge canines, long claws, keen senses, swiftness, and playfulness. They share characteristics with humans such as generalist life history strategies. extended periods of maternal care, and omnivorous diets. These factors capture the human imagination in ways distinct from other North American mammals. Precontact Native American legends reflected the same fascination with the grizzly bear as modern stories and legends (Rockwell 1991).

  7. Polar Bears

    USGS Publications Warehouse

    Amstrup, Steven C.; Douglas, David C.; Reynolds, Patricia E.; Rhode, E.B.

    2002-01-01

    Polar bears (Ursus maritimus) are hunted throughout most of their range. In addition to hunting polar bears of the Beaufort Sea region are exposed to mineral and petroleum extraction and related human activities such as shipping road-building, and seismic testing (Stirling 1990).Little was known at the start of this project about how polar bears move about in their environment, and although it was understood that many bears travel across political borders, the boundaries of populations had not been delineated (Amstrup 1986, Amstrup et al. 1986, Amstrup and DeMaster 1988, Garner et al. 1994, Amstrup 1995, Amstrup et al. 1995, Amstrup 2000).As human populations increase and demands for polar bears and other arctic resources escalate, managers must know the sizes and distributions of the polar bear populations. Resource managers also need reliable estimates of breeding rates, reproductive intervals, litter sizes, and survival of young and adults.Our objectives for this research were 1) to determine the seasonal and annual movements of polar bears in the Beaufort Sea, 2) to define the boundaries of the population(s) using this region, 3) to determine the size and status of the Beaufort Sea polar bear population, and 4) to establish reproduction and survival rates (Amstrup 2000).

  8. Polar Bear

    USGS Publications Warehouse

    Amstrup, S.D.; ,; Lentfer, J.W.

    1988-01-01

    Polar bears are long-lived, late-maturing carnivores that have relatively low rates of reproduction and natural mortality. Their populations are susceptible to disturbance from human activities, such as the exploration and development of mineral resources or hunting. Polar bear populations have been an important renewable resource available to coastal communities throughout the Arctic for thousands of years.

  9. Correlation of distribution of sulphonated aluminium phthalocyanines with their photodynamic effect in tumour and skin of mice bearing CaD2 mammary carcinoma.

    PubMed Central

    Peng, Q.; Moan, J.

    1995-01-01

    A chemical extraction assay and fluorescence microscopy incorporating a light-sensitive thermoelectrically cooled charge-coupled device (CCD) camera was used to study the kinetics of uptake, retention and localisation of disulphonated aluminium phthalocyanine (A1PcS2) and tetrasulphonated aluminium phthalocyanine (A1PcS4) at different time intervals after an i.p. injection at a dose of 10 mg kg-1 body weight (b.w.) in tumour and surrounding normal skin and muscle of female C3D2/F1 mice bearing CaD2 mammary carcinoma. Moreover, the photodynamic effect on the tumour and normal skin using sulphonated aluminium phthalocyanines (A1PcS1, A1PcS2, A1pcS4) and Photofrin was compared with respect to dye, dye dose and time interval between dye administration and light exposure. The maximal concentrations of A1PcS2 in the tumour tissue were reached 2-24 h after injection of the dye, while the amounts of A1PcS4 peaked 1-2 h after the dye administration. A1PcS2 was simultaneously localised in the interstitium and in the neoplastic cells of the tumour, whereas A1PcS4 appeared to localise only in the stroma of the tumour. The photodynamic efficiency (light was applied 24 h after dye injection at a dose of 10 mg kg-1 b.w.) of the tumours was found to decrease in the following order: A1PcS2 > A1PcS4 > Photofrin > A1PcS1. Furthermore, photodynamic efficacy was strongly dependent upon dye doses and time intervals between dye administration and light exposure: the higher the dose, the higher the photodynamic efficiency. The most efficient photodynamic therapy (PDT) of the tumour was reached (day 20 tumour-free) when light exposure took place 2 h after injection of A1PcS2 (10 mg kg-1). A dual intratumoral localisation pattern of the dye, as found for A1PcS2, seems desirable to obtain a high photodynamic efficiency. The kinetic patterns of uptake, retention and localisation of A1PcS2 and A1PcS4 are roughly correlated with their photodynamic effect on the tumour and normal skin. Images

  10. Influence of administration route on tumor uptake and biodistribution of etoposide loaded solid lipid nanoparticles in Dalton's lymphoma tumor bearing mice.

    PubMed

    Harivardhan Reddy, L; Sharma, R K; Chuttani, K; Mishra, A K; Murthy, R S R

    2005-07-20

    The study evaluates the capability of tripalmitin nanoparticles in enhancing the tumor uptake of etoposide, and the influence of administration route on the biodistribution and tumor uptake of etoposide loaded tripalmitin (ETPL) nanoparticles in Dalton's lymphoma tumor bearing mice. ETPL nanoparticles were prepared by melt-emulsification and high pressure homogenization followed by the spray drying of nanodispersion. Characterization of the nanoparticles was done by particle size analysis, zeta potential measurement and scanning electron microscopy. The size of ETPL nanoparticles was 387 nm and possessed negative charge. Etoposide and ETPL nanoparticles were radiolabeled with 99mTc with high labeling efficiency. The labeled complexes showed good in vitro stability in the presence of DTPA/cysteine and serum stability. Etoposide and ETPL nanoparticles were injected by subcutaneous, intravenous or intraperitoneal routes and their biodistribution and tumor uptake were determined. Subcutaneous injection reduced the distribution of ETPL nanoparticles to all the tissues studied whereas after intraperitoneal injection, the distribution of ETPL nanoparticles to tissues was higher than free etoposide. The intravenous injection resulted in lower concentrations of ETPL nanoparticles in the organs of RES compared to free etoposide. ETPL nanoparticles experienced significantly high brain distribution after intraperitoneal injection indicating its potential use in targeting etoposide to brain tumors. After subcutaneous injection, the tissue distribution of ETPL nanoparticles increased with time indicating their accumulation at the injection site for a longer time. The tumor uptake of both etoposide and ETPL nanoparticles was significantly high after subcutaneous injection (P<0.001) compared to the other routes of administration. The tumor concentration of ETPL nanoparticles after subcutaneous injection was 59 folds higher than that obtained after intravenous and 8 folds higher

  11. Curcumin attenuates carcinogenesis by down regulating proinflammatory cytokine interleukin-1 (IL-1α and IL-1β) via modulation of AP-1 and NF-IL6 in lymphoma bearing mice.

    PubMed

    Das, Laxmidhar; Vinayak, Manjula

    2014-05-01

    Interleukin-1 (IL-1α and IL-1β) is a prototypic, potent, multifunctional proinflammatory cytokine affecting almost all cell types. Expression of IL-1 is up regulated in different tumor phenotypes and is implicated as an important factor in tumor progression via expression of metastatic, angiogenic genes and growth factors. Therefore, down regulation of expression of IL-1 may be able to inhibit cancer progression. Mechanism of transcriptional regulation of mouse IL-1α is not yet reported. AP-1 binding site at -12 to -6 on human IL-1α promotor is highly conserved in rat IL-1α gene and regulates its expression. Based on in silico analysis, regions -12 to -6bp is found to be conserved in human and mouse IL-1α gene promotor and therefore selected to study activation of IL-1α. Further, the regions -12 to -6bp in mouse IL-1α gene promotor corresponding to AP-1 binding element show 3'→5' orientation, necessary for AP-1 binding. The present work is focused on long term effect of curcumin on expression of IL-1α and IL-1β in liver of lymphoma bearing mice. Transcriptional regulation of IL-1α and IL-1β was analyzed by AP-1 and NF-IL-6 respectively. Elevated expression and protein level of IL-1α and IL-1β were found in lymphoma bearing mice compared to normal, which were significantly down regulated by curcumin treatment. Similarly, curcumin treatment down regulated activation of IL-1α and IL-1β via AP-1 and NF-IL-6 respectively. The findings conclude that curcumin attenuates carcinogenesis by down regulating proinflammatory cytokine interleukin-1 (IL-1α and IL-1β) via modulation of AP-1 and NF-IL6 respectively in lymphoma bearing mice.

  12. Magnetic Bearing

    NASA Technical Reports Server (NTRS)

    1996-01-01

    AVCON, Inc. produces advanced magnetic bearing systems for industrial use, offering a unique technological approach based on contract work done at Marshall Space Flight Center and Lewis Research Center. Designed for the turbopump of the Space Shuttle main engine, they are now used in applications such as electric power generation, petroleum refining, machine tool operation and natural gas pipelines. Magnetic bearings support moving machinery without physical contact; AVCON's homopolar approach is a hybrid of permanent and electromagnets which are one-third the weight, smaller and more power- efficient than previous magnetic bearings.

  13. Intraoral Mitochondrial-Targeted GS-Nitroxide, JP4-039, Radioprotects Normal Tissue in Tumor-Bearing Radiosensitive Fancd2−/− (C57BL/6) Mice

    PubMed Central

    Shinde, Ashwin; Berhane, Hebist; Rhieu, Byung Han; Kalash, Ronny; Xu, Karen; Goff, Julie; Epperly, Michael W.; Franicola, Darcy; Zhang, Xichen; Dixon, Tracy; Shields, Donna; Wang, Hong; Wipf, Peter; Parmar, Kalindi; Guinan, Eva; Kagan, Valerian; Tyurin, Vladimir; Ferris, Robert L.; Zhang, Xiaolan; Li, Song; Greenberger, Joel S.

    2016-01-01

    We evaluated normal tissue specific radioprotection of the oral cavity in radiosensitive Fanconi Anemia (FA) Fancd2−/−mice with orally established tumors using mitochondrial-targeted GS-nitroxide (JP4-039). Adult (10–12 weeks old) Fancd2+/+, Fancd2+/− and Fancd2−/− mice (C57BL/6 background) and subgroups with orally established TC-1 epithelial cell tumors received a single fraction of 28 Gy or four daily fractions of 8 Gy to the head and neck. Subgroups received JP4-039 in F15 emulsion (F15/JP4-039; 0.4 mg/mouse), 4-amino-Tempo in F15 emulsion (F15/4-amino-Tempo; 0.2 mg/ mouse) or F15 emulsion alone prior to each irradiation. Oral mucosa of Fancd2−/− mice showed baseline elevated RNA transcripts for Sod2, p53, p21 and Rad51 (all P < 0.0012) and suppressed levels of Nfkb and Tgfb, (all P < 0.0020) compared with Fancd2+/+ mice. The oral mucosa in tumor-bearing mice of all genotypes showed decreased levels of p53 and elevated Tgfb and Gadd45a (P ≤ 0.0001 for all three genotypes). Intraoral F15/JP4-039, but not F15/4-amino-Tempo, modulated radiation-induced normal tissue transcript elevation, ameliorated mucosal ulceration and reduced the depletion of antioxidant stores in oral cavity tissue of all genotypes, but did not radioprotect tumors. Mitochondrial targeting makes F15/JP4-039 an effective normal tissue radioprotector for Fancd2−/− mice, as well as wild-type mice. PMID:26789701

  14. Long-term treatment with a health product (Squina Diacylglyceryl Ether) enhances innate and adaptive immunity in mice.

    PubMed

    Leung, Hoi Yan; Ko, Kam Ming

    2012-11-26

    This study aimed to investigate the effects of a health product Squina (Diacylglyceryl Ether) (DAGE) on innate and adaptive immunity in mice. Both ex vivo/ in vivo mouse models and an in vitro system using cultured mouse splenocytes were recruited for the assessment of innate and adaptive immunity. For the innate immune response, DAGE extract treatment enhanced the LPS-induced IL1-β secretion by activated macrophages in vitro and long-term DAGE treatment (0.18 and 1.8 g/kg × 20 doses) elevated the phagocytic activity of macrophages, as well as natural killer cell activity in mice. The DAGE-induced increase in macrophage phagocytic and natural killer cell activities were accompanied by the suppression of tumor growth in Sarcoma-180 cell-inoculated mice. For the adaptive immune response, long-term DAGE treatment enhanced the splenocyte index and concanavalin A- stimulated proliferation ex vivo in mice. Consistently, the incubation with DAGE extract potentiated the concanavalin A-stimulated proliferation in mouse splenocytes in vitro. In conclusion, the results show that long-term DAGE treatment produces stimulatory effects on both innate and adaptive immunity in mice.

  15. Foil bearings

    NASA Astrophysics Data System (ADS)

    Elrod, David A.

    1993-11-01

    The rolling element bearings (REB's) which support many turbomachinery rotors offer high load capacity, low power requirements, and durability. Two disadvantages of REB's are: (1) rolling or sliding contact within the bearing has life-limiting consequences; and (2) REB's provide essentially no damping. The REB's in the Space Shuttle Main Engine (SSME) turbopumps must sustain high static and dynamic loads, at high speeds, with a cryogenic fluid as lubricant and coolant. The pump end ball bearings limit the life of the SSME high pressure oxygen turbopump (HPOTP). Compliant foil bearing (CFB) manufacturers have proposed replacing turbopump REB's with CFB's CFB's work well in aircraft air cycle machines, auxiliary power units, and refrigeration compressors. In a CFB, the rotor only contracts the foil support structure during start up and shut down. CFB damping is higher than REB damping. However, the load capacity of the CFB is low, compared to a REB. Furthermore, little stiffness and damping data exists for the CFB. A rotordynamic analysis for turbomachinery critical speeds and stability requires the input of bearing stiffness and damping coefficients. The two basic types of CFB are the tension-dominated bearing and the bending-dominated bearing. Many investigators have analyzed and measured characteristics of tension-dominated foil bearings, which are applied principally in magnetic tape recording. The bending-dominated CFB is used more in rotating machinery. This report describes the first phase of a structural analysis of a bending-dominated, multileaf CFB. A brief discussion of CFB literature is followed by a description and results of the present analysis.

  16. Foil bearings

    NASA Technical Reports Server (NTRS)

    Elrod, David A.

    1993-01-01

    The rolling element bearings (REB's) which support many turbomachinery rotors offer high load capacity, low power requirements, and durability. Two disadvantages of REB's are: (1) rolling or sliding contact within the bearing has life-limiting consequences; and (2) REB's provide essentially no damping. The REB's in the Space Shuttle Main Engine (SSME) turbopumps must sustain high static and dynamic loads, at high speeds, with a cryogenic fluid as lubricant and coolant. The pump end ball bearings limit the life of the SSME high pressure oxygen turbopump (HPOTP). Compliant foil bearing (CFB) manufacturers have proposed replacing turbopump REB's with CFB's CFB's work well in aircraft air cycle machines, auxiliary power units, and refrigeration compressors. In a CFB, the rotor only contracts the foil support structure during start up and shut down. CFB damping is higher than REB damping. However, the load capacity of the CFB is low, compared to a REB. Furthermore, little stiffness and damping data exists for the CFB. A rotordynamic analysis for turbomachinery critical speeds and stability requires the input of bearing stiffness and damping coefficients. The two basic types of CFB are the tension-dominated bearing and the bending-dominated bearing. Many investigators have analyzed and measured characteristics of tension-dominated foil bearings, which are applied principally in magnetic tape recording. The bending-dominated CFB is used more in rotating machinery. This report describes the first phase of a structural analysis of a bending-dominated, multileaf CFB. A brief discussion of CFB literature is followed by a description and results of the present analysis.

  17. Tumor targeting properties of monoclonal antibodies with different affinity for target antigen CD44V6 in nude mice bearing head-and-neck cancer xenografts.

    PubMed

    Verel, Iris; Heider, Karl-Heinz; Siegmund, Miranda; Ostermann, Elínborg; Patzelt, Erik; Sproll, Marlies; Snow, Gordon B; Adolf, Günther R; van Dongen, Guus A M S

    2002-05-20

    The CD44 protein family consists of isoforms with tissue-specific expression, which are encoded by standard exons and up to 9 alternatively spliced variant exons (v2-v10) of the same gene. The murine MAbs U36 and BIWA-1, directed against overlapping epitopes within the v6 region of CD44, have previously been shown to efficiently target HNSCC. We herein report on the construction of 1 chimeric (BIWA-2) and 2 humanized (BIWA-4 and BIWA-8) derivatives of BIWA-1. Together with U36 and BIWA-1, these new antibodies were evaluated for affinity to the antigen in vitro as well as for biodistribution and efficacy in RIT using nude mice bearing the HNSCC xenograft line HNX-OE. As determined by surface plasmon resonance, the MAbs bound to CD44v6 with an up to 46-fold difference in affinity (K(d) ranging from 1.1 x 10(-8) to 2.4 x 10(-10) M) with the following ranking: mMAb U36 < hMAb BIWA-4 < hMAb BIWA-8 < mMAb BIWA-1 approximately cMAb BIWA-2. To evaluate their in vivo tumor-targeting properties, 2 MAbs with identical murine or human isotype were labeled with either (131)I or (125)I and administered simultaneously (50 microg/10 microCi each) as pairs showing a stepwise decrease in the difference in affinity: U36 vs. BIWA-1 (35.0-fold difference), BIWA-4 vs. BIWA-2 (14.0-fold) and BIWA-4 vs. BIWA-8 (4.0-fold). Biodistribution was assessed at 1, 2, 3 or 4 and 7 days after injection. Remarkably, for all 3 MAb pairs tested, the lower-affinity MAb showed a higher degree and specificity of tumor localization. The difference in tumor localization was more pronounced when the difference in affinity was larger. For example, 3 days after injection, the lower-affinity mMAb U36 showed a 50% higher tumor uptake than the higher-affinity mMAb BIWA-1, while blood levels and uptake in organs were similar. After labeling with (186)Re (300 or 400 microCi), the same MAb pairs showed RIT efficacy consistent with the biodistribution data: (186)Re-U36 was more effective than (186)Re-BIWA-1, (186)Re

  18. Seismic bearing

    NASA Astrophysics Data System (ADS)

    Power, Dennis

    2009-05-01

    Textron Systems (Textron) has been using geophones for target detection for many years. This sensing capability was utilized for detection and classification purposes only. Recently Textron has been evaluating multiaxis geophones to calculate bearings and track targets more specifically personnel. This capability will not only aid the system in locating personnel in bearing space or cartesian space but also enhance detection and reduce false alarms. Textron has been involved in the testing and evaluation of several sensors at multiple sites. One of the challenges of calculating seismic bearing is an adequate signal to noise ratio. The sensor signal to noise ratio is a function of sensor coupling to the ground, seismic propagation and range to target. The goals of testing at multiple sites are to gain a good understanding of the maximum and minimum ranges for bearing and detection and to exploit that information to tailor sensor system emplacement to achieve desired performance. Test sites include 10A Site Devens, MA, McKenna Airfield Ft. Benning, GA and Yuma Proving Ground Yuma, AZ. Geophone sensors evaluated include a 28 Hz triax spike, a 15 Hz triax spike and a hybrid triax spike consisting of a 10 Hz vertical geophone and two 28 Hz horizontal geophones. The algorithm uses raw seismic data to calculate the bearings. All evaluated sensors have triaxial geophone configuration mounted to a spike housing/fixture. The suite of sensors also compares various types of geophones to evaluate benefits in lower bandwidth. The data products of these tests include raw geophone signals, seismic features, seismic bearings, seismic detection and GPS position truth data. The analyses produce Probability of Detection vs range, bearing accuracy vs range, and seismic feature level vs range. These analysis products are compared across test sites and sensor types.

  19. Immunomodulatory and antitumor activities of grape seed proanthocyanidins.

    PubMed

    Tong, Haibin; Song, Xiangfu; Sun, Xin; Sun, Guangren; Du, Fengfuo

    2011-11-09

    Proanthocyanidins are naturally occurring compounds that are widely available in many kinds of plants; particularly, the grape seeds are a rich source of proanthocyanidins. Grape seed proanthocyanidins (GSPs) have been demonstrated to possess a wide range of health beneficial properties. This study was carried out to elucidate the molecular mechanisms involved in the antitumor therapeutic and immunomodulating effects of GSPs through in vivo and in vitro models. The results showed that GSPs could significantly inhibit the growth of Sarcoma 180 tumor cells in vivo and remarkably increase thymus and spleen weight of Sarcoma 180-bearing mice and upgrade the secretion level of tumor necrosis factor-α (TNF-α) in serum. Moreover, GSPs could stimulate lymphocyte transformation, enhance lysosomal enzyme activity and phagocytic capability of peritoneal macrophages, and remarkably promote the production of TNF-α. These results suggested that GSPs could improve functional activation of the immune system, and the antitumor effects of GSPs were achieved by immunostimulating properties.

  20. Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene

    PubMed Central

    Fujihira, Haruhiko; Masahara-Negishi, Yuki; Tamura, Masaru; Huang, Chengcheng; Harada, Yoichiro; Wakana, Shigeharu; Takakura, Daisuke; Kawasaki, Nana; Taniguchi, Naoyuki; Kondoh, Gen; Yamashita, Tadashi; Funakoshi, Yoko; Suzuki, Tadashi

    2017-01-01

    The cytoplasmic peptide:N-glycanase (Ngly1 in mammals) is a de-N-glycosylating enzyme that is highly conserved among eukaryotes. It was recently reported that subjects harboring mutations in the NGLY1 gene exhibited severe systemic symptoms (NGLY1-deficiency). While the enzyme obviously has a critical role in mammals, its precise function remains unclear. In this study, we analyzed Ngly1-deficient mice and found that they are embryonic lethal in C57BL/6 background. Surprisingly, the additional deletion of the gene encoding endo-β-N-acetylglucosaminidase (Engase), which is another de-N-glycosylating enzyme but leaves a single GlcNAc at glycosylated Asn residues, resulted in the partial rescue of the lethality of the Ngly1-deficient mice. Additionally, we also found that a change in the genetic background of C57BL/6 mice, produced by crossing the mice with an outbred mouse strain (ICR) could partially rescue the embryonic lethality of Ngly1-deficient mice. Viable Ngly1-deficient mice in a C57BL/6 and ICR mixed background, however, showed a very severe phenotype reminiscent of the symptoms of NGLY1-deficiency subjects. Again, many of those defects were strongly suppressed by the additional deletion of Engase in the C57BL/6 and ICR mixed background. The defects observed in Ngly1/Engase-deficient mice (C57BL/6 background) and Ngly1-deficient mice (C57BL/6 and ICR mixed background) closely resembled some of the symptoms of patients with an NGLY1-deficiency. These observations strongly suggest that the Ngly1- or Ngly1/Engase-deficient mice could serve as a valuable animal model for studies related to the pathogenesis of the NGLY1-deficiency, and that cytoplasmic ENGase represents one of the potential therapeutic targets for this genetic disorder. PMID:28426790

  1. Synthetic phosphoethanolamine a precursor of membrane phospholipids reduce tumor growth in mice bearing melanoma B16-F10 and in vitro induce apoptosis and arrest in G2/M phase.

    PubMed

    Ferreira, Adilson Kleber; Meneguelo, Renato; Marques, Fabio Luiz Navarro; Radin, Adriano; Filho, Otaviano Mendonça R; Neto, Salvador Claro; Chierice, Gilberto Orivaldo; Maria, Durvanei Augusto

    2012-10-01

    Phosphoethanolamine (Pho-s) is a compound involved in phospholipid turnover, acting as a substrate for many phospholipids of the cell membranes, especially phosphatidylcholine. We recently reported that synthetic Pho-s has potent effects on a wide variety of tumor cells. To determine if Pho-s has a potential antitumor activity, in this study we evaluated the activity of Pho-s against the B16-F10 melanoma both in vitro and in mice bearing a dorsal tumor. The treatment of B16F10 cells with Pho-s resulted in a dose-dependent inhibition of cell proliferation. At low concentrations, this activity appears to be involved in the arrest of the cell cycle at G2/M, while at high concentrations Pho-s induces apoptosis. In accordance with these results, the loss of mitochondrial potential and increased caspase-3 activity suggest that Pho-s has dual antitumor effects; i.e. it induces apoptosis at high concentrations and modulates the cell cycle at lower concentrations. In vivo, we evaluated the effect of Pho-s in mice bearing B16-F10 melanoma. The results show that Pho-s reduces the tumoral volume increasing survival rate. Furthermore, the tumor doubling time and tumor delays were substantially reduced when compared with untreated mice. Histological analyses reveal that Pho-s induces changes in cell morphology, typical characteristics of apoptosis, in addition the large areas of necrosis correlating with a reduction of tumor size. The results presented here support the hypothesis that Pho-s has antitumor effects by the induction of apoptosis as well as the inhibition of cell proliferation by arrest at G2/M. Thus, Pho-s can be regarded as a promising agent for the treatment of melanoma. Published by Elsevier SAS.

  2. Characterization of V beta-bearing cells in athymic (nu/nu) mice suggests an extrathymic pathway for T cell differentiation.

    PubMed

    Rocha, B

    1990-04-01

    In the present article, the expression of the T cell receptor (TcR) beta chain and other T cell molecules was evaluated in surface immunoglobulin-negative spleen cell populations of young and old BALB/c and C57BL/6 nude mice, using a panel of monoclonal antibodies. The results obtained show that in young nude mice, most Thy-1high cells do not express other T cell markers. These mice have, however, a sizable population of Thy-1low cells with the same phenotype of alpha/beta+, CD4-CD8- thymocytes or MRL/lpr peripheral T cells, expressing predominantly genes of the V beta 8 family. The evolution of alpha/beta+ cells in aging nudes is strongly suggestive of an extrathymic pathway of differentiation of these cells since (a) the acquisition of high density TcR and CD3, as well as Thy-1 or CD4CD8 antigens at the cell surface of nude V beta+ T cells is not simultaneous; (b) alpha/beta+ cells in nude mice co-express other T cell markers at random and, even in old mice, they never completely resemble to the predominant high Thy-1+ CD3+ TcR alpha/beta+, CD4+CD8+ cells of euthymic controls; and (c) BALB/c nude T cells express V beta 11 genes, that are deleted in euthymic BALB/c mice. This latter finding may also indicate differences in the mechanisms of selection of T cells specificities in the thymus vs. the peripheral pools.

  3. System for testing bearings

    NASA Technical Reports Server (NTRS)

    Gibson, John C. (Inventor)

    1993-01-01

    Disclosed here is a system for testing bearings wherein a pair of spaced bearings provides support for a shaft on which is mounted a bearing to be tested, this bearing being mounted in a bearing holder spaced from and in alignment with the pair of bearings. The bearing holder is provided with an annular collar positioned in an opening in the bearing holder for holding the bearing to be tested. A screw threaded through the bearing holder into engagement with the annular collar can be turned to force the collar radially out of alignment with the pair of bearings to apply a radial load to the bearing.

  4. CUSHIONED BEARING

    DOEpatents

    Rushing, F.C.

    1960-09-01

    A vibration damping device effective to dampen vibrations occurring at the several critical speeds encountered in the operation of a high-speed centrifuge is described. A self-centering bearing mechanism is used to protect both the centrifuge shaft and the damping mechanism. The damping mechanism comprises spaced-apant, movable, and stationary sleeve members arranged concentrically of a rotating shaft with a fluid maintained between the members. The movable sleeve member is connected to the shaft for radial movement therewith.

  5. Camshaft bearing arrangement

    SciTech Connect

    Aoi, K.; Ozawa, T.

    1986-06-10

    A bearing arrangement is described for the camshaft of an internal combustion engine or the like which camshaft is formed along its length in axial order with a first bearing surface, a first cam lobe, a second bearing surface, a second cam lobe, a third bearing surface, a third cam lobe and a fourth bearing surface, the improvement comprising first bearing means extending around substantially the full circumference of the first bearing surface and journaling the first bearing surface, second bearing means extending around substantially less than the circumference of the second bearing surface and journaling the second bearing surface, third bearing means extending around substantially less than the circumference of the third bearing surface and journaling the third bearing surface, and fourth bearing means extending around substantially the full circumference of the fourth bearing surface and journaling the first bearing surface.

  6. Tooling Converts Stock Bearings To Custom Bearings

    NASA Technical Reports Server (NTRS)

    Fleenor, E. N., Jr.

    1983-01-01

    Technique for reworking stock bearings saves time and produces helicopter-rotor bearings ground more precisely. Split tapered ring at one end of threaded bolt expands to hold inside of inner race bearing assembly; nut, at other end of bolt, adjusts amount of spring tension. Piece of hardware grasps bearing firmly without interfering with grinding operation. Operation produces bearing of higher quality than commercially available bearings.

  7. The protective effects of paeonol against epirubicin-induced hepatotoxicity in 4T1-tumor bearing mice via inhibition of the PI3K/Akt/NF-kB pathway.

    PubMed

    Wu, Jing; Xue, Xia; Zhang, Bin; Jiang, Wen; Cao, Hongmei; Wang, Rongmei; Sun, Deqing; Guo, Ruichen

    2016-01-25

    Epirubicin is widely used for the treatment of various breast cancers; however, it has serious adverse side effects, such as hepatotoxicity, which require dose-adjustment or therapy substitution. Paeonol, an active component from Moutan Cortex, has a variety of biological activities, including preventing or reducing various toxicities induced by antineoplastics. Protection by paeonol against hepatotoxicity induced by epirubicin and the underlying mechanism of action were investigated in this study. Cytosolic enzymes in the serum and oxidative stress indices in the liver were determined. The protective effects were determined using the MTT assay in vitro or by evaluating the expression of apoptotic factors and crucial proteins in the PI3K/Akt/NF-kB pathway using western blot analysis. It is concluded that paeonol alleviates epirubicin-induced hepatotoxicity in 4T1-tumor bearing mice by inhibiting the PI3K/Akt/NF-kB pathway.

  8. Biological features of core networks that result from a high-fat diet in hepatic and pulmonary tissues in mammary tumour-bearing, obesity-resistant mice.

    PubMed

    Kim, Eun Ji; Oh, Hea Young; Heo, Hyoung-Sam; Hong, Ji Eun; Jung, Sung-Jae; Lee, Ki Won; Park, Jong Hoon; Hur, Cheol-Goo; Park, Jung Han Yoon

    2013-07-28

    We previously demonstrated that the chronic consumption of a high-fat diet (HFD) promotes lung and liver metastases of 4T1 mammary carcinoma cells in obesity-resistant BALB/c mice. To examine early transcriptional responses to tumour progression in the liver and lungs of HFD-fed mice, 4-week-old female BALB/c mice were divided into four groups: sham-injected, control diet (CD)-fed; sham-injected, HFD-fed (SH); 4T1 cell-injected, CD-fed (TC); 4T1 cell-injected, HFD-fed (TH). Following 16 weeks of either a CD or HFD, 4T1 cells were injected into the mammary fat pads of mice in the TC and TH groups and all mice were continuously fed identical diets. At 14 d post-injection, RNA was isolated from hepatic and pulmonary tissues for microarray analysis of mRNA expression. Functional annotation and core network analyses were conducted for the TH/SH Unique gene set. Inflammation in hepatic tissues and cell mitosis in pulmonary tissues were the most significant biological functions in the TH/SH Unique gene set. The biological core networks of the hepatic TH/SH Unique gene set were characterised as those genes involved in the activation of acute inflammatory responses (Orm1, Lbp, Hp and Cfb), disordered lipid metabolism and deregulated cell cycle progression. Networks of the pulmonary Unique gene set displayed the deregulation of cell cycle progression (Cdc20, Cdk1 and Bub1b). These HFD-influenced alterations may have led to favourable conditions for the formation of both pro-inflammatory and pro-mitotic microenvironments in the target organs that promote immune cell infiltration and differentiation, as well as the infiltration and proliferation of metastatic tumour cells.

  9. Receptor-binding, biodistribution, dosimetry, and micro-SPECT/CT imaging of 111In-[DTPA(1), Lys(3), Tyr(4)]-bombesin analog in human prostate tumor-bearing mice.

    PubMed

    Ho, Chung-Li; Chen, Liang-Cheng; Lee, Wan-Chi; Chiu, Shu-Pei; Hsu, Wei-Chuan; Wu, Yu-Hsien; Yeh, Chung-Hsin; Stabin, Michael G; Jan, Meei-Ling; Lin, Wuu-Jyh; Lee, Te-Wei; Chang, Chih-Hsien

    2009-08-01

    Gastrin-releasing peptide receptors (GRPRs) are overexpressed on a variety of human tumors, such as prostate, breast, and lung cancer. Bombesin (BN) is a 14-amino-acid peptide with high affinity for these GRPRs. We synthesized DTPA-Q-K-Y-G-N-Q-W-A-V-G-H-L-M, a 13-amino-acid peptide chelated with diethylenetriaminepentaacetic acid (DTPA), and radiolabeled this BN analog with 111InCl(3). Biologic activity of 111In-[DTPA(1), Lys(3), Tyr(4)]-BN was evaluated in PC-3 prostate tumor-bearing severely compromised immunodeficient (SCID) mice. The purity of synthesized [DTPA(1), Lys(3), Tyr(4)]-BN was greater than 95%. The radiolabeling efficiency of 111In-[DTPA(1), Lys(3), Tyr(4)]-BN was 96.9% +/- 2.46%. The IC(50) and K(i) of [DTPA(1), Lys(3), Tyr(4)]-BN in the human bombesin 2 receptor were 1.05 +/- 0.46 and 0.83 +/- 0.36 nM, respectively. The K(d) of 111In-[DTPA(1), Lys(3), Tyr(4)]-BN in GRPR-expressing PC-3 tumor cells was 22.9 +/- 6.81 nM. Both biodistribution and micro-SPECT/CT (single-photon emission computed tomography/computed tomography) imaging studies with 111In-[DTPA(1), Lys(3), Tyr(4)]-BN demonstrated the highest uptake at 8 hours postinjection. The Pearson correlation analysis showed a positive correlation of tumor uptake between biodistribution and micro-SPECT/CT semiquantification imaging analysis (r = 0.832). Our results revealed 111In-[DTPA(1), Lys(3), Tyr(4)]-BN has high affinity with BN type 2 receptor. The results demonstrated a good uptake in the GRPR-overexpression of PC-3 tumor-bearing SCID mice. 111In-[DTPA(1), Lys(3), Tyr(4)]-BN is a potential agent for imaging GRPR-positive tumors in humans.

  10. Paullinia cupana Mart. var. sorbilis, guarana, increases survival of Ehrlich ascites carcinoma (EAC) bearing mice by decreasing cyclin-D1 expression and inducing a G0/G1 cell cycle arrest in EAC cells.

    PubMed

    Fukumasu, Heidge; Latorre, Andreia Oliveira; Zaidan-Dagli, Maria Lucia

    2011-01-01

    The objective of this work is to report the antiproliferative effect of P. cupana treatment in Ehrlich Ascites Carcinoma (EAC)-bearing animals. Female mice were treated with three doses of powdered P. cupana (100, 1000 and 2000 mg/kg) for 7 days, injected with 10(5) EAC cells and treated up to day 21. In addition, a survival experiment was carried out with the same protocol. P. cupana decreased the ascites volume (p = 0.0120), cell number (p = 0.0004) and hemorrhage (p = 0.0054). This occurred through a G1-phase arrest (p < 0.01) induced by a decreased gene expression of Cyclin D1 in EAC cells. Furthermore, P. cupana significantly increased the survival of EAC-bearing animals (p = 0.0012). In conclusion, the P. cupana growth control effect in this model was correlated with a decreased expression of cyclin D1 and a G1 phase arrest. These results reinforce the cancer therapeutic potential of this Brazilian plant. Copyright © 2010 John Wiley & Sons, Ltd.

  11. Advances In Magnetic Bearings

    NASA Technical Reports Server (NTRS)

    Fleming, David P.

    1994-01-01

    NASA technical memorandum reviews state of technology of magnetic bearings, focusing mainly on attractive bearings rather than repulsive, eddy-current, or Lorentz bearings. Attractive bearings offer greater load capacities and preferred for aerospace machinery.

  12. The effect of exercise training on the level of tissue IL-6 and vascular endothelial growth factor in breast cancer bearing mice.

    PubMed

    Shalamzari, Sadegh Amani; Agha-Alinejad, Hamid; Alizadeh, Shaban; Shahbazi, Shirin; Khatib, Zahra Kashani; Kazemi, AbdolReza; Saei, Mohamad Amin; Minayi, Neda

    2014-01-01

    The goal of this study was assessing the prophylactic effect of exercise and its role as an adjuvant therapy on level of cytokines involved in angiogenesis in estrogen-dependent breast cancer. Forty female BALB/c mice were randomly assigned to exercise-tumor-exercise (ETE), exercise-tumor-rest (ETR), rest-tumor-exercise (RTE) and rest-tumor-rest (RTR) groups. After orientation in the environment, two groups of mice performed continuous endurance exercise for 8 weeks, and thereafter estrogen-dependent MC4L2 cancer cells were injected to them. Then, one group of each of trained and non-trained mice performed endurance exercise 5 days per week for 6 weeks. Tumor volume was measured by a digital caliper weekly. Finally, the mice were sacrificed; tumor tissue was removed, immediately frozen and kept in -70°C. Tumor sample was homogenized; levels of cytokines were measured and quantified using ELISA. There was significant reduction in the level of interlukin-6 (IL-6) (P=0.001), Vascular endothelial growth factor (VEGF) (P=0.0001) and tumor volume (P=0.0001) among the groups performing endurance exercise after malignancy (RTE and ETE) in comparison with groups not performing endurance exercise (ETR and RTR), and these results were in agreement with tumor growth rate. Exercise can cause reduction in levels of pro-inflammatory cytokines in tumor tissue. Decreased IL-6 production could reduce the generation of VEGF, resulting in reduced intra-tumor angiogenesis. Due to reduction of the level of these cytokines in groups doing exercise before and after malignancy, exercise is presumed to be an adjuvant therapy in estrogen-receptor dependent tumors in addition to its effective prophylactic role.

  13. Blood kinetics, tissue distribution, and radioimaging of anti-common chronic lymphatic leukemia antigen (cCLLa) monoclonal antibody CLL2 in mice transplanted with cCLLa-bearing human leukemia cells

    SciTech Connect

    Faguet, G.B.; Agee, J.F.; DiPiro, J.T. )

    1990-05-01

    The blood kinetics and biodistribution of anti-common chronic lymphatic leukemia antigen (cCLLa) monoclonal antibody (MoAb) CLL2 were assessed in mice bearing cCLLa+ tumors. The cCLLa is a 69-Kd glycoprotein antigen expressed selectively by malignant B cells in human CLL, hairy cell leukemia (HCL), and prolymphocytic leukemia. Immunoreactive 125I-CLL2 (5 micrograms/mouse, specific activity 4.3 microCi/micrograms) was injected intravenously in mice bearing HCL-derived EH xenografts, and blood kinetics and biodistribution were ascertained up to 16 days postinjection. Radioimages were also obtained up to 72 hours after injecting 10 micrograms/mouse (specific activity 50.1 microCi/micrograms) of 125I-CLL2. Distinct 125I-CLL2 blood kinetics were observed in EH engrafted compared with tumor-free mice including: a longer 125I-CLL2 T 1/2 (153 hours v 72 hours), and a considerably greater blood clearance (173 mg/h v 54.7 mg/h) with biexponential rather than monoexponential configuration; and a greater volume of antibody distribution (31,483 mg v 5,729 mg). These data suggest more rapid tissue uptake by grafted tumours. Preferential 125I-CLL2 uptake by EH tumours relative to normal tissues was observed beginning 24 hours postinjection (mean ratio, 4.2) with average peak tumor 125I-CLL2 levels of 428.7 pg/mg. 125I-CLL2 uptake selectivity by EH tumor cells was also supported by: (1) negligible 125I-CLL2 uptake by cCLLa- Molt-4 xenografts (average 29.1 pg/mg 24 hours postinjection); (2) background uptake of cCLLa-irrelevant MoAb 131I-LEU1 by CD5- EH xenografts (average 31.4 pg/mg 48 hours postinjection); and (3) by scintigraphy. The EH xenograft mouse model might be useful to ascertain preclinically the anti-tumor effect of anti-cCLLa MoAbs and of their conjugated derivatives.

  14. Non invasive imaging assessment of the biodistribution of GSK2849330, an ADCC and CDC optimized anti HER3 mAb, and its role in tumor macrophage recruitment in human tumor-bearing mice.

    PubMed

    Alsaid, Hasan; Skedzielewski, Tinamarie; Rambo, Mary V; Hunsinger, Kristen; Hoang, Bao; Fieles, William; Long, Edward R; Tunstead, James; Vugts, Danielle J; Cleveland, Matthew; Clarke, Neil; Matheny, Christopher; Jucker, Beat M

    2017-01-01

    The purpose of this work was to use various molecular imaging techniques to non-invasively assess GSK2849330 (anti HER3 ADCC and CDC enhanced 'AccretaMab' monoclonal antibody) pharmacokinetics and pharmacodynamics in human xenograft tumor-bearing mice. Immuno-PET biodistribution imaging of radiolabeled 89Zr-GSK2849330 was assessed in mice with HER3 negative (MIA-PaCa-2) and positive (CHL-1) human xenograft tumors. Dose dependency of GSK2849330 disposition was assessed using varying doses of unlabeled GSK2849330 co-injected with 89Zr-GSK2849330. In-vivo NIRF optical imaging and ex-vivo confocal microscopy were used to assess the biodistribution of GSK2849330 and the HER3 receptor occupancy in HER3 positive xenograft tumors (BxPC3, and CHL-1). Ferumoxytol (USPIO) contrast-enhanced MRI was used to investigate the effects of GSK2849330 on tumor macrophage content in CHL-1 xenograft bearing mice. Immuno-PET imaging was used to monitor the whole body drug biodistribution and CHL-1 xenograft tumor uptake up to 144 hours post injection of 89Zr-GSK2849330. Both hepatic and tumor uptake were dose dependent and saturable. The optical imaging data in the BxPC3 xenograft tumor confirmed the tumor dose response finding in the Immuno-PET study. Confocal microscopy showed a distinguished cytoplasmic punctate staining pattern within individual CHL-1 cells. GSK2849330 inhibited tumor growth and this was associated with a significant decrease in MRI signal to noise ratio after USPIO injection and with a significant increase in tumor macrophages as confirmed by a quantitative immunohistochemistry analysis. By providing both dose response and time course data from both 89Zr and fluorescently labeled GSK2849330, complementary imaging studies were used to characterize GSK2849330 biodistribution and tumor uptake in vivo. Ferumoxytol-enhanced MRI was used to monitor aspects of the immune system response to GSK2849330. Together these approaches potentially provide clinically translatable

  15. Non-extended cryoablation could be a new strategy in lung cancer management: An experiment on green fluorescent protein-labeled Lewis lung cancer-bearing mice.

    PubMed

    Zhou, Tian; Chen, Yujia; Li, Linyi; Qi, Hui; Shi, Jinping; Lu, Chongyi; Jiang, Sida; Geng, Tan; Yang, Meng; Li, Quanwang; Hu, Kaiwen

    2015-08-01

    Modern cryoablation has been performed in solid tumor management for more than two decades. Following the surgical spirits, it seems natural to pursue radical procedures in clinical practice, which results in unnecessary adverse effects. The attempt to use non-extended procedure made some marked achievements in practice but was criticized severely, because it was supposed to induce residual tumors, which would trigger the rapid development of cancer. Oncologists favored this procedure, however, claiming that non-extended cryoablation let lung cancer patients have higher quality of lives and longer survivals, in light of clinical observations. Therefore, this study was conducted trying to solve this controversy. In this study, fifty female C57BL/6J mice were grafted green fluorescent protein (GFP)-labeled Lewis lung cancer and randomized into two groups. The bidirectional diameters and fluorescence intensity of tumors, and the body weight of mice were recorded. Two weeks after the intervention, tumor volumes increased 20.95% in the cryoablation group, significantly different from that in the control group; the fluorescence intensity decreased 49.85% in the cryoablation group but increased 125.07% in the control group. Lung metastases could be observed in only 20% of mice in the cryosurgery group, contrasted to 64% in the control group. The non-extended lung cancer cryoablation does induce marginal tumor residuals, but will not trigger rapid tumor development. Inversely, the residual tumor cells are severely struck and the metastases are suppressed after the intervention. It could be a new strategy in lung cancer management, even for patients not in early stage.

  16. Fluid lubricated bearing construction

    DOEpatents

    Dunning, John R.; Boorse, Henry A.; Boeker, Gilbert F.

    1976-01-01

    1. A fluid lubricated thrust bearing assembly comprising, in combination, a first bearing member having a plain bearing surface, a second bearing member having a bearing surface confronting the bearing surface of said first bearing member and provided with at least one spiral groove extending inwardly from the periphery of said second bearing member, one of said bearing members having an axial fluid-tight well, a source of fluid lubricant adjacent to the periphery of said second bearing member, and means for relatively rotating said bearing members to cause said lubricant to be drawn through said groove and to flow between said bearing surfaces, whereby a sufficient pressure is built up between said bearing surfaces and in said well to tend to separate said bearing surfaces.

  17. Targeting, bio distributive and tumor growth inhibiting characterization of anti-HER2 affibody coupling to liposomal doxorubicin using BALB/c mice bearing TUBO tumors.

    PubMed

    Akhtari, Javad; Rezayat, Seyed Mahdi; Teymouri, Manouchehr; Alavizadeh, Seyedeh Hoda; Gheybi, Fatemeh; Badiee, Ali; Jaafari, Mahmoud Reza

    2016-05-30

    Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20-30% of breast cancer tumors. In the current investigation, we exploited such a feature and utilized an anti-HER2 affibody (ZHER2:477) in combination with a pegylated liposomal doxorubicin (PLD) for concurrent passive and active targeting of HER2 overexpressing TUBO tumor, using BALB/c mice. It was determined that the affibody coupled liposomes (affisomes) was capable of increasing doxorubicin (Dox) delivery to HER2+ cells (SK-BR-3 and TUBO cells), while transferring drug similarly as low as naïve PLD to HER2- MDA-MB-231 cells. This also resulted in selectively enhance cytotoxicity. The veracity of targeting was further assessed utilizing DiD lipophilic tracer model liposomes via competition assay. An approximated 10 ligand/liposome integration caused Dox delivery at 50% of maximal delivery capacity (Kd). Such integration did not alter Dox release in vitro, while it affected the serum clearance profile. Affibody integration to PLD increased drug concentration in tumor and led to significantly further augmentation of drug in liver and spleen compared to those of PLD. Overall, such differences led to prolonging the mice life spans as compared to PLD. Copyright © 2016. Published by Elsevier B.V.

  18. Evaluation of Novel 64Cu-Labeled Theranostic Gadolinium-Based Nanoprobes in HepG2 Tumor-Bearing Nude Mice

    NASA Astrophysics Data System (ADS)

    Hu, Pengcheng; Cheng, Dengfeng; Huang, Tao; Banizs, Anna B.; Xiao, Jie; Liu, Guobing; Chen, Quan; Wang, Yuenan; He, Jiang; Shi, Hongcheng

    2017-09-01

    Radiation therapy of liver cancer is limited by low tolerance of the liver to radiation. Radiosensitizers can effectively reduce the required radiation dose. AGuIX nanoparticles are small, multifunctional gadolinium-based nanoparticles that can carry radioisotopes or fluorescent markers for single-photon emission computed tomography (SPECT), positron emission tomography (PET), fluorescence imaging, and even multimodality imaging. In addition, due to the high atomic number of gadolinium, it can also serve as a tumor radiation sensitizer. It is critical to define the biodistribution and pharmacokinetics of these gadolinium-based nanoparticles to quantitate the magnitude and duration of their retention within the tumor microenvironment during radiotherapy. Therefore, in this study, we successfully labeled AGuIX with 64Cu through the convenient built-in chelator. The biodistribution studies indicated that the radiotracer 64Cu-AGuIX accumulates to high levels in the HepG2 xenograft of nude mice, suggesting that it would be a potential theranostic nanoprobe for image-guided radiotherapy in HCC. We also used a transmission electron microscope to confirm AGuIX uptake in the HepG2 cells. In radiation therapy studies, a decrease in 18F-FDG uptake was observed in the xenografts of the nude mice irradiated with AGuIX, which was injected 1 h before. These results provide proof-of-concept that AGuIX can be used as a theranostic radiosensitizer for PET imaging to guide radiotherapy for liver cancer.

  19. Evaluation of Novel (64)Cu-Labeled Theranostic Gadolinium-Based Nanoprobes in HepG2 Tumor-Bearing Nude Mice.

    PubMed

    Hu, Pengcheng; Cheng, Dengfeng; Huang, Tao; Banizs, Anna B; Xiao, Jie; Liu, Guobing; Chen, Quan; Wang, Yuenan; He, Jiang; Shi, Hongcheng

    2017-09-06

    Radiation therapy of liver cancer is limited by low tolerance of the liver to radiation. Radiosensitizers can effectively reduce the required radiation dose. AGuIX nanoparticles are small, multifunctional gadolinium-based nanoparticles that can carry radioisotopes or fluorescent markers for single-photon emission computed tomography (SPECT), positron emission tomography (PET), fluorescence imaging, and even multimodality imaging. In addition, due to the high atomic number of gadolinium, it can also serve as a tumor radiation sensitizer. It is critical to define the biodistribution and pharmacokinetics of these gadolinium-based nanoparticles to quantitate the magnitude and duration of their retention within the tumor microenvironment during radiotherapy. Therefore, in this study, we successfully labeled AGuIX with (64)Cu through the convenient built-in chelator. The biodistribution studies indicated that the radiotracer (64)Cu-AGuIX accumulates to high levels in the HepG2 xenograft of nude mice, suggesting that it would be a potential theranostic nanoprobe for image-guided radiotherapy in HCC. We also used a transmission electron microscope to confirm AGuIX uptake in the HepG2 cells. In radiation therapy studies, a decrease in (18)F-FDG uptake was observed in the xenografts of the nude mice irradiated with AGuIX, which was injected 1 h before. These results provide proof-of-concept that AGuIX can be used as a theranostic radiosensitizer for PET imaging to guide radiotherapy for liver cancer.

  20. Donor-Specific Regulatory T Cells Acquired from Tolerant Mice Bearing Cardiac Allograft Promote Mixed Chimerism and Prolong Intestinal Allograft Survival

    PubMed Central

    Shen, Xiao-Fei; Jiang, Jin-Peng; Yang, Jian-Jun; Wang, Wei-Zhong; Guan, Wen-Xian; Du, Jun-Feng

    2016-01-01

    The induction of donor-specific transplant tolerance has always been a central problem for small bowel transplantation (SBT), which is thought to be the best therapy for end-stage bowel failure. With the development of new tolerance-inducing strategies, mixed chimerism induced by co-stimulation blockade has become most potent for tolerance of allografts, such as skin, kidney, and heart. However, a lack of clinically available co-stimulation blockers has hindered efficient application in humans. Furthermore, unlike those for other types of solid organ transplantation, strategies to induce robust mixed chimerism for intestinal allografts have not been fully developed. To improve current mixed chimerism induction protocols for future clinical application, we developed a new protocol using donor-specific regulatory T (Treg) cells from mice with heart allograft tolerance, immunosuppressive drugs which could be used clinically and low doses of irradiation. Our results demonstrated that donor-specific Treg cells acquired from tolerant mice after in vitro expansion generate stable chimerism and lead to acceptance of intestinal allograft. Increased intragraft Treg cells and clonal deletion contribute to the development of SBT tolerance. PMID:27909438

  1. Dose estimation in B16 tumour bearing mice for future irradiation in the thermal column of the TRIGA reactor after B/Gd/LDL adduct infusion.

    PubMed

    Protti, N; Ballarini, F; Bortolussi, S; Bruschi, P; Stella, S; Geninatti, S; Alberti, D; Aime, S; Altieri, S

    2011-12-01

    To test the efficacy of a new (10)B-vector compound, the B/Gd/LDL adduct synthesised at Torino University, in vivo irradiations of murine tumours are in progress at the TRIGA Mark II reactor of the Pavia University. A localised B16 melanoma tumour is generated in C57BL/6 mice and subsequently infused with the adduct. During the irradiation, the mouse will be put in a shield to protect the whole body except the tumour in the back-neck area. To optimise the treatment set-up, MCNP simulations were performed. A very simplified mouse model was built using MCNP geometry capabilities, as well as the geometry of the shield made of 99% (10)B enriched boric acid. A hole in the shield is foreseen in correspondence of the back-neck region. Many configurations of the shield were tested in terms of neutron flux, dose distribution and mean induced activity in the tumour region and in the radiosensitive organs of the mouse. In the final set-up, up to five mice can be treated simultaneously in the reactor thermal column and the neutron fluence in the tumour region for 10 min of irradiation is of about 5×10(12) cm(-2).

  2. In vivo evidences of nanosecond pulsed electric fields for melanoma malignancy treatment on tumor-bearing BALB/c nude mice.

    PubMed

    Guo, F; Yao, C; Li, C; Mi, Y; Peng, Q; Tang, J

    2014-08-01

    In order to get in vivo evidences of nanosecond pulsed electric fields (nsPEF) for skin tumor treatment, tumor models in 10 female BALB/c nude mice were established by inoculating them with human melanoma cells A375. These mice were randomly divided into treated group (exposed to nsPEF with intensity of 20 kV/cm and duration of 300 ns) and control group equally. Five days post-nsPEF treatment, tumor growth in the treated group was effectively inhibited (P < 0.01 compared with that in control group), typical apoptotic characteristics (DNA damage and fragmentation) were observed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and significant increases in Bax and decreases in Bcl-2, micro-vessel density (MVD), vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) were observed by immunohistochemistry (P < 0.01). These experimental results indicate that in vivo tumor growth can be effectively inhibited by nsPEF, which activate two targets, apoptosis initiation and angiogenesis inhibition.

  3. INFLUENCE OF SURGICAL TECHNIQUE IN THE PERITONEAL CARCINOMATOSIS SURGICAL WOUND IMPLANT: EXPERIMENTAL MODEL IN MICE

    PubMed Central

    ROSA, Roberto Maranhão; CAIADO, Rafael Coelho; REIS, Paulo Roberto de Melo; LACERDA, Elisângela de Paula Silveira; SUGITA, Denis Masashi; MRUÉ, Fátima

    2015-01-01

    Background The number of malignancies increased alarmingly. Surgery constitutes one of the most efficient therapeutic modalities for the treatment of solid tumors. The neoplastic implant in surgical wound is a complication whose percentage of occurrence reported in the literature is variable, but sets with high morbidity and therapeutic difficulties. Protecting the wound is one of the recommended principles of oncologic surgery. Aim To evaluate the influence of wound protection in the development of tumor implantation. Methods Sarcoma 180 tumor cells were used, with intraperitoneal inoculation in Swiss mice. After the establishment of neoplastic ascites, animals were randomized into two groups of 10, each group consisting of five males and five females. In both groups, laparotomy and manipulation of intra-abdominal organs was performed. In a group laparotomy was performed using the protection of the abdominal wound and the other group without it. On the 9th postoperative day macroscopic evaluation of the operative scar was performed, which was later removed for microscopic evaluation. Results There was microscopic infiltration of tumor cells in the wound of all animals. However, the group that held the protection, infiltration was less intense when compared to the group without it. The infiltration was also more severe in females than in males of the same group. Conclusion Tumor infiltration into the wound was more intense in the group in which the protection of the surgical site was not performed, and in females when compared to males of the same group. PMID:25861061

  4. In vivo assessment of toxicity and pharmacokinetics of methylglyoxal. Augmentation of the curative effect of methylglyoxal on cancer-bearing mice by ascorbic acid and creatine.

    PubMed

    Ghosh, Manju; Talukdar, Dipa; Ghosh, Swapna; Bhattacharyya, Nivedita; Ray, Manju; Ray, Subhankar

    2006-04-01

    Previous in vivo studies from several laboratories had shown remarkable curative effect of methylglyoxal on cancer-bearing animals. In contrast, most of the recent in vitro studies have assigned a toxic role for methylglyoxal. The present study was initiated with the objective to resolve whether methylglyoxal is truly toxic in vivo and to reassess its therapeutic potential. Four species of animals, both rodent and non-rodent, were treated with different doses of methylglyoxal through oral, subcutaneous and intravenous routes. Acute (treatment for only 1 day) toxicity tests had been done with mouse and rat. These animals received 2, 1 and 0.3 g of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. Chronic (treatment for around a month) toxicity test had been done with mouse, rat, rabbit and dog. Mouse, rat and dog received 1, 0.3 and 0.1 g of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. Rabbit received 0.55, 0.3 and 0.1 g of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. It had been observed that methylglyoxal had no deleterious effect on the physical and behavioral pattern of the treated animals. Fertility and teratogenecity studies were done with rats that were subjected to chronic toxicity tests. It had been observed that these animals produced healthy litters indicating no damage of the reproductive systems as well as no deleterious effect on the offspring. Studies on several biochemical and hematological parameters of methylglyoxal-treated rats and dogs and histological studies of several organs of methylglyoxal-treated mouse were performed. These studies indicated that methylglyoxal had no apparent deleterious effect on some vital organs of these animals. A detailed pharmacokinetic study was done with mouse after oral administration of methylglyoxal. The effect of methylglyoxal alone and in

  5. 177 Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice

    SciTech Connect

    Choy, Cindy J.; Ling, Xiaoxi; Geruntho, Jonathan J.; Beyer, Sophia K.; Latoche, Joseph D.; Langton-Webster, Beatrice; Anderson, Carolyn J.; Berkman, Clifford E.

    2017-01-01

    Prostate-specific membrane antigen (PSMA) continues to be an active biomarker for small-molecule PSMA-targeted imaging and therapeutic agents for prostate cancer and various non-prostatic tumors that are characterized by PSMA expression on their neovasculature. One of the challenges for small-molecule PSMA inhibitors with respect to delivering therapeutic payloads is their rapid renal clearance. In order to overcome this pharmacokinetic challenge, we outfitted a 177Lu-labeled phosphoramidate-based PSMA inhibitor (CTT1298) with an albumin-binding motif (CTT1403) and compared its in vivo performance with that of an analogous compound lacking the albumin-binding motif (CTT1401). The radiolabeling of CTT1401 and CTT1403 was achieved using click chemistry to connect 177Lu-DOTA-N3 to the dibenzocyclooctyne (DBCO)-bearing CTT1298 inhibitor cores. A direct comparison in vitro and in vivo performance was made for CTT1401 and CTT1403; the specificity and efficacy by means of cellular uptake and internalization, biodistribution, and therapeutic efficacy were determined for both compounds. While both compounds displayed excellent uptake and rapid internalization in PSMA+ PC3-PIP cells, the albumin binding moiety in CTT1403 conferred clear advantages to the PSMA-inhibitor scaffold including increased circulating half-life and prostate tumor uptake that continued to increase up to 168 h post-injection. This increased tumor uptake translated into superior therapeutic efficacy of CTT1403 in PSMA+ PC3-PIP human xenograft tumors.

  6. 177 Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice

    DOE PAGES

    Choy, Cindy J.; Ling, Xiaoxi; Geruntho, Jonathan J.; ...

    2017-04-27

    Prostate-specific membrane antigen (PSMA) continues to be an active biomarker for small-molecule PSMA-targeted imaging and therapeutic agents for prostate cancer and various non-prostatic tumors that are characterized by PSMA expression on their neovasculature. One of the challenges for small-molecule PSMA inhibitors with respect to delivering therapeutic payloads is their rapid renal clearance. In order to overcome this pharmacokinetic challenge, we outfitted a 177Lu-labeled phosphoramidate-based PSMA inhibitor (CTT1298) with an albumin-binding motif (CTT1403) and compared its in vivo performance with that of an analogous compound lacking the albumin-binding motif (CTT1401). The radiolabeling of CTT1401 and CTT1403 was achieved using click chemistrymore » to connect 177Lu-DOTA-N3 to the dibenzocyclooctyne (DBCO)-bearing CTT1298 inhibitor cores. A direct comparison in vitro and in vivo performance was made for CTT1401 and CTT1403; the specificity and efficacy by means of cellular uptake and internalization, biodistribution, and therapeutic efficacy were determined for both compounds. And while both compounds displayed excellent uptake and rapid internalization in PSMA+ PC3-PIP cells, the albumin binding moiety in CTT1403 conferred clear advantages to the PSMA-inhibitor scaffold including increased circulating half-life and prostate tumor uptake that continued to increase up to 168 h post-injection. This then increased tumor uptake translated into superior therapeutic efficacy of CTT1403 in PSMA+ PC3-PIP human xenograft tumors.« less

  7. Pharmacokinetics, Brain Delivery, and Efficacy in Brain Tumor-Bearing Mice of Glutathione Pegylated Liposomal Doxorubicin (2B3-101)

    PubMed Central

    Gaillard, Pieter J.; Appeldoorn, Chantal C. M.; Dorland, Rick; van Kregten, Joan; Manca, Francesca; Vugts, Danielle J.; Windhorst, Bert; van Dongen, Guus A. M. S.; de Vries, Helga E.; Maussang, David; van Tellingen, Olaf

    2014-01-01

    Brain cancer is a devastating disease affecting many people worldwide. Effective treatment with chemotherapeutics is limited due to the presence of the blood-brain barrier (BBB) that tightly regulates the diffusion of endogenous molecules but also xenobiotics. Glutathione pegylated liposomal doxorubicin (2B3-101) is being developed as a new treatment option for patients with brain cancer. It is based on already marketed pegylated liposomal doxorubicin (Doxil®/Caelyx®), with an additional glutathione coating that safely enhances drug delivery across the BBB. Uptake of 2B3-101 by human brain capillary endothelial cells in vitro was time-, concentration- and temperature-dependent, while pegylated liposomal doxorubicin mainly remained bound to the cells. In vivo, 2B3-101 and pegylated liposomal doxorubicin had a comparable plasma exposure in mice, yet brain retention 4 days after administration was higher for 2B3-101. 2B3-101 was overall well tolerated by athymic FVB mice with experimental human glioblastoma (luciferase transfected U87MG). In 2 independent experiments a strong inhibition of brain tumor growth was observed for 2B3-101 as measured by bioluminescence intensity. The effect of weekly administration of 5 mg/kg 2B3-101 was more pronounced compared to pegylated liposomal doxorubicin (p<0.05) and saline (p<0.01). Two out of 9 animals receiving 2B3-101 showed a complete tumor regression. Twice-weekly injections of 5 mg/kg 2B3-101 again had a significant effect in inhibiting brain tumor growth (p<0.001) compared to pegylated liposomal doxorubicin and saline, and a complete regression was observed in 1 animal treated with 2B3-101. In addition, twice-weekly dosing of 2B3-101 significantly increased the median survival time by 38.5% (p<0.001) and 16.1% (p<0.05) compared to saline and pegylated liposomal doxorubicin, respectively. Overall, these data demonstrate that glutathione pegylated liposomal doxorubicin enhances the effective delivery of doxorubicin to brain

  8. Apigenin inhibits COX-2, PGE2, and EP1 and also initiates terminal differentiation in the epidermis of tumor bearing mice.

    PubMed

    Kiraly, Alex J; Soliman, Eman; Jenkins, Audrey; Van Dross, Rukiyah T

    2016-01-01

    Non-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States. NMSC overexpresses cyclooxygenase-2 (COX-2). COX-2 synthesizes prostaglandins such as PGE2 which promote proliferation and tumorigenesis by engaging G-protein-coupled prostaglandin E receptors (EP). Apigenin is a bioflavonoid that blocks mouse skin tumorigenesis induced by the chemical carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the effect of apigenin on the COX-2 pathway has not been examined in the DMBA/TPA skin tumor model. In the present study, apigenin decreased tumor multiplicity and incidence in DMBA/TPA-treated SKH-1 mice. Analysis of the non-tumor epidermis revealed that apigenin reduced COX-2, PGE2, EP1, and EP2 synthesis and also increased terminal differentiation. In contrast, apigenin did not inhibit the COX-2 pathway or promote terminal differentiation in the tumors. Since fewer tumors developed in apigenin-treated animals which contained reduced epidermal COX-2 levels, our data suggest that apigenin may avert skin tumor development by blocking COX-2.

  9. Z-360 Suppresses Tumor Growth in MIA PaCa-2-bearing Mice via Inhibition of Gastrin-induced Anti-Apoptotic Effects.

    PubMed

    Shiomi, Yoshihiro; Yoshimura, Makoto; Kuki, Kazumasa; Hori, Yuko; Tanaka, Takao

    2017-08-01

    The aim of the study was to evaluate the anti-tumor mechanism of Z-360, a gastrin/cholecystokinin-2 receptor (CCK2R) antagonist, in MIA PaCa-2 cells and in a subcutaneous xenograft mice model. The anti-tumor effects of Z-360 and/or gemcitabine were monitored using a MIA PaCa-2 xenograft model. The effect of Z-360 on apoptosis in the model was examined by TUNEL staining and real-time PCR analysis and the effect in MIA PaCa-2 cells stably expressing human CCK2R was also evaluated by caspase-3/7 activity. In this xenograft model, Z-360 significantly reduced the tumor weight, increased TUNEL-positive cells and suppressed the expression of anti-apoptosis factors such as survivin, XIAP and Mcl-1, and these effects of Z-360 combined with gemcitabine were more effective. Furthermore, gastrin-17 and gastrin-34 inhibited apoptosis in vitro and Z-360 dose-dependently abrogated this effect. These results suggest that Z-360 exerts an anti-tumor effect through a reduction in anti-apoptosis factors by blocking CCK2R. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  10. Pharmacokinetics in melanoma-bearing mice of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a candidate compound for boron neutron capture therapy.

    PubMed

    Verrijk, R; Smolders, I J; Huiskamp, R; Gavin, P R; Philipp, K H; Begg, A C

    1994-04-01

    Blood pharmacokinetics and tissue distribution of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a boron carrier with postulated melanin-seeking properties for boron neutron capture therapy, were determined in C57/BL mice with subcutaneous pigmented or non-pigmented B16 melanomas. Borocaptate sodium (BSH) was used as a boron compound without melanin-seeking properties in a comparative biodistribution study in the same animal tumour models. Administration of single doses showed that BPTU was retained better in the pigmented B16 tumour than in the non-pigmented variant. BPTU was found in large concentrations in kidney and liver. Brain boron was approximately 10-fold lower than tumour boron. On a molar basis, BPTU demonstrated higher affinity for B16 tumours than BSH. Owing to solubility limits, tumour boron concentrations in this mouse study were too low for effective application of BNCT. However, the high tumour-to-blood and tumour-to-normal tissues ratios indicate that, with appropriate formulation, BPTU could be a promising candidate for clinical BNCT.

  11. Application of a liquid chromatography – tandem mass spectrometry (LC/MS/MS) method to the pharmacokinetics of ON01910 in brain tumor-bearing mice

    PubMed Central

    Nuthalapati, Silpa; Guo, Ping; Zhou, Qingyu; Ramana Reddy, M. V.; Reddy, E. Premkumar; Gallo, James M.

    2011-01-01

    ON01910 is a small molecular weight benzyl styryl sulfone currently under investigation as a novel anticancer agent. The purpose of the investigation was to develop a sensitive and reproducible liquid chromatography-tandem mass spectrometry (LC/MS/MS) method to quantitate levels of ON01910 in small amounts of five biological matrices; mouse plasma, feces, urine, normal brain and brain tumor. For all matrices, protein precipitation sample preparation was used that led to linear calibration curves with coefficients of determination greater than 0.99. The lower limit of quantitation (LLOQ) for all matrices was 5 ng/ml except that for mouse urine which was 10 ng/ml. The calibration standard curves were reproducible for all matrices with inter- and intra-day variability in precision and accuracy being less than 15% at all quality control concentrations except for the LLOQ in mouse plasma for which the accuracy was within 17%. The assay was successfully applied to characterize the systemic pharmacokinetics of ON01910 as well as its disposition in brain and brain tumor in mice. ON01910 exhibited a clearance of 3.61 ± 0.85 l/hr/Kg and a half life of 8.66 ± 3.30 hrs at 50 mg/kg dose given I.V. PMID:21880454

  12. α-Tocopherol attenuates NF-κB activation and pro-inflammatory cytokine IL-6 secretion in cancer-bearing mice.

    PubMed

    Sharma, Renu; Vinayak, Manjula

    2011-10-01

    Cancer development and progression are closely associated with inflammation. NF-κB (nuclear factor κB) provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of malignant cells to resist tumour surveillance mechanisms. NF-κB might also regulate tumour angiogenesis and invasiveness and the signalling pathways that mediate its activation provide attractive targets for new chemopreventive and chemotherapeutic approaches. ROS (reactive oxygen species) initiate inflammation by up-regulation of pro-inflammatory cytokines and therefore antioxidants provide a major defence against inflammation. α-Tocopherol is a lipid-soluble antioxidant. In addition to decreasing lipid peroxidation, α-tocopherol may exert intracellular effects. Hence, the aim of this study was to test the effect of α-tocopherol supplementation in cancer prevention via suppression of NF-κB-mediated pro-inflammatory cytokines. α-Tocopherol treatment significantly down-regulates expression, synthesis as well as secretion of pro-inflammatory cytokine IL-6 (interleukin-6) in cancerous mice. It also suppresses NF-κB binding to IL-6 promoter in liver leading to decreased secretion of IL-6 in serum. The regulation of the signalling pathway by α-tocopherol is found apart from its antioxidant capacity to reduce lipid peroxidation. Thus, the present study provides evidence for the hypothesis that besides the powerful free radical scavenging effects, α-tocopherol has genomic effects in down-regulation of pro-inflammatory cytokine and cancer prevention via the NF-κB-dependent pathway.

  13. Comparative plasma and tissue distribution of Sun Pharma's generic doxorubicin HCl liposome injection versus Caelyx(®) (doxorubicin HCl liposome injection) in syngeneic fibrosarcoma-bearing BALB/c mice and Sprague-Dawley rats.

    PubMed

    Burade, Vinod; Bhowmick, Subhas; Maiti, Kuntal; Zalawadia, Rishit; Jain, Deepak; Rajamannar, Thennati

    2017-05-01

    The liposomal formulation of doxorubicin [doxorubicin (DXR) hydrochloride (HCl) liposome injection, Caelyx(®)] alters the tissue distribution of DXR as compared with nonliposomal DXR, resulting in an improved benefit-risk profile. We conducted studies in murine models to compare the plasma and tissue distribution of a proposed generic DXR HCl liposome injection developed by Sun Pharmaceuticals Industries Limited (SPIL DXR HCl liposome injection) with Caelyx(®). The plasma and tissue distributions of the SPIL and reference DXR HCl liposome injections were compared in syngeneic fibrosarcoma-bearing BALB/c mice and Sprague-Dawley rats. Different batches and different lots of the same batch of the reference product were also compared with each other. The SPIL and reference DXR HCl liposome injections exhibited generally comparable plasma and tissue distribution profiles in both models. While minor differences were observed between the two products in some tissues, different batches and lots of the reference product also showed some differences in the distribution of various analytes in some tissues. The ratios of estimated free to encapsulated DXR for plasma and tissue were generally comparable between the SPIL and reference DXR HCl liposome injections in both models, indicating similar extents of absorption into the tissues and similar rates of drug release from liposomes. The plasma and tissue distribution profiles of the SPIL and reference DXR HCl liposome injections were shown to be generally comparable. Inconsistencies between the products observed in some tissues were thought to be due to biological variation.

  14. Isolation of myeloid-derived suppressor cells subsets from spleens of orthotopic liver cancer-bearing mice by fluorescent-activated and magnetic-activated cell sorting: similarities and differences.

    PubMed

    Xu, Yaping; Zhao, Wenxiu; Wu, Duan; Xu, Jianfeng; Lin, Suqiong; Tang, Kai; Yin, Zhenyu; Wang, Xiaomin

    2014-01-01

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that commonly expand during tumor development and that play a critical role in suppression of immune responses. MDSCs can be classified into two groups: Mo-MDSCs and G-MDSCs. These cells differ in their morphology, phenotype, differentiation ability, and immunosuppressive activity, and inhibit immune responses via different mechanisms. Therefore, identifying an effective method for isolating viable Mo-MDSCs and G-MDSCs is important. Here, we demonstrated the differences and similarities between fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) in sorting G-MDSCs and Mo-MDSCs. Both MACS and FACS could obtain G-MDSCs and Mo-MDSCs with high viability and purity. A high yield and purity of G-MDSCs could be obtained both by using FACS and MACS, because G-MDSCs are highly expressed in the spleen of tumor-bearing mice. However, Mo-MDSCs, which comprise a small population among leukocytes, when sorted by MACS, could be obtained at much greater cell number, although with a slightly lower purity, than when sorted by FACS. In conclusion, we recommended using both FACS and MACS for isolating G-MDSCs, and using MACS for isolation of Mo-MDSCs.

  15. Passive magnetic bearing configurations

    DOEpatents

    Post, Richard F [Walnut Creek, CA

    2011-01-25

    A journal bearing provides vertical and radial stability to a rotor of a passive magnetic bearing system when the rotor is not rotating and when it is rotating. In the passive magnetic bearing system, the rotor has a vertical axis of rotation. Without the journal bearing, the rotor is vertically and radially unstable when stationary, and is vertically stable and radially unstable when rotating.

  16. Restoration of bearings

    NASA Technical Reports Server (NTRS)

    Parker, R. J.; Zaretsky, E. V.; Hanau, H.

    1977-01-01

    Process consisting of grinding raceways to oversize but original quality condition and installing new oversize balls or bearings restores wornout ball and roller bearings to original quality, thereby doubling their operating life. Evaluations reveal process results in restoration of 90% of replaced bearings at less than 50% of new-bearing costs.

  17. Rolling-Element Bearings

    NASA Technical Reports Server (NTRS)

    Hamrock, B. J.; Anderson, W. J.

    1983-01-01

    Rolling element bearings are a precision, yet simple, machine element of great utility. A brief history of rolling element bearings is reviewed and the type of rolling element bearings, their geometry and kinematics, as well as the materials they are made from and the manufacturing processes they involve are described. Unloaded and unlubricated rolling element bearings, loaded but unlubricated rolling element bearings and loaded and lubricated rolling element bearings are considered. The recognition and understanding of elastohydrodynamic lubrication covered, represents one of the major development in rolling element bearings.

  18. Cryogenic foil bearing turbopumps

    NASA Technical Reports Server (NTRS)

    Gu, Alston L.

    1993-01-01

    Cryogenic foil bearing turbopumps offer high reliability and low cost. The fundamental cryogenic foil bearing technology has been validated in both liquid hydrogen and liquid oxygen. High load capacity, excellent rotor dynamics, and negligible bearing wear after over 100 starts and stops, and over many hours of testing, were observed in both fluids. An experimental liquid hydrogen foil bearing turbopump was also successfully demonstrated. The results indicate excellent stability, high reliability, wide throttle-ability, low bearing cooling flow, and two-phase bearing operability. A liquid oxygen foil bearing turbopump has been built and is being tested at NASA MSFC.

  19. Introduction to ball bearings

    NASA Technical Reports Server (NTRS)

    Hamrock, B. J.; Dowson, D.

    1981-01-01

    The purpose of a ball bearing is to provide a relative positioning and rotational freedom while transmitting a load between two structures, usually a shaft and a housing. For high rotational speeds (e.g., in gyroscope ball bearings) the purpose can be expanded to include rotational freedom with practically no wear in the bearing. This condition can be achieved by separating the bearing parts with a coherent film of fluid known as an elastohydrodynamic film. This film can be maintained not only when the bearing carries the load on a shaft, but also when the bearing is preloaded to position the shaft to within micro- or nano-inch accuracy and stability. Background information on ball bearings is provided, different types of ball bearings and their geometry and kinematics are defined, bearing materials, manufacturing processes, and separators are discussed. It is assumed, for the purposes of analysis, that the bearing carries no load.

  20. High efficiency magnetic bearings

    NASA Technical Reports Server (NTRS)

    Studer, Philip A.; Jayaraman, Chaitanya P.; Anand, Davinder K.; Kirk, James A.

    1993-01-01

    Research activities concerning high efficiency permanent magnet plus electromagnet (PM/EM) pancake magnetic bearings at the University of Maryland are reported. A description of the construction and working of the magnetic bearing is provided. Next, parameters needed to describe the bearing are explained. Then, methods developed for the design and testing of magnetic bearings are summarized. Finally, a new magnetic bearing which allows active torque control in the off axes directions is discussed.

  1. Immune recognition of tumor cells in mice infected with Pichinde virus.

    PubMed

    Molomut, N; Padnos, M; Papperman, T W; Pevear, D C; Pfau, C J

    1984-01-01

    Pichinde virus (PV), a member of the Arenaviridae family, protects mice from a lethal inoculation with the sarcoma 180 (S180) tumor cell line. Virus replication, which is required for protection, occurs primarily in the spleen and tumor. During the first 4 days, elevated natural killer (NK) cell activity parallels an increase in serum interferon in PV-infected mice. On day 7 after infection virus-specific cytotoxic T cells (CTLs) are found in the mouse. This strong response peaks on day 13 and gradually declines over the next 17 days. The tumor-specific CTL response appears more slowly and is less intense than the virus-specific response, especially in the uninfected mouse. However, CTLs from either type of mouse recognize PV-infected tissue culture S180 target cells better than uninfected ones. Even though the primary tumor-specific immune response appears weak, mice that have cleared both virus and tumor are refractory to a subsequent challenge with S180 cells and rapidly produce tumor-specific CTLs. Thus, our data indicate a number of ways in which virus infection could lead to immune elimination of tumors: (1) Virus-induced interferon stimulates NK-cell activity, which in turn could control tumor load until a specific response is mounted against the S180 cells; (2) early onset of the tumor-specific T-cell response could be brought about by viral-enhanced tumor antigen presentation to the immune system; and (3) the tumor-specific T-cell response could be augmented through a "bystander' phenomenon involving factors associated with T cells responding specifically and vigorously to the virus itself.

  2. Comparative evaluation of synthetic anti-HER2 Affibody molecules site-specifically labelled with 111In using N-terminal DOTA, NOTA and NODAGA chelators in mice bearing prostate cancer xenografts.

    PubMed

    Malmberg, Jennie; Perols, Anna; Varasteh, Zohreh; Altai, Mohamed; Braun, Alexis; Sandström, Mattias; Garske, Ulrike; Tolmachev, Vladimir; Orlova, Anna; Karlström, Amelie Eriksson

    2012-03-01

    In disseminated prostate cancer, expression of human epidermal growth factor receptor type 2 (HER2) is one of the pathways to androgen independence. Radionuclide molecular imaging of HER2 expression in disseminated prostate cancer might identify patients for HER2-targeted therapy. Affibody molecules are small (7 kDa) targeting proteins with high potential as tracers for radionuclide imaging. The goal of this study was to develop an optimal Affibody-based tracer for visualization of HER2 expression in prostate cancer. A synthetic variant of the anti-HER2 Z(HER2:342) Affibody molecule, Z(HER2:S1), was N-terminally conjugated with the chelators DOTA, NOTA and NODAGA. The conjugated proteins were biophysically characterized by electrospray ionization mass spectroscopy (ESI-MS), circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR)-based biosensor analysis. After labelling with (111)In, the biodistribution was assessed in normal mice and the two most promising conjugates were further evaluated for tumour targeting in mice bearing DU-145 prostate cancer xenografts. The HER2-binding equilibrium dissociation constants were 130, 140 and 90 pM for DOTA-Z(HER2:S1), NOTA-Z(HER2:S1) and NODAGA-Z(HER2:S1), respectively. A comparative study of (111)In-labelled DOTA-Z(HER2:S1), NOTA-Z(HER2:S1) and NODAGA-Z(HER2:S1) in normal mice demonstrated a substantial influence of the chelators on the biodistribution properties of the conjugates. (111)In-NODAGA-Z(HER2:S1) had the most rapid clearance from blood and healthy tissues. (111)In-NOTA-Z(HER2:S1) showed high hepatic uptake and was excluded from further evaluation. (111)In-DOTA-Z(HER2:S1) and (111)In-NODAGA-Z(HER2:S1) demonstrated specific uptake in DU-145 prostate cancer xenografts in nude mice. The tumour uptake of (111)In-NODAGA-Z(HER2:S1), 5.6 ± 0.4%ID/g, was significantly lower than the uptake of (111)In-DOTA-Z(HER2:S1), 7.4 ± 0.5%ID/g, presumably because of lower bioavailability due to more rapid clearance

  3. Targeted radiotherapy with [(90)Y]-SMT 487 in mice bearing human nonsmall cell lung tumor xenografts induced to express human somatostatin receptor subtype 2 with an adenoviral vector.

    PubMed

    Rogers, Buck E; Zinn, Kurt R; Lin, Chin-Yu; Chaudhuri, Tandra R; Buchsbaum, Donald J

    2002-02-15

    Novel approaches to increasing the therapeutic efficacy of targeted radiotherapy of cancer are required. One strategy to achieve this goal is to induce high-level expression of a receptor on the surface of tumor cells that can be targeted with a radiolabeled peptide. The objectives of this study were to 1) induce somatostatin receptor (SSTr2) expression in tumor cells using an adenovirus encoding the SSTr2 gene (AdSSTr2), 2) demonstrate tumor localization of [(111)In]-DTPA-D-Phe(1)-octreotide in AdSSTr2-injected tumors, and 3) show therapeutic efficacy with [(90)Y]-DOTA-D-Phe(1)-Tyr(3)-octreotide ([(90)Y]-SMT 487). SSTr2 expression was validated in vitro by the binding and subsequent internalization of [(111)In]-DTPA-D-Phe(1)-octreotide (21.3% per mg of total protein) in A-427 cells infected with AdSSTr2. In vivo imaging confirmed 5- to 10-fold greater uptake 5.5 hours after intravenous administration of [(111)In]-DTPA-D-Phe(1)-octreotide in AdSSTr2-injected tumors relative to control tumors. For therapy studies, mice bearing established subcutaneous A-427 tumors were given two intratumoral injections of AdSSTr2 1 week apart, followed by an intravenous injection of 400 microCi or 500 microCi [(90)Y]-SMT 487 at 2 and 4 days after each adenoviral administration. Control animals either were not treated or were administered 500 microCi [(90)Y]-SMT 487 with no AdSSTr2 injection. These studies showed that untreated animals and animals treated with no virus and 500 microCi [(90)Y]-SMT 487 had median tumor quadrupling times of 16 and 25 days, respectively. Mice administered AdSSTr2 and either 400 microCi or 500 microCi of [(90)Y]-SMT 487 demonstrated significantly longer median tumor quadrupling times of 40 and 44 days, respectively (P < 0.02). These studies are the first to demonstrate in vivo therapeutic efficacy using a radiolabeled peptide targeted to a receptor expressed on the surface of tumor cells following gene transfer. Future studies will focus on the

  4. Site-specific conjugation of chain-terminal chelating polymers to Fab' fragments of anti-CEA mAb: effect of linkage type and polymer size on conjugate biodistribution in nude mice bearing human colorectal carcinoma.

    PubMed

    Slinkin, M A; Curtet, C; Sai-Maurel, C; Gestin, J F; Torchilin, V P; Chatal, J F

    1992-01-01

    Polylysine-based chelating polymers were used for site-specific modification of anti-CEA mAb Fab' fragments via their SH group distal to the antigen-binding site of the antibody molecule. Conjugation was performed using chain-terminal (pyridyldithio)propionate or 4-(p-maleimidophenyl)butyrate moieties to form reducible (S-S) or stable (S-C) bonds between a polymer and Fab' molecule, respectively. One S-S conjugate (S-S9) and two different S-C conjugates (S-C3 and S-C9) were prepared using 3- and 9-kDa molecular weight polymers. No significant loss of immunoreactivity was observed in solid-phase immunoassay, 90-95% of 111In-labeled conjugates being bound to CEA-coated Sepharose beads. After labeling with 111In, the conjugates had a specific radioactivity of 90-120 microCi/micrograms. Injected in nude mice bearing LS 174T carcinoma, the conjugates produced different biodistribution patterns. S-S9 was practically unable to accumulate in tumor and produced very rapid blood clearance of radioactivity and high uptake of radioactivity in liver, spleen, and especially kidneys (225% ID/g 24 h postinjection). S-C3 and S-C9 produced practically the same blood clearances (much slower than that of S-S9) and significant tumor uptake (9-10% ID/g at 24 h). S-C3 gave significantly lower radioactivity in spleen, skin, and bones, and cleared more rapidly from liver and kidneys. Renal uptake for S-C3 and S-C9 was rather high (45% ID/g at 24 h), but much lower than for S-S9.

  5. Investigating Science through Bears (and Teddy Bears).

    ERIC Educational Resources Information Center

    Smith, Karlene Ray

    1997-01-01

    Presents cooperative classroom projects using science as the initial basis for the study of bears. These projects may also involve other areas of the curriculum such as mathematics, art, and music. "Black Bear" activities include following a park ranger to study our National Parks and researching and building a full-sized brown bear…

  6. Investigating Science through Bears (and Teddy Bears).

    ERIC Educational Resources Information Center

    Smith, Karlene Ray

    1997-01-01

    Presents cooperative classroom projects using science as the initial basis for the study of bears. These projects may also involve other areas of the curriculum such as mathematics, art, and music. "Black Bear" activities include following a park ranger to study our National Parks and researching and building a full-sized brown bear…

  7. Experiments with needle bearings

    NASA Technical Reports Server (NTRS)

    Ferretti, Pericle

    1933-01-01

    Experiments and results are presented in testing needle bearings, especially in comparison with roller bearings. Reduction in coefficient of friction is discussed as well as experimental methods and recording devices.

  8. Mechanical spin bearings

    NASA Technical Reports Server (NTRS)

    Vranish, John M. (Inventor)

    1998-01-01

    A spin bearing assembly including, a pair of mutually opposing complementary bearing support members having mutually spaced apart bearing support surfaces which may be, for example, bearing races and a set of spin bearings located therebetween. Each spin bearing includes a pair of end faces, a central rotational axis passing through the end faces, a waist region substantially mid-way between the end faces and having a first thickness dimension, and discrete side surface regions located between the waist region and the end faces and having a second thickness dimension different from the first thickness dimension of the waist region and wherein the side surface regions further have respective curvilinear contact surfaces adapted to provide a plurality of bearing contact points on the bearing support members.

  9. Axial Halbach Magnetic Bearings

    NASA Technical Reports Server (NTRS)

    Eichenberg, Dennis J.; Gallo, Christopher A.; Thompson, William K.

    2008-01-01

    Axial Halbach magnetic bearings have been investigated as part of an effort to develop increasingly reliable noncontact bearings for future high-speed rotary machines that may be used in such applications as aircraft, industrial, and land-vehicle power systems and in some medical and scientific instrumentation systems. Axial Halbach magnetic bearings are passive in the sense that unlike most other magnetic bearings that have been developed in recent years, they effect stable magnetic levitation without need for complex active control.

  10. 1-Way Bearing

    NASA Technical Reports Server (NTRS)

    Vranish, John M. (Inventor)

    2003-01-01

    A one-way bearing is provided having sprags and rolling bearings both disposed between an inner and an outer race. The sprags may comprise three-dimensional sprags for preventing rotation in a non-preferential direction. The roll- ing bearings may comprise thrust rollers for transmitting axial, tilt, and radial loads between the inner and outer races.

  11. Supertough Stainless Bearing Steel

    NASA Technical Reports Server (NTRS)

    Olson, Gregory B.

    1995-01-01

    Composition and processing of supertough stainless bearing steel designed with help of computer-aided thermodynamic modeling. Fracture toughness and hardness of steel exceeds those of other bearing steels like 440C stainless bearing steel. Developed for service in fuel and oxidizer turbopumps on Space Shuttle main engine. Because of strength and toughness, also proves useful in other applications like gears and surgical knives.

  12. Cryogenic Hybrid Magnetic Bearing

    NASA Technical Reports Server (NTRS)

    Meeks, Crawford R.; Dirusso, Eliseo; Brown, Gerald V.

    1994-01-01

    Cryogenic hybrid magnetic bearing is example of class of magnetic bearings in which permanent magnets and electromagnets used to suspend shafts. Electromagnets provide active control of position of shaft. Bearing operates at temperatures from -320 degrees F (-196 degrees C) to 650 degrees F (343 degrees C); designed for possible use in rocket-engine turbopumps, where effects of cryogenic environment and fluid severely limit lubrication of conventional ball bearings. This and similar bearings also suitable for terrestrial rotating machinery; for example, gas-turbine engines, high-vacuum pumps, canned pumps, precise gimbals that suspend sensors, and pumps that handle corrosive or gritty fluids.

  13. Cryogenic Hybrid Magnetic Bearing

    NASA Technical Reports Server (NTRS)

    Meeks, Crawford R.; Dirusso, Eliseo; Brown, Gerald V.

    1994-01-01

    Cryogenic hybrid magnetic bearing is example of class of magnetic bearings in which permanent magnets and electromagnets used to suspend shafts. Electromagnets provide active control of position of shaft. Bearing operates at temperatures from -320 degrees F (-196 degrees C) to 650 degrees F (343 degrees C); designed for possible use in rocket-engine turbopumps, where effects of cryogenic environment and fluid severely limit lubrication of conventional ball bearings. This and similar bearings also suitable for terrestrial rotating machinery; for example, gas-turbine engines, high-vacuum pumps, canned pumps, precise gimbals that suspend sensors, and pumps that handle corrosive or gritty fluids.

  14. TOPICAL REVIEW: Superconducting bearings

    NASA Astrophysics Data System (ADS)

    Hull, John R.

    2000-02-01

    The physics and technology of superconducting bearings is reviewed. Particular attention is given to the use of high-temperature superconductors (HTSs) in rotating bearings. The basic phenomenology of levitational forces is presented, followed by a brief discussion of the theoretical models that can be used for conceptual understanding and calculations. The merits of various HTS bearing designs are presented, and the behaviour of HTS bearings in typical situations is discussed. The article concludes with a brief survey of various proposed applications for HTS bearings.

  15. Bearings: Technology and needs

    NASA Technical Reports Server (NTRS)

    Anderson, W. J.

    1982-01-01

    A brief status report on bearing technology and present and near-term future problems that warrant research support is presented. For rolling element bearings a material with improved fracture toughness, life data in the low Lambda region, a comprehensive failure theory verified by life data and incorporated into dynamic analyses, and an improved corrosion resistant alloy are perceived as important needs. For hydrodynamic bearings better definition of cavitation boundaries and pressure distributions for squeeze film dampers, and geometry optimization for minimum power loss in turbulent film bearings are needed. For gas film bearings, foil bearing geometries that form more nearly optimum film shapes for maximum load capacity, and more effective surface protective coatings for high temperature operation are needed.

  16. Bear Spray Safety Program

    USGS Publications Warehouse

    Blome, C.D.; Kuzniar, R.L.

    2009-01-01

    A bear spray safety program for the U.S. Geological Survey (USGS) was officially initiated by the Firearms Safety Committee to address accident prevention and to promote personnel training in bear spray and its transportation, storage, and use for defense against wild animals. Used as part of a system including firearms, or used alone for those who choose not to carry a firearm, bear spray is recognized as an effective tool that can prevent injury in a wild animal attack.

  17. Bearing restoration by grinding

    NASA Technical Reports Server (NTRS)

    Hanau, H.; Parker, R. J.; Zaretsky, E. V.; Chen, S. M.; Bull, H. L.

    1976-01-01

    A joint program was undertaken by the NASA Lewis Research Center and the Army Aviation Systems Command to restore by grinding those rolling-element bearings which are currently being discarded at aircraft engine and transmission overhaul. Three bearing types were selected from the UH-1 helicopter engine (T-53) and transmission for the pilot program. No bearing failures occurred related to the restoration by grinding process. The risk and cost of a bearing restoration by grinding programs was analyzed. A microeconomic impact analysis was performed.

  18. Linear magnetic bearing

    NASA Technical Reports Server (NTRS)

    Studer, P. A. (Inventor)

    1983-01-01

    A linear magnetic bearing system having electromagnetic vernier flux paths in shunt relation with permanent magnets, so that the vernier flux does not traverse the permanent magnet, is described. Novelty is believed to reside in providing a linear magnetic bearing having electromagnetic flux paths that byp