Regulation of immune responses in SJL and F1 hybrid mice by gamma-irradiated syngeneic lymphoma cells

International Nuclear Information System (INIS)

Katz, I.R.; Nagase, F.; Bell, M.K.; Ponzio, N.M.; Thorbecke, G.J.

1984-01-01

Syngeneic mixed lymphocyte-stimulating la+ lymphomas of SJL mice [reticulum cell sarcoma(s) (RCS)] were found to modulate immune responses in vivo. Simultaneous injection of 2 X 10(7) gamma-irradiated or glutaraldehyde-fixed RCS cells with the antigen sheep red blood cells (SRBC) or 2,4,6-trinitrophenol (TNP)-Ficoll markedly suppressed the subsequent plaque-forming cell response in the spleen. The suppression of the anti-SRBC response was prevented by pretreatment of the mice with cyclophosphamide, whereas the suppression of the anti-TNP-Ficoll response was not affected. RCS injection induced high interferon serum titers within 24 hours after injection, which were not prevented by pretreatment with cyclophosphamide. Injection of gamma-irradiated RCS cells (gamma-RCS) or RCS cell extract 2 days prior to antigen enhanced the anti-SRBC but markedly suppressed the anti- TNP-Ficoll response. Injection of RCS both on day -2 and day 0 enhanced the anti-SRBC response. SJL mice 8-9 months of age showed much less or no suppression when gamma-RCS cells were injected on day 0. Certain F1 hybrids of SJL also showed the gamma-RCS-induced suppression of the anti-SRBC response. Suppression was seen in SJL X BALB.B but not in SJL X BALB/c mice and in SJL X A.TH but not in SJL X A.TL mice, suggesting an I-region effect. F1 hybrids of SJL by B10 background mice showed no significant suppression. Enhancement of the anti-SRBC response by prior injection of gamma-RCS was seen in all F1 hybrid mice examined

Irradiation effects on the tumor and adjacent tissues of brain tumor-bearing mice

International Nuclear Information System (INIS)

Yoshii, Yoshihiko; Maki, Yutaka; Tsunemoto, Hiroshi; Koike, Sachiko; Furukawa, Shigeo.

1979-01-01

C 3 H mice aged 56 - 70 days, weighing 27 - 37 g were used throughout this experiment. A transplantable fibrosarcoma arising spontaneously from C 3 H mice was used. For experiment, 10 4 tumor cells suspended in 0.025 ml of saline solution were injected into the cerebral hemisphere by a 26 gauge needle with a micrometer syringe under nembutal anesthesia. Whole brain irradiation was performed at 7 days after injection of the tumor cells and the radiation doses were 2,000 and 20,000 rads, respectively. The feature of x-rays were 200 kVp, 20 mA, 0.5 mm Cu + 0.5 mm Al filtration and TSD 20 cm. The dose-rate was 340 - 360 R/min. The articles of this study were as follows: a) Determination of LD 50 values for the mice, tumor-bearing in the brain or non-tumor-bearing; and b) Observation of clinical features and gross autopsy findings of the mice following irradiation. The LD 50 values for 2,000 rad irradiation in the tumor-bearing or non-tumor-bearing mice were 10.9 and 11.4 days, respectively. LD 50 values of 3.7 days and 4.3 days were the results for the tumor-bearing and non-tumor-bearing mice irradiated by 20,000 rad, respectively. On the other hand, the LD 50 value for the control group, i.e. non-irradiated mice, was 6.7 days. At postmortem examinations, gastrointestinal bleeding was observed frequently in mice bearing tumor in the brain. Whole brain irradiation is effective to prolong the life of tumor-bearing mice. However, in some instances, deaths have occurred earlier in tumor-bearing mice compared to the control group. (author)

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

Science.gov (United States)

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

Attenuation of primary nonfunction for syngeneic islet graft using sodium 4-phenylbutyrate.

Science.gov (United States)

Fu, S-H; Chen, S-T; Hsu, B R-S

2005-05-01

Sodium 4-phenylbutyrate (4-SPB), an aromatic derivative of butyric acid, was examined to elucidate its effect on islet engraftment in a syngeneic transplantation model using C57BL/6 mice. Diabetic mice that received subrenal implantation of 150 islets on day 0 and oral administration of twice daily 4-SPB (500 mg/kg body weight) on days -2 through 28 displayed a significantly shorter duration of posttransplantation temporary hyperglycemia than diabetic mice that received islets in isotonic sodium chloride solution (NaCl), namely 16 +/- 2 (n = 12) vs 23 +/- 2 days (n = 7; P < .05). Four weeks after transplantation, the insulin content (IC) of grafts from mice treated with islets and 4-SPB was substantially higher than that of grafts from mice treated with islets and NaCl, namely 2.59 +/- 0.37 (n = 8) vs 1.36 +/- 0.36 mug (n = 13; P < .01). The IC of pancreatic remnants showed no significant difference between groups after 2 and 4 weeks of incubation. In vitro studies demonstrated that the net glucose-stimulated insulin secretion (GSIS) and the ratio of net GSIS to the IC of islets cultured with 4-SPB (1 mM) did not differ significantly from those cultured with NaCl. The lipopolysaccharide-stimulated secretions of IL-1beta, IL-10, and IFNgamma from peritoneal exudate monocytes were significantly reduced by co-incubation with 4-SPB (1 mM). In conclusion, our data suggest that daily administration of 4-SPB reduces primary nonfunction and enhances islet engraftment in a syngeneic mouse transplantation model.

Functional evaluation of bone marrow derived DC of tumor bearing mice after immunotherapy

International Nuclear Information System (INIS)

Li Min; Chen Cheng; Gu Tao; Zhou Huan; Zhang Feng; Zhu Yibei; Yu Gehua; Zhang Xueguang; Gu Zongjiang

2006-01-01

Objective: To evaluate the function of bone marrow derived DC of tumor bearing mice after immunotherapy. Methods: Tumor bearing mice were immunized with DC vaccine plus injection of agonistic anti-4-1BB monoclonal antibody. The proliferation of T cells primed with bone marrow derived DC of tumor bearing mice after immunotherapy was tested by 3 H-TdR incorporation. ELISA was employed to determine the levels of IL-2, IFN-γ and IL-10 secreted by DC primed T cells. Results: Bone marrow derived DC of tumor bearing mice was less efficient in stimulating the proliferation of T cells and IL-2 and IFN-γ secretion made by T cells. After immunotherapy, the proliferation of cells and IL-2 and IFN-γ secretionmade by T cells were enhanced. Conclusion: The function of bone marrow derived DC of tumor bearing mice after immunotherapy was ameliorated. (authors)

Cell-mediated immune response to syngeneic uv induced tumors. I. The presence of tumor associated macrophages and their possible role in the in vitro generation of cytotoxic lymphocytes

International Nuclear Information System (INIS)

Woodward, J.G.; Daynes, R.A.

1978-01-01

A primary in vitro sensitization system employing a chromium release assay was utilized to investigate reactivity of murine spleen cells toward syngeneic ultraviolet (uv) light induced fibrosarcomas. These tumors are immunologically rejected in vivo when implanted into normal syngeneic mice but grow progressively when implanted into syngeneic mice that had previously been irradiated with subcarcinogenic levels of uv light. Following appropriate sensitization, spleen cells from both normal and uv irradiated mice are capable of developing cytotoxic lymphocytes in vitro against the uv induced tumors. It was subsequently discovered that in situ uv induced tumors all contained macrophages of host origin that became demonstrable only after enzymatic dissociation of the tumor tissue. These macrophages were immunologically active in vitro as their presence in the stimulator cell population was necessary to achieve an optimum anti-tumor cytotoxic response following in vitro sensitization. Anti-tumor reactivity generated by mixing spleen cells and tumor cells in the absence of tumor derived macrophages could be greatly enhanced by the addition of normal syngeneic peritoneal macrophages. When in vitro anti-tumor reactivity of spleen cells from normal and uv treated mice was compared under these conditions we again found no significant difference in the magnitude of the responses. In addition, the cytotoxic cells generated in response to uv induced tumors appeared to be highly cross reactive with respect to their killing potential

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

International Nuclear Information System (INIS)

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

1981-01-01

Three to 20 hr after an i.p. injection of 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 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 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 64 Cu' was preferentially associated with the protein fraction from liver. Further experiments indicated that, in vivo, 64 Cu was bound to the DNA of ascites cells

Syngeneic transplantation in aplastic anemia

DEFF Research Database (Denmark)

Gerull, Sabine; Stern, Martin; Apperley, Jane

2013-01-01

Aplastic anemia is usually treated with immunosuppression or allogeneic transplant, depending on patient and disease characteristics. Syngeneic transplant offers a rare treatment opportunity with minimal transplant-related mortality, and offers an insight into disease mechanisms. We present here...... a retrospective analysis of all syngeneic transplants for aplastic anemia reported to the European Group for Blood and Marrow Transplantation. Between 1976 and 2009, 88 patients received 113 transplants. Most transplants (n=85) were preceded by a conditioning regimen, 22 of these including anti-thymocyte globulin...

Migration of polypotent hemopoietic stem cells from mouse bone marrow shielded during irradiation after hemorrhage and transfusion of syngeneic erythrocytes

International Nuclear Information System (INIS)

Kozlov, V.A.; Lozovoj, V.P.; Zhuravkin, I.N.

1977-01-01

CBA mice have been X-irradiated with a lethal dose of 850 R. The rate of migration of hemopoietic stem cells has been studied at varying times after hemorrhage and administration of syngeneic erythrocytes. Hemorrhage has been shown to enhance markedly the stem cell migration. Administration of syngeneic erythrocytes decreases considerably the rate of stem cell migaration. It is suggested that the erythropoiesis stimulation is responsible for the increased yield of stem cells from the bone marrow, and that the suppression of erythropoiesis inhibits migration of the stem cells

Liver protein synthesis stays elevated after chemotherapy in tumour-bearing mice.

Science.gov (United States)

Samuels, Sue E; McLaren, Teresa A; Knowles, Andrew L; Stewart, Sarah A; Madelmont, Jean-Claude; Attaix, Didier

2006-07-28

We studied the effect of chemotherapy on liver protein synthesis in mice bearing colon 26 adenocarcinoma (C26). Liver protein mass decreased (-32%; Psynthesis increased (20-35%; Psynthesis. Increased protein synthesis in tumour-bearing mice was primarily mediated by increasing ( approximately 15%; Psynthesis (Cs; mg RNA/g protein). Cystemustine, a nitrosourea chemotherapy that cures C26 with 100% efficacy, rapidly restored liver protein mass; protein synthesis however stayed higher than in healthy mice ( approximately 15%) throughout the initial and later stages of recovery. Chemotherapy had no significant effect on liver protein mass and synthesis in healthy mice. Reduced food intake was not a factor in this model. These data suggest a high priority for liver protein synthesis during cancer cachexia and recovery.

Anti-hepatoma activity and mechanism of corn silk polysaccharides in H22 tumor-bearing mice.

Science.gov (United States)

Yang, Jingyue; Li, Xiao; Xue, Yan; Wang, Nan; Liu, Wenchao

2014-03-01

Corn silk is a well known traditional Chinese herbal medicine and corn silk polysaccharides (CSP) possess multiple pharmacological activities. However, the antitumor effect of CSP on hepatocarcinoma has not been studied. This study aimed to investigate the effects of CSP on tumor growth and immune functions in H22 hepatocarcinoma tumor-bearing mice. The results demonstrated that CSP could not only inhibit the tumor growth, but also extended the survival time of H22 tumor-bearing mice. Besides, CSP administration could increase the body weight, peripheral white blood cells (WBC) count, thymus index and spleen index of H22 tumor-bearing mice. Furthermore, the production of serum cytokines in H22 tumor-bearing mice, such as IL-2, IL-6 and TNF-α, was enhanced by CSP treatment. In addition, no toxicological effects were observed on hepatic function and renal function in CSP-treated mice transplanted H22 tumor cells. In summary, this experimental finding indicated that CSP could elevate the immune functions in H22 tumor-bearing mice to enhance its antitumor activity and CSP seems to be a safe and effective agent for the treatment of hepatocellular carcinoma. Copyright © 2013 Elsevier B.V. All rights reserved.

Effects of low dose radiation on antioxidant enzymes after radiotherapy of tumor-bearing mice

International Nuclear Information System (INIS)

Li Jin; Gao Gang; Wang Qin; Tang Weisheng; Liu Xiaoqiu; Wang Zhiquan

2005-01-01

Objective: To search for effects of low dose radiation on the activities of antioxidant enzymes after radiotherapy of tumor-bearing mice. Methods: Superoxide dismutase (SOD), glutathione-S-transferase (GST) and catalase (CAT) were all determined by chemical colorimetry. Results: Low dose radiation increase the activities of antioxidant enzymes superoxide dismutase (SOD), glutathione-S-transferase (GST) and catalase (CAT) in serum of tumor-bearing mice more markedly than those in the unirradiated controls. The activities of antioxidant enzymes SOD, GST, CAT in serum of tumor-bearing mice (d 5 , d 3 ) irradiated with 5cGy 6h before 2.0 Gy radiation are obviously higher than those of the group (c 3 , c 5 ) given with radiotherapy only. Conclusion: The increase in the activities of antioxidant enzymes in serum of tumor-bearing mice triggered by low dose radiation could partly contribute to the protective mechanism. (authors)

Immuno-enhancement in tumor-bearing mice induced by whole body X-irradiation with 75 mGy

International Nuclear Information System (INIS)

Zhang Ying; Li Xiuyi; Gong Shouliang; Liu Shuzheng

2000-01-01

Objective: In present study the authors observed the effect of whole body irradiation (WBI) with 75 mGy X-rays on the immune function of tumor-bearing mice. Methods: Lewis lung carcinoma cells were implanted into the right thigh muscle of C57BL/6J mice. Ten days after tumor implantation, the tumor-bearing mice were administrated with 75 mGy X-rays WBI, then the mice were sacrificed 18 h after irradiation to detect the immune parameters including the spontaneous proliferation of thymocytes, the proliferative response of splenocytes to ConA and LPS, the cytotoxic activities of specific cytotoxic lymphocytes (CTL) and natural killer cells (NK), as well as lymphokine activated killer cells (LAK) in spleen. The methods the authors used were 3 H-TdR incorporation or release assay. Results: the immune parameters of exposed tumor-bearing mice were much higher than those of sham-irradiated tumor-bearing mice (P<0.01). Conclusion: These results suggested that low dose radiation (LDR) could enhance the immune function of tumor-bearing mice, which might be of practical significance in the prevention and therapy of cancer

Inhibition of tumor growth in syngenetic chimeric mice mediated by a depletion of suppressor T cells

International Nuclear Information System (INIS)

Rotter, V.; Trainin, N.

1975-01-01

Syngeneic chimeric (lethally irradiated and reconstituted with syngeneic bone marrow cells) mice manifested an increased resistance to the development of Lewis lung carcinoma. In addition, these mice had a higher response to polyvinylpyrrolidone and a reduced reactivity to T mitogens. The present findings suggest that syngeneic chimeric mice lack suppressor T cells shown to regulate the development of Lewis lung tumor and the response to polyvinylpyrrolidone. Other components of the T cell population, such as helper cells responding to sheep red blood cells or cells involved in allograft rejection, assayed in these syngeneic chimeras were found unaffected. The fact that chimeric mice are deficient in a certain suppressor T cell population whereas other T activities are normal suggests the existence of different cell lines within the T cell population. (U.S.)

VEGF expression in hepatectomized tumor-bearing mice.

Science.gov (United States)

Andrini, L; Blanco, A Fernandez; Inda, A; García, M; Garcia, A; Errecalde, A

2011-01-01

The experiments were designed in order to study the VEGF expression in intact (group I), hepatectomized (group II), and hepatectomized-tumor bearing mice (group III) throughout one complete circadian time span. Adult male mice were used for the VEGF expression study. The statistical analysis was performed using analysis of variance (ANOVA). The results showed statistical differences in the VEGF expression between groups I and II, but the most significant differences were found between groups I and III. In conclusion, these expressions have a circadian rhythm in all groups; moreover, in group III, this expression was higher and appeared before than in the others.

Liposome-mediated transfer of IL-1 receptor antagonist gene to dispersed islet cells does not prevent recurrence of disease in syngeneically transplanted NOD mice

DEFF Research Database (Denmark)

Saldeen, J; Sandler, S; Bendtzen, K

2000-01-01

transplanted non-obese diabetic (NOD) mice. NOD mouse islet cells were transfected using liposome-mediated gene transfer with a human IL-1ra cDNA construct and transplanted two days later to prediabetic NOD mice. Graft infiltration and destruction were monitored three, five and eight days posttransplantation...... by histology and determination of insulin and cytokine content. IL-1ra gene transfer resulted in transient expression of IL-1ra protein in islet cells in vitro as assessed by ELISA and of IL-1ra mRNA in transplanted islets as revealed by RT-PCR. However, both control and IL-1ra transfected NOD grafts exhibited......IL-1beta is cytotoxic to pancreatic beta-cells in vitro but its role in the vicinity of beta-cells in vivo is unknown. We explored whether liposome-mediated transfer of the interleukin 1 receptor antagonist (IL-1ra) gene to islet cells might prevent recurrence of disease in syngeneically...

Effect of administration of some antitumor extracts on Ehrlich ascites carcinoma-bearing mice

International Nuclear Information System (INIS)

Mesalam, N.M.A.

2013-01-01

Cancer is considered one of the most common causes of morbidity and mortality worldwide. Many researches have been studied on the discovery of natural and synthetic compounds that can be used in the prevention and/or treatment of cancer. Many chemo preventive agents have been associated with antiproliferative and apoptotic effects on cancer cells because of their high antioxidant activity. The present study was undertaken to investigate the antioxidant and antitumor effects of three natural extracts including (propolis, green tea and Chlorella vulgaris) without or with radiation exposure in Ehrlich ascites carcinoma (EAC) - bearing female albino mice. The animals were randomly distributed into three major groups as follows:- Group A (control group).This group consists of 10 mice kept on normal standard rodent diet without any treatment and housed in two cages: mice of the first cage served as control for non tumor-bearing group and the second cage served as control for tumor-bearing group. Group B (Non tumor - bearing group).This group consists of 30 mice and used to study the effect of the vehicle solutions (gum acacia, DMSO), propolis, green tea, Chlorella vulgaris and gamma irradiation on normal mice. Mice of this group were equally distributed into six subgroups receiving gum acacia, DMSO, propolis, green tea and Chlorella vulgaris for two weeks and whole body gamma irradiated. Group C (Tumor- bearing group): This group consists of 160 mice randomly and equally distributed into 8 subgroups: Ehrlich ascites carcinoma(mice were inoculated with 2.5 x 10 6 intra-peretoneally(i.p), Ehrlich ascites carcinoma and 2 Gy irradiated, Ehrlich ascites carcinoma and propolis treated (150 mg/kg b.w), Ehrlich ascites carcinoma, propolis treated and irradiated, Ehrlich ascites carcinoma and green tea treated (150 mg/kg b.w), Ehrlich ascites carcinoma, green tea treated and irradiated, Ehrlich ascites carcinoma and Chlorella vulgaris treated (150 mg/kg b.w) and Ehrlich ascites

Specific inhibition of cytotoxic memory cells produced against uv-induced tumors in uv-irradiation mice

International Nuclear Information System (INIS)

Thorn, R.M.

1978-01-01

Cytotoxic responses of uv-irradiated mice against syngeneic uv-induced tumors were measured by using a 51 Cr-release assay to determine if uv treatment induced a specific reduction of cytotoxic activity. The in vivo and in vitro primary responses against syngeneic tumors and allogeneic cells were unaffected, as was the ''memory'' response (in vivo stimulation, in vitro restimulation) against alloantigens. In contrast, the memory response of uv-treated mice against syngeneic, uv-induced tumors was consistently and significantly depressed. The cytotoxicity generated by tumor cell stimulation in vivo or in vitro was tumor-specific and T cell-dependent. Since the primary response against syngeneic uv-induced tumors produces apparently normal amounts of tumor-specific cytotoxic activity, uv-treated mice may not reject transplanted syngeneic tumors because of too few T effector memory cells. These results imply that, at least in this system, tumor rejection depends mostly on the secondary responses against tumor antigens and that at least one carcinogen can, indirectly, specifically regulate immune responses

Stimulatory effect of low dose radiation on the immune function in tumor-bearing mice

International Nuclear Information System (INIS)

Zhang Ying; Li Xiujuan; Li Xiuyi; Liu Shuzheng

1999-01-01

Objective: The author aims at investigating the effect of whole body irradiation (WBI) with low dose radiation on immune function in tumor-bearing mice. Methods: C57BL/6J mine implanted with Lewis lung carcinoma cells in the right thighs were used as an experimental animal model. WBI with 75 mGy X-rays was given at the 10 th day after implantation and immunological parameters were detected 18 hours after irradiation. The immunological parameters included the spontaneous incorporation of 3 H-TdR into thymocytes, the number of splenocytes, the reaction of splenocytes to ConA and LPS, the splenic production of IL-2, the cytotoxic activities of natural killer (NK) and lymphokine activated killer cells (LAK) as well as specific cytotoxic T lymphocytes (CTL). Results: The immunological parameters of irradiated tumor-bearing mice were significantly increased compared with those of sham-irradiated tumor-bearing mice (P<0.05∼0.01). Conclusion: Low dose radiation could significantly increase the immune function of tumor-bearing mice, and this stimulatory effect may be of some potential significance in tumor therapy

Radioprotection of normal tissues in tumor-bearing mice by troxerutin

International Nuclear Information System (INIS)

Maurya, D.K.; Salvi, V.P.; Krishnan Nair, C.K.

2004-01-01

The flavanoid derivative troxerutin, used clinically for treating venous disorders, protected biomembranes and cellular DNA against the deleterious effects of γ-radiation. The peroxidation of lipids (measured as thiobarbituric acid-reacting substances, or TBARS) in rat liver microsomal and mitochondrial membranes resulting from γ-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 intraperitoneal (ip) one hour prior to 4 Gy whole-body γ-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 γ-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. (author)

Continuous in vivo infusion of interferon-gamma (IFN-gamma) enhances engraftment of syngeneic wild-type cells in Fanca-/- and Fancg-/- mice.

Science.gov (United States)

Si, Yue; Ciccone, Samantha; Yang, Feng-Chun; Yuan, Jin; Zeng, Daisy; Chen, Shi; van de Vrugt, Henri J; Critser, John; Arwert, Fre; Haneline, Laura S; Clapp, D Wade

2006-12-15

Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. However, strategies to enhance the mobilization, transduction, and engraftment of exogenous stem cells are required to optimize efficacy prior to widespread clinical use. Hypersensitivity of Fancc-/- cells to interferon-gamma (IFN-gamma), a nongenotoxic immune-regulatory cytokine, enhances engraftment of syngeneic wild-type (WT) cells in Fancc-/- mice. However, whether this phenotype is of broad relevance in other FA complementation groups is unresolved. Here we show that primitive and mature myeloid progenitors in Fanca-/- and Fancg-/- mice are hypersensitive to IFN-gamma and that in vivo infusion of IFN-gamma at clinically relevant concentrations was sufficient to allow consistent long-term engraftment of isogenic WT repopulating stem cells. Given that FANCA, FANCC, and FANCG complementation groups account for more than 90% of all FA patients, these data provide evidence that IFN-gamma conditioning may be a useful nongenotoxic strategy for myelopreparation in FA patients.

Sex differences in the MB49 syngeneic, murine model of bladder cancer.

Science.gov (United States)

White-Gilbertson, Shai; Davis, Megan; Voelkel-Johnson, Christina; Kasman, Laura M

The MB49 syngeneic, murine model of bladder cancer has been widely used for more than 35 years. In humans, bladder cancer is one third as prevalent in women as in men, with a trend toward lower prevalence in parous compared to nulliparous women. Our objective was to determine if the MB49 bladder cancer model reproduces the sex differences observed in humans, and to determine its sensitivity to testosterone and the pregnancy hormone, human chorionic gonadotropin (hCG). Male and female C57BL/6 mice were implanted with MB49 murine bladder cancer cells, and observed for tumor growth. MB49 dose responses to hCG and dihydrotestosterone were determined in vitro . MB49 tumor growth was significantly greater in male mice than female mice. Pregnancy did not affect MB49 tumor growth in female mice. MB49 cells did not proliferate in response to hCG in vitro and the functional receptor for gonadotropins was absent. Dihydrotestosterone strongly stimulated growth of MB49 cells in vitro . The MB49 murine model of bladder cancer reproduced some aspects of the sex differences observed in humans. Our results suggest that testosterone may stimulate MB49 cell proliferation, which may explain the more rapid MB49 tumor growth observed in male mice.

Immunologic parameters of ultraviolet carcinogenesis

International Nuclear Information System (INIS)

Kripke, M.L.; Fisher, M.S.

1976-01-01

Skin tumors induced in mice by uv light are usually immunologically rejected by normal syngeneic recipients. We evaluated, the immune status of primary hosts against these highly antigenic tumors immediately after surgical removal of the primary tumor. All primary hosts were susceptible to challenge with their autochthonous tumors, though most of these were rejected by untreated control mice. Primary hosts were also susceptible to challenge with isografts of antigenically dissimilar uv-induced neoplasms. The susceptibility of the primary hosts to tumor challenge was probably induced by chronic exposure to uv light, since uv-irradiated non-tumor-bearing mice were also susceptible to challenge with these tumors. Although uv-treated mice were unable to reject these syngeneic tumors, they could reject skin and tumor allografts. Further, uv irradiation did not interfere with the second-set rejection of syngeneic uv-induced tumors in mice that were specifically immunized before uv treatment

Immune responsiveness and incidence of reticulum cell sarcoma in long-term syngeneic radiation chimeras

International Nuclear Information System (INIS)

Adorini, L.; Gorini, G.; Covelli, V.; Ballardin, E.; di Michele, A.; Bassani, B.; Metalli, P.; Doria, G.

1976-01-01

Long-term syngeneic radiation chimeras displayed a very low incidence of reticulum cell sarcoma as compared with control mice. Immune reactivity of these animals was studied in vivo by anti-dinitrophenyl antibody titer and affinity and in vitro by mitotic responsiveness to phytohemagglutinin, concanavalin A and lipopolysaccharide. Antibody titer and affinity as well as the response to T lectins were found to be increased in chimeras. These results were attributed to increased function of mature T2 cells, which could explain the reduced incidence of reticulum cell sarcoma in chimeras

Trehalose Liposomes Suppress the Growth of Tumors on Human Lung Carcinoma-bearing Mice by Induction of Apoptosis In Vivo.

Science.gov (United States)

Ichihara, Hideaki; Kuwabara, Keiji; Matsumoto, Yoko

2017-11-01

Previous evidence demonstrates that trehalose liposomes (DMTreC14) composed of L-α-dimyristoylphosphatidylcholine (DMPC) and α-D-glycopyranosyl-α-D-glucopyranoside monomyristate (TreC14) inhibit proliferation and invasion on lung carcinoma (A549 cells) in vitro. Here, we aimed to investigate suppressive effects of DMTreC14 on the growth of tumor on human lung carcinoma bearing mice. DMTreC14 composed of 30 mol% DMPC and 70 mol% TreC14 were prepared by the sonication method. Anti-tumor activities of DMTreC14 using the subcutaneous and orthotopic graft-bearing mice of A549 cells were investigated in vivo. The remarkable reduction of volume and weight in subcutaneous tumors on subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were obtained. Apoptotic-positive cells in the subcutaneous tumor slice of subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were observed using TUNEL staining. Lung weights on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 were markedly decreased compared to those of the control group. Remarkable decrease in dimensions of tumor area of lung on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 was obtained in histological analysis using the hematoxylin and eosin staining. Remarkably high anti-tumor activities of DMTreC14 for the subcutaneous and orthotopic graft-bearing mice of lung carcinoma accompanied with apoptosis were revealed for the first time in vivo. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Effect of allogenic thymic cells on radioleukaemogenesis in AKR-T1ALD mice

International Nuclear Information System (INIS)

Legrand, E.; Sankar-Mistry, P.; Kressmann, M.C.

1975-01-01

When AKR mice are irradiated with a sub-lethal dose (4 times 175 R), thymic lymphosarcomas (L.S.) occur earlier than in controls. This accelerated leukaemogenesis is not inhibited by syngenic restoration with bone marrows cells (BM). Using the AKR/T1ALD substrain which bears 38 chromosomes with 1 metacentric markers, it has been shown that AKR radio-chimaeras restored by T1ALD BM developed two kinds of L.S.: early (radiation-induced) L.S. originating mainly from host cells surviving irradiation and late L.S. from donor cells. The experiments were to investigate the potential influence of normal allogenic thymic cells, with or without syngenic B.M., on the incidence, latency and origin of LS appearing in irradiated AKR recipients. Adding C3H allogenic thymic cells to syngenic B.M. increases the percentage of early L.S. whose latencies are unchanged. Besides, when C3H thymic cells are injected to irradiated controls without syngenic B.M. cells, L.S. are seen to occur significantly earlier than in just the irradiated animals alone. In radio-chimaeras restored by allogenic thymic cells and syngenic B.M., except in one case, all the L.S. were seen to originate from B.M. cells. The interpretation of these results depends on the possible role of allogenic thymic cells on host cells surviving the irradiation, or the exogeneous B.M. In the first case, allogenic thymocytes could induce a graft versus host reaction increasing the post-irradiation depletion of lymphoid system and hastening thymic endoregeneration which is supposed to be the first step towards leukaemogenesis. The second hypothesis, which seems the most likely, would be that C1H thymic cells could selectively act on host cells surviving irradiation and enhance the differenciation of haemopoietic precursors at the expense of the lymphoid cells [fr

Inhibiting effect of plasma from normal and tumour bearing mice on the mitotic rate of regenerating liver.

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Echave Llanos, J M; Moreno, F R; Badrán, A F

1986-01-01

Plasma from normal mice and from mice bearing the ES2 transplantable malignant tumour was injected intraperitoneally at a dose of 0.01 ml/g body weight in partially hepatectomized mice. Control animals were injected with a solution of sodium citrate in saline. The recipients were killed at the first (14:00 hours/48 h). These times are the time of day and the number of h after partial hepatectomy and second (14:00 hours/72 h) peak times after partial hepatectomy. The number of colchicine metaphases per 1000 nuclei was determined for hepatocytes and litoral cells. A different effect was obtained with plasma from tumour-bearing compared with normal mice. Plasma from both sources when injected 26 h after partial hepatectomy (16:00 hours/26 h) inhibited the mitotic activity of hepatocytes at the next peak of regenerative activity (14:00 hours/48 h). The plasma from tumour-bearing mice also inhibited the peak on the following day (14:00 hours/72 h), whereas plasma from normal mice had no inhibitory effect and, indeed, a compensatory wave was observed at this time. Furthermore, plasma from tumour-bearing mice also showed an inhibitory effect at the first peak (14:00 hours/48 h) when injected at the time of partial hepatectomy (14:00 hours/00 h) or at 22 h before partial hepatectomy (16:00 hours/-22 h) whereas the injection of plasma from normal mice at these times had no inhibitory effect. In the litoral cells the injection of plasma from tumour-bearing mice made 22 h before hepatectomy (16:00 hours/-22 h) led to a stimulation of mitotic activity which was controlled at 14:00 hours/48 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of low dose radiation on tumor-bearing mice

International Nuclear Information System (INIS)

Feng Li; Hou Dianjun; Huang Shanying; Deng Daping; Wang Linchao; Cheng Yufeng

2007-01-01

Objective: To explore the effects of low-dose radiation on tumor-bearing mice and radiotherapy induced by low-dose radiation. Methods: Male Wistar mice were implanted with Walker-256 sarcoma cells in the right armpit. On day 4, the mice were given 75 mGy whole-body X-ray radiation. From the fifth day, tumor volume was measured, allowing for the creation of a graph depicting tumor growth. Lymphocytes activity in mice after whole-body X-ray radiation with LDR was determinned by FCM. Cytokines level were also determined by ELISA. Results: Compared with the radiotherapy group, tumor growth was significantly slower in the mice pre-exposed to low-dose radiation (P<0.05), after 15 days, the average tumor weight in the mice pre- exposed to low-dose radiation was also significantly lower (P<0.05). Lymphocytes activity and the expression of the CK in mice after whole-body y-ray radiation with LDR increased significantly. Conclusions: Low-dose radiation can markedly improve the immune function of the lymphocyte, inhibit the tumor growth, increase the resistant of the high-dose radiotherapy and enhance the effect of radiotherapy. (authors)

Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer.

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Vichaya, Elisabeth G; Vermeer, Daniel W; Christian, Diana L; Molkentine, Jessica M; Mason, Kathy A; Lee, John H; Dantzer, Robert

2017-05-01

Patients with cancer often experience a high symptom burden prior to the start of treatment. As disease- and treatment-related neurotoxicities appear to be additive, targeting disease-related symptoms may attenuate overall symptom burden for cancer patients and improve the tolerability of treatment. It has been hypothesized that disease-related symptoms are a consequence of tumor-induced inflammation. We tested this hypothesis using a syngeneic heterotopic murine model of human papilloma virus (HPV)-related head and neck cancer. This model has the advantage of being mildly aggressive and not causing cachexia or weight loss. We previously showed that this tumor leads to increased IL-6, IL-1β, and TNF-α expression in the liver and increased IL-1β expression in the brain. The current study confirmed these features and demonstrated that the tumor itself exhibits high inflammatory cytokine expression (e.g., IL-6, IL-1β, and TNF-α) compared to healthy tissue. While there is a clear relationship between cytokine levels and behavioral deficits in this model, the behavioral changes are surprisingly mild. Therefore, we sought to confirm the relationship between behavior and inflammation by amplifying the effect using a low dose of lipopolysaccharide (LPS, 0.1mg/kg). In tumor-bearing mice LPS induced deficits in nest building, tail suspension, and locomotor activity approximately 24h after LPS. However, these mice did not display an exacerbation of LPS-induced weight loss, anorexia, or anhedonia. Further, while heightened serum IL-6 was observed there was minimal priming of liver or brain cytokine expression. Next we sought to inhibit tumor-induced burrowing deficits by reducing inflammation using minocycline. Minocycline (∼50mg/kg/day in drinking water) was able to attenuate tumor-induced inflammation and burrowing deficits. These data provide evidence in favor of an inflammatory-like mechanism for the behavioral alterations associated with tumor growth in a syngeneic

Effect of Ganoderma lucidum (G. lucidum) on the Liver of Mice Bearing Ehrlich Solid Tumor (EST) and Exposed to γ-Radiation

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Ibrahim, S.I.; El-Kabany, H.

2013-01-01

The present study was performed to investigate the antitumor and radio sensitizing efficacy of Ganodarma lucidum (G. lucidum) and to evaluate its potential to improve hepatic dysfunction in Ehrlich solid tumor (EST) bearing mice. G. lucidum (100 mg/Kg body weight) was administered orally to EST bearing mice for 15 days before and 15 days after tumor inoculation. Irradiation was carried out the 8th day of tumor inoculation when the diameter of the tumor reached approximately 10 mm. Mice were exposed to fractionated doses of whole body γ-radiation (3x2Gy) at two days interval to attain a total dose of 6 Gy. Mice were divided into 6 groups (15 mice in each group) as follows: normal control, mice treated with G. lucidum for 30 days, EST bearing mice, EST bearing mice exposed to fractionated doses of γ-radiation (2Gy x 3), EST bearing mice treated with G. lucidum for 15 days before and 15 days after tumor inoculation and EST bearing mice received combined treatment radiation and G. lucidum. Five mice from each group were sacrificed, after 18 hr fasting after the last dose of G. lucidum treatment. Blood was collected, liver and tumor were removed for biochemical and histopathological studies. The remaining animals were observed for recording survival percentage and tumor size. In vitro study on Ehrlich Ascites Carcinoma cells showed that the percentage of nonviable cells (NVC%) increase with increasing G. lucidum concentration. The results revealed also that treatment of EST bearing mice with G. lucidum and/or γ- radiation increased the survivability and decrease the tumor size as compared to EST group. The biochemical analysis for EST bearing group recorded an elevation in the activities of lactate dehydrogenase (LDH), asparta amino transferase (AST) and alanine amino transferase (ALT) in the serum. Also, there was an elevation in the concentration of malondialdehyde (MDA), a marker of lipid peroxidation, accompanied by a decrease in superoxide dismutase (SOD

[Autoantibody formation against the antigens of the synaptonemal complex in the syngeneic immunization of male Mus musculus].

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Dadashev, S Ia; Gorach, G G; Kolomiets, O L

1994-01-01

Male mice were immunized with the suspension of synaptonemal complexes (SC) isolated from mouse spermatocytes nuclei. The indirect immunofluorescent analysis showed the active binding of sera obtained from immunized mice to SC of mouse spermatocyte spreads. At early and mid-pachytene, SC can be clearly identified in 19 autosome bivalents and in sex chromosome bivalent. According to the electron microscopic analysis, all structural elements of SC bind antibodies. Metaphase chromosomes were not stained with the immune sera. Specificity of interaction between SC components and antibodies was confirmed in a series of control experiments. Analysis of sera obtained from mice after their syngeneic immunization with isolated SC fraction suggested that certain mouse SC components induce the formation of autoantibodies. This, in turn, suggests that these SC components are meiosis-specific.

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

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Kim Sung-Ho

2009-03-01

Full Text Available Abstract 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 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.

Continuous in vivo infusion of interferon-gamma (IFN-γ) enhances engraftment of syngeneic wild-type cells in Fanca–/– and Fancg–/– mice

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Si, Yue; Ciccone, Samantha; Yang, Feng-Chun; Yuan, Jin; Zeng, Daisy; Chen, Shi; van de Vrugt, Henri J.; Critser, John; Arwert, Fre; Haneline, Laura S.; Clapp, D. Wade

2006-01-01

Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. However, strategies to enhance the mobilization, transduction, and engraftment of exogenous stem cells are required to optimize efficacy prior to widespread clinical use. Hypersensitivity of Fancc–/– cells to interferon-gamma (IFN-γ), a nongenotoxic immune-regulatory cytokine, enhances engraftment of syngeneic wild-type (WT) cells in Fancc–/– mice. However, whether this phenotype is of broad relevance in other FA complementation groups is unresolved. Here we show that primitive and mature myeloid progenitors in Fanca–/– and Fancg–/– mice are hypersensitive to IFN-γ and that in vivo infusion of IFN-γ at clinically relevant concentrations was sufficient to allow consistent long-term engraftment of isogenic WT repopulating stem cells. Given that FANCA, FANCC, and FANCG complementation groups account for more than 90% of all FA patients, these data provide evidence that IFN-γ conditioning may be a useful nongenotoxic strategy for myelopreparation in FA patients. PMID:16946306

Radiosensitizing effects of 9401 on mice bearing H22 hepatoma

International Nuclear Information System (INIS)

Liu Xiaoqiu; Wang Qin; Zhou Zewei; Han Ying; Wang Dezhi; Shen Xiu

2013-01-01

Objective: To investigate the radiosensitizing effects of 9401 on mice bearing H22 hepatoma. Methods: Mouse model bearing H22 hepatoma cells were established. Mice were randomly divided into six groups, the control group,the radiation group and four treatment groups including 9401 at high, medium and low dosages and nicotinamide combined with radiation. After irradiated, the growth of tumor was observed, the time of tumor growth was recorded, the delay time of tumor growth and enhancement factor (EF) were calculated. After 28 days, the mice were killed, the tumors were stripped and inhibition rate was calculated. Results: Groups of 9401 combined with radiation could postpone tumor growth. The difference was statistically significant between 9401 groups at high, medium dosages combined with radiation and nicotinamide combined with radiation group (t=24.7 and 7.5, both P<0.01). Compared with radiation alone group, groups of 9401 combined with radiation had significant radiosensitizing effect. The enhancement factor of 9401 combined with radiation groups at high and medium dosages were 2.13 and 1.73 respectively, they were significant higher than nicotinamide combined with radiation group (t=2.26 and 9.04, both P<0.05). The inhibition rate of 9401 groups at high, medium and low dosages combined with radiation were 64.5%, 50.9% and 42.6% respectively. The inhibition rate of nicotinamide group combined radiation was 53.2%. The inhibition rate of 9401 at high dosage combined with radiation had significant difference with nicotinamide combined radiation (t =2.8, P<0.05). Nicotinamide combined with radiation group, 9401 combined with radiation groups could significant inhibit the growth of tumors compared with radiation alone group (t=5.7, 4.0 and 2.2, all P<0.05). Conclusion: 9401 can inhibit the tumor growth and the inhibition effect increases gradually with the drug dose increasing. It also has radiosensitizing effects on mice bearing H22 hepatoma and present broadly

Changes of natural killer activity following local 60Co irradiation in intracranial tumor-bearing mice

International Nuclear Information System (INIS)

Otsuka, Shin-ichi; Suda, Kinya; Yamashita, Junkoh; Takeuchi, Juji; Handa, Hajime

1982-01-01

Changes of natural killer activity (NK activity) by local 60 Co irradiation in intracranial tumor-bearing mice were studied by the method of 51 Cr release assay. Local irradiation was administered 10 days after intracranial transplantation of 203-Glioma which had been originally induced by 20-methylcholanthrene in C57BL mice. Irradiation suppressed the growth of tumor and prolonged the mean survival time. The 50% survival time of untreated mice was about 2.5 weeks but that of mice treated by a single dose of 1000 rad and 1500 rad of irradiation was about 4.5 weeks and 6.5 weeks respectively. NK activity of spleen cells in these mice was serially examined. NK activity was gradually increased in mice treated by local irradiation, while it was gradually decreased in mice without treatment. On the other hand, NK activity remained unchanged in non-tumor-bearing control mice. Mice treated with 1000 rad and 1500 rad of irradiation showed 44.0% and 47.6% of % specific 51 Cr release respectively 11 days after irradiation while normal mice showed 18.0%. The increased NK activity after local irradiation suggested that local irradiation might have enhanced the immunological defence mechanisms against the tumor in the tumor-bearing hosts. Some characteristics of effector cells in this assay system were examined. The cytotoxicity of spleen cells was removed by the treatment of anti-BAT serum and complement but was not removed by the treatment of anti-Thy-1.2 serum and complement. Since NK activity reflects the immunological resistance to tumors to some extent, it is felt important to clarify the significance of changes of NK activity in patients with brain tumors in relation to various treatments including surgery, radiotherapy, chemotherapy and immunotherapy in the next step. (author)

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

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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 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.

57Co-bleomycin kinetics in normal and tumour-bearing mice after systemic and local administration

International Nuclear Information System (INIS)

Bier, J.; Benders, P.; Bitter, K.; Wenzel, M.

1979-01-01

In tumour-free and tumour-bearing mice the body clearance and organ distribution of 57 Co-BLM was measured at different time intervals after i.v., sc, and it. administration of the drug. No significant difference could be demonstrated in body clearance following different doses and routes of application of labelled BLM in tumour-free and tumour-bearing mice. The organ distribution studies showed higher concentrations following iv. compared to sc. or it of 57 Co-BLM: however, the activity in the ipsilateral injection sites was significantly increased after sc. and it. injection. In tumour-bearing mice the activity in the lymph nodes draining injection site was as high as that seen in the draining lymph modes following iv. injection. However, on the contralateral side, the lymph mode concentration was significantly reduced after it injection. These results indicate on the basis of organ distribution of 57 Co-BLM a rational basis for it treatment of malignant tumours. (orig.) [de

Skin allografts in lethally irradiated animals repopulated with syngeneic hemopoietic cells

International Nuclear Information System (INIS)

Schwadron, R.B.

1983-01-01

Total body irradiation and repopulation with syngeneic hemopoietic cells can be used to induce tolerance to major histocompatibility complex (MHC) mismatched heart and kidney grafts in rats and mice. However, this protocol does not work for MHC mismatched skin grafts in rats or mice. Furthermore, LEW rats that accept WF cardiac allografts after irradiation and repopulation reject subsequent WF skin grafts. Treatment of skin allograft donors with methotrexate prior to grafting onto irradiated and reconstituted mice resulted in doubling of the mean survival time. Analysis of which antigens provoked skin graft rejection by irradiation and reconstituted animals revealed the importance of I region antigens. Cardiac allograft acceptance by irradiated and reconstituted animals is mediated by suppressor cells found in the spleen. Adoptively tolerant LEW rats accepted WF skin grafts in 50% of grafted animals. Analysis of this phenomenon revealed that the adoptive transfer procedure itself was important in achieving skin allograft acceptance by these animals. In general, it seems that the lack of ability of irradiated and reconstituted animals to accept fully MHC disparate skin grafts results from the inability of these animals to suppress lymph node effector cells against I region antigen seen on highly immunogenic allogeneic Langerhans cells in the skin

Immunomodulatory efficacy of ethanol extract of propolis on tumor-bearing mice with disseminated candidiasis.

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Khosravi, A R; Shokri, H; Darvishi, S; Taghavi, M

2014-12-01

This study was aimed at investigating the effect of propolis on immunosurveillance by measuring the levels of serum interleukin (IL)-4, IL-10, IL-17, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in tumor-bearing mice with disseminated candidiasis. The ethanol extract of propolis was selected for this study. Balb/C female mice were infected with Candida albicans (C. albicans) and inoculated with spontaneous mouse mammary tumor (SMMT). The serum levels of tissue inhibitor of metalloproteinase-1(TIMP-1) were assessed by enzyme- linked immunosorbent assay (ELISA). Mice were treated daily with propolis solution (100mg/kg, 0.1 mL, orally) for 3 days before IV challenge with C. albicans and SC challenge with SMMT and continued for 10 days. The rates of survival and tumor growth of understudy mice were investigated as well. The levels of TNF-α, IFN-γ, IL-4, IL-10 and IL-17 cytokines in culture supernatants were determined by ELISA. The mean tumor size was significantly increased in tumor-bearing mice infected with C. albicans (16.98 ± 0.49 mm(2)) as compared to other mice groups (P<0.05). The results showed a significant decline of IL-4 and IL-10 levels after propolis administration to tumor-bearing mice infected with C. albicans (53.41 pg/mL, 156.81 pg/mL and 63.45 pg/mL) (P < 0.05). The increment of TNF-α (433.85 pg/mL) and IFN-γ (120.43 pg/mL) levels were also observed. Data revealed that propolis has remarkable immunomodulatory effect, which provides a scientific validation for the popular use of this natural substance, and further investigation will help to understand propolis usefulness during immunosuppressive conditions. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

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

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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...

Effect of Bidens pilosa extract on renal functions and some tumor markers of Ehrlich Ascites Carcinoma bearing mice exposed to γ-radiation

International Nuclear Information System (INIS)

El-Kabany, H.; Ibrahim, S.I.

2013-01-01

The Ethanolic extract of Bidens pilosa (EtBP) was tested in Swiss albino mice transplanted with Ehrlich ascites carcinoma (EAC) and exposed to γ-radiation. EAC mice received intraperitoneal (i.p) 250 mg/kg body weight EtBP for nine days , 24hr after tumor inoculation. Mice exposed to 4 Gy γ-radiation 30 min after the first dose of EtBP. Seventy female mice were classified into 6 groups (15 mice in each group) as follows, control, mice treated with EtBP for 9 consecutive days, mice bearing EAC cells, EAC bearing mice treated with EtBP, 24 hour after tumor inoculation, EAC bearing mice and irradiated, and EAC bearing mice treated with EtBP and exposed to γ-radiation. Five animals from each group were sacrificed 18 hr after administration of the last EtBP dose. Blood and ascetic fluid were collected and kidneys were removed for biochemical and histopathological studies. The remaining animals were observed daily for recording survival percentage and body weight. Results showed that treatment of EAC bearing mice with EtBP and/or exposure to γ- radiation increased the survival percentage of the animals and decreased their body weight compared to EAC group. Inoculation of mice with EAC cells resulted in biochemical and histopathological changes leading to kidney damage. Animals of EAC bearing mice with EtBP and /or exposure to γ- radiation significantly restored the elevated levels of serum urea and creatinine, tumor necrosis factor-alpha (TNF-α), metalo matrix protein (mmp-2 and mmp9), also the elevated level of lipid peroxidation (MDA) in kidneys tissue, compared to EAC group. On the other hand, a significantly decline was observed in glutathione (GSH) and super oxide dismutase (SOD) contents in kidney tissue of EAC group. Treatment of EAC bearing mice with EtBP and/or exposure to γ-radiation resulted in increase GSH and SOD in kidney tissue and increased caspase-3 in ascetic fluid, comparing to EAC group. It could be concluded that EtBP through its antioxidant

Metastasis and growth of friend tumor cells in irradiated syngeneic hosts

International Nuclear Information System (INIS)

Matioli, G.

1974-01-01

Friend tumor cells (FTC) have been studied by growing them in lethally irradiated syngeneic mice. After establishing the FTC dilution factor (delta), extinction factor (Q), and the optimal time for colony counts, the FTC kinetic was analyzed by the recovery curve method. It was found that FTC growth is different from that experienced by normal or leukemic Friend stem cells when tested by the same in vivo assay. The most interesting differences were the high metastatic activity, the lack of differentiation, the deterministic growth, and the independence from the spleen microenvironment experienced by the FTC, in contrast with the normal and leukemic stem cells. In addition, the estimate of the critical size the FTC colony has to reach before releasing the first metastatic cells is presented. (U.S.)

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

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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.

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

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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 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.

Syngeneic graft-versus-host disease: a report of two cases and literature review.

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Latif, T; Pohlman, B; Kalaycio, M; Sobecks, R; Hsi, E D; Andresen, S; Bolwell, B J

2003-09-01

Rappeport et al first reported the clinical syndrome of graft-versus-host disease (GVHD) in syngeneic bone marrow transplant patients. Recently, there have been more reports of a GVHD-like syndrome in syngeneic bone marrow transplant patients (SGVHD) that may result in significant clinical morbidity. A total of 17 cases of SGVHD in syngeneic bone marrow transplant patients have been reported to date in the medical literature. The current report reviews these cases and presents two additional cases of severe SGVHD that have occurred at our institution.

Delayed erythropoiesis in irradiated rats grafted with syngeneic marrow: effects of cytotoxic drugs and iron-deficiency anemia

International Nuclear Information System (INIS)

Rodday, P.; Bennett, M.; Vitalle, J.J.

1976-01-01

Erythropoiesis in spleens of lethally irradiated Lewis rats grafted with 4-35 x 10 6 syngeneic marrow cells was inhibited or delayed during the test period of 5 days; this was in marked contrast to observations in irradiated mice. The mechanism of this inhibition was the subject of this study. Pretreatment of recipients 9 days prior to irradiation with the cytotoxic drugs cyclophosphamide (CY), busulfan (BUS), or dimethylmyleran (DMM), or the induction of iron deficiency with anemia in recipients reversed this delayed erythropoiesis. However, neither iron-deficiency anemia nor pretreatment with BUS or DMM affected the ability of irradiated recipients to reject 20 to 50 x 10 6 allogeneic marrow cells. The administration of commercial preparations of erythropoietin to hosts stimulated erythropoiesis moderately. However, proliferation of syngeneic marrow cells was not enhanced when infused into lethally irradiated spontaneous hypertensive (SH) inbred-strain rats which have high levels of endogenous erythropoietin. Finally, plasma from irradiated rats treated with phenylhydrazine to produce severe anemia was rich in erythropoietin but failed to stimulate erythropoiesis in the cell transfer system. Two hypotheses are considered

Biological markers as predictors of radiosensitivity in syngeneic murine tumors

International Nuclear Information System (INIS)

Chang, Sei Kyung; Shin, Hyun Soo; Seong, Jin Sil; Kim, Sung Hee

2006-01-01

We investigated whether a relationship exists between tumor control dose 50 (TCD 50 ) or tumor growth delay (TGD) and radiation induced apoptosis (RIA) in syngeneic murine tumors. Also we investigated the biological markers that can predict radiosensitivity in murine tumor system through analysis of relationship between TCD 50 , TGD, RIA and constitutive expression levels of the genetic products regulating RIA. Syngeneic murine tumors such as ovarian adenocarcinoma, mammary carcinoma, squamous cell carcinoma, fibrosarcoma, hepatocarcinoma were used in this study. C3H/HeJ mice were bred and maintained in our specific pathogen free mouse colony and were 8 ∼ 12 weeks old when used for the experiments. The tumors, growing in the right hind legs of mice, were analyzed for TCD 50 , TGD, and RIA at 8 mm in diameter. The tumors were also analyzed for the constitutive expression levels of p53, p21 WAF1/CIP1 , BAX, Bcl-2, Bcl-x L , Bcl-x S , and p34. Correlation analysis was performed whether the level of RIA were correlated with TCD 50 or TGD, and the constitutive expression levels of genetic products regulating RIA were correlated with TCD 50 , TGD, RIA. The level of RIA showed a significant positive correlation (R = 0.922, ρ = 0.026) with TGD, and showed a trend to correlation (R = -0.848), marginally significant correlation with TCD 50 (ρ = 0.070). It indicates that tumors that respond to radiation with high percentage of apoptosis were more radiosensitive. The constitutive expression levels of p21 WAF1/CIP1 and p34 showed a significant correlation either with TCD 50 (R = 0.893, ρ = 0.041 and R = 0.904, ρ = 0.035) or with TGD (R = -0.922, ρ 0.026 and R = -0.890, ρ = 0.043). The tumors with high constitutive expression levels of p21 WAF1/CIP1 or p34 were less radiosensitive than those with low expression. Radiosensitivity may be predicted with the level of RIA in murine tumors. The constitutive expression levels of p21 WAF1/CIP1 or p34 can be used as biological

Biological markers as predictors of radiosensitivity in syngeneic murine tumors

Energy Technology Data Exchange (ETDEWEB)

Chang, Sei Kyung; Shin, Hyun Soo [Bundang CHA General Hospital, Seongnam (Korea, Republic of); Seong, Jin Sil; Kim, Sung Hee [Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (Korea, Republic of)

2006-06-15

We investigated whether a relationship exists between tumor control dose 50 (TCD{sub 50}) or tumor growth delay (TGD) and radiation induced apoptosis (RIA) in syngeneic murine tumors. Also we investigated the biological markers that can predict radiosensitivity in murine tumor system through analysis of relationship between TCD{sub 50}, TGD, RIA and constitutive expression levels of the genetic products regulating RIA. Syngeneic murine tumors such as ovarian adenocarcinoma, mammary carcinoma, squamous cell carcinoma, fibrosarcoma, hepatocarcinoma were used in this study. C3H/HeJ mice were bred and maintained in our specific pathogen free mouse colony and were 8 {approx} 12 weeks old when used for the experiments. The tumors, growing in the right hind legs of mice, were analyzed for TCD{sub 50}, TGD, and RIA at 8 mm in diameter. The tumors were also analyzed for the constitutive expression levels of p53, p21{sup WAF1/CIP1}, BAX, Bcl-2, Bcl-x{sub L}, Bcl-x{sub S}, and p34. Correlation analysis was performed whether the level of RIA were correlated with TCD{sub 50} or TGD, and the constitutive expression levels of genetic products regulating RIA were correlated with TCD{sub 50}, TGD, RIA. The level of RIA showed a significant positive correlation (R = 0.922, {rho} = 0.026) with TGD, and showed a trend to correlation (R = -0.848), marginally significant correlation with TCD{sub 50} ({rho} = 0.070). It indicates that tumors that respond to radiation with high percentage of apoptosis were more radiosensitive. The constitutive expression levels of p21{sup WAF1/CIP1} and p34 showed a significant correlation either with TCD{sub 50} (R = 0.893, {rho} = 0.041 and R = 0.904, {rho} = 0.035) or with TGD (R = -0.922, {rho} 0.026 and R = -0.890, {rho} = 0.043). The tumors with high constitutive expression levels of p21{sup WAF1/CIP1} or p34 were less radiosensitive than those with low expression. Radiosensitivity may be predicted with the level of RIA in murine tumors. The

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

Science.gov (United States)

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.

Survival of tumor-bearing mice exposed to heavy water or heavy water plus methotrexate

International Nuclear Information System (INIS)

Laissue, J.A.; Buerki, H.; Berchtold, W.

1982-01-01

Moderate body deuteration combined with a cytostatic drug [methotrexate (MTX)] significantly increases the survival time of young adult DBA/2 mice bearing transplantable P815. L5178Y, or L1210 tumors. Neoplastic cells were grown in vitro from tumor stock and injected i.p. into mice from two groups, one drinking tap water, and other drinking 30% heavy water in tap water. One-half of the animals in each of these two groups was given a single injection of MTX (4 mg/kg body weight) on 3 consecutive days per week. At death, extension of primary and metastatic tumors was examined and was found to be macro- and microscopically comparable in the corresponding groups. The mean survival time of untreated mice drinking tap water was about 2 weeks following injection of the fast-growing P815, L5178Y, or L1210 (V) tumors and approximately 5 weeks after injection of cells from a slower-growing L1210 subline. Body deuteration alone roughly doubled the survival time solely of mice bearing this L1210 subline. Treatment with MTX approximately doubled the mean survival time of hosts bearing one of the fast-growing tumors. Combined treatment with heavy water and MTX increased the mean survival time of the mice in all groups by 15 to 125% as compared to control values. The reasons for this effect are unknown. However, heavy water has been shown to exert antimitotic activity and to depress the incorporation of radioactive precursors into DNA of proliferating mammalian cells. The depression of antibody formation following antigenic stimulation and the reduction in numbers of nonneoplastic lymphoid cells of mice following moderate body deuteration may have contributed to the enhancement of MTX activity in addition to other effects of deuterium

Induction of immune resistance against L1210 lymphatic leukemia in mice after chemoradiotherapy of the leukemia and reconstitution with bone marrow purged from the leukemia with mafosfamide

International Nuclear Information System (INIS)

Skorski, T.; Kawalec, M.

1988-01-01

Lymphatic leukemia L1210-bearing semisyngeneic Balb/c x DBA/2Wf F1 (CD2F1) mice were subjected to chemoradiotherapy (2 x 100 mg/kg of cyclophosphamide i.p. and 1000 cGy of total body irradiation) and reconstitution with 10(7) syngeneic bone marrow cells i.v. The bone marrow obtained from leukemic mice was previously ex vivo purged of the leukemia cells with mafosfamide (ASTA Z7654) and stored in liquid nitrogen. Eight weeks after cytoreductive therapy and bone marrow transplantation we tried to immunize the mice against the lethal dose of the leukemia by i.p. injections of L1210-Maf cells (L1210 cells treated in vitro with mafosfamide for inhibition of their growth). About 75% of such mice were able to reject the subsequent 10(3) L1210 leukemia cell challenge, as compared with 70% of normal immunized mice and 55% of mice reconstituted with bone marrow cells not treated with mafosfamide

Antitumor activity of baicalein on the mice bearing U14 cervical cancer

African Journals Online (AJOL)

Administrator

2011-10-17

Oct 17, 2011 ... administered with vehicle alone (distilled water, 0.2 ml/day, p.o.) was taken as ... Effect of baicalein on tumor, liver and kidney in mice bearing tumor ... The cells were overnight fixed with cold 70% ethanol, mixed with. Annexin ...

Effects of perfluorochemical emulsion on the timing of administration and irradiation in tumor bearing mice

International Nuclear Information System (INIS)

Hishikawa-Itoh, Youko; Ayakawa, Yoshio; Miyata, Nobuki

1988-01-01

Perfluorochemical content was examined periodically, in blood, tumor and some organs using gas chromatography, after Fluosol-DA saline 20 % (FDAS) was injected into LLC bearing mice. The blood half-life of FDAS in LLC bearing mice was 3.76 hrs (5 ml/kg injection) or 6.15 hrs (20 ml/kg injection) respectively, and FDAS almost disapeared from the blood after about 2 days (5 ml/kg) and 3 days (20 ml/kg) of FDAS-injection. Most of FDAS was accumulated into spleen and the liver. FDAS accumulation into the tumor tissue was 1 ∼ 6 % of injected-FDAS dose and the peak of FDAS accumulation was 1 ∼ 3 days after injection. The timing of FDAS-injection and irradiation in tumor bearing mice determined according to the results above (half-life and accumulation of FDAS in tumor). FDAS (5, 10, 20 ml/kg) was injected to LLC-bearing mice on 3, 2, 1 and 0 day before irradiation and they were irradiated 15 Gray under oxygen-breathing, respectively. FDAS-injected groups before irradiation (3, 2, 1 day before, respectively) showed a tendency of tumor growth delay, but didn't show significant difference as compared with oxygen-breathing group without FDAS, because they had not enough effective FDAS content in the blood. Although the FDAS-injected groups just before irradiation significantly showed the delay of tumor growth. These results demonstrate that oxygen and FDAS existing in the blood injected just before irradiation effectively delay tumor growth in which the lowest effective dose is 5 ml/kg. In the case of clinical application of FDAS, FDAS may be most effective, when administrated just before irradiation in every fractionated irradiation. (author)

Distribution of various water soluble radioactive metalloporphyrins in tumor bearing mice

International Nuclear Information System (INIS)

Hambright, P.; Fawwaz, R.; Valk, P.; McRae, J.; Bearden, A.J.

1975-01-01

The distribution of a variety of water soluble 109 Pd and 64 Cu porphyrins were studied in mice bearing three types of tumors. While the metalloporphyrins are found to have an affinity for neoplastic tissue, substantial extra-tumor concentrations are also noted. Although this limits their value as specific tumor imaging agents, their use in localized therapy is discussed

Comparison of folylderivative biosynthesis in Ehrlich ascites carcinoma cells and in some organs of healthy and tumor-bearing mice

Energy Technology Data Exchange (ETDEWEB)

Sikora, E; Grzelakowska-Sztabert, B [Polska Akademia Nauk, Warsaw. Inst. Biologii Doswiadczelnej

1984-01-01

Biosynthesis of folyl derivatives derived from subcutaneously injected 2-(/sup 14/C)folate was studied in Ehrlich ascites carcinoma (EAC) cells and in mouse liver and kidneys. Retention of exogenous folate was followed by measurements of the total radioactivity of folyl derivatives present in the EAC cells and organs examined. Identification of unconjugated and conjugated folyl derivatives was done by means of column chromatography on Sephadex G-25, G-15 and cellulose sheets. The level of retained radioactivity in folyl derivatives, being 5% in the liver and 1% in the kidneys of the radioactivity administered to mice, was similar in healthy and tumor-bearing animals. Moreover, no quantitative and qualitative differences were found in folyl mono- and polyglutamates originating from the organs of healthy or tumor-bearing mice although the content of folyl polyglutamates rose faster in liver and kidneys of EAC cells-bearing mice as well as in the tumor cells, than in the organs of healthy mice.

[Imiquimod combined with dendritic cell vaccine decreases Treg proportion and enhances anti-tumor responses in mice bearing melanoma].

Science.gov (United States)

Ren, Shurong; Wang, Qiubo; Zhang, Yanli; Lu, Cuixiu; Li, Ping; Li, Yumei

2017-02-01

Objective To investigate the therapeutic effect of Toll-like receptor 7 (TLR7) agonist imiquimod combined with dendritic cell (DC)-based tumor vaccine on melanoma in mice and the potential mechanism. Methods Melanoma-bearing mouse models were established by subcutanous injection of B16-OVA cells into C57BL/6 mice. DCs were isolated from mouse bone marrow and propagated in culture medium with recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and recombinant mouse interleukin-4 (rmIL-4). DC vaccine (OVA-DC) was prepared by overnight incubation of DCs added with chicken ovalbumin. C57BL/6 mice were separated into four groups which were treated with PBS, topical imiquimod application, OVA-DC intradermal injection and imiquimod plus OVA-DC, respectively. The tumor size was calculated by digital vernier caliper. Peripheral blood CD4 + FOXP3 + Tregs of the tumor-bearing mice was detected by flow cytometry. The cytotoxicity of splenic lymphocyte against B16-OVA was assessed in vitro by CCK-8 assay. Results Compared with the other three groups, B16-OVA-bearing mice treated with imiquimod plus DC vaccine had the smallest tumor volume. The percentage of CD4 + FOXP3 + Tregs decreased significantly in the combined treated mice. The combined treatment enhanced significantly cytotoxicity of splenic lymphocytes against B16-OVA cells. Conclusion Imiquimod combined with antigen-pulsed-DC vaccine could reduce CD4 + FOXP3 + Treg proportion and promote anti-tumor effect in mice with melanoma.

Disposition of TF-PEG-Liposome-BSH in tumor-bearing mice

Energy Technology Data Exchange (ETDEWEB)

Ito, Y. [Department of Dentistry and Oral Surgery, Division of Medicine for Function and Morphology of Sensory Organs, Osaka Medical College (Japan)], E-mail: ora059@poh.osaka-med.ac.jp; Kimura, Y.; Shimahara, T.; Ariyoshi, Y.; Shimahara, M. [Department of Dentistry and Oral Surgery, Division of Medicine for Function and Morphology of Sensory Organs, Osaka Medical College (Japan); Miyatake, S.; Kawabata, S. [Department of Neurosurgery, Osaka Medical College (Japan); Kasaoka, S. [Faculty of Pharmaceutical Sciences, Hiroshima-International University (Japan); Ono, K. [Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University (Japan)

2009-07-15

BNCT requires high concentration and selective delivery of {sup 10}B to the tumor cell. To improve the drug delivery in BNCT, we conducted a study by devising TPLB. We administrated three types of boron delivery systems: BSH, PLB and TPLB, to Oral SCC bearing mice. Results confirmed that {sup 10}B concentration is higher in the TPLB group than in the BSH group and that TPLB is significantly effective as boron delivery system.

Metabolism of 64Cu and transfer of 125I-MT in the bearing liver ascites tumor (H22) mice

International Nuclear Information System (INIS)

Huai Qing; Fang Xingwang; Wang Wenqing

1998-01-01

The metabolism of 64 Cu in some tissues of the bearing liver ascites tumor mice has been studied. The liver in normal and tumor bearing mice preferentially accumulates intravenous injection copper, however, the liver in the later mice accumulates much less copper than that of the former. It suggests that in the bearing ascites tumor mice, ascites tumor influences the metabolism of copper. It is found that the content of 64 Cu in the tumor cell is more than 85% in ascites tumor. Gel filtration profile of mice liver homogenate on Sephadex G-75 shows that injected 64 Cu is mainly bound with metallothionein. The tissues uptake of 125 I-labelled (Cd, Zn)-MT which is given in abdominal cavity are also reported. Of the tissues studied, the ascites tumor and kidney accumulate the highest concentration of given 125 I-MT, since over 20% of entire dose accumulated in them. After 125 I-MT is given, it soon goes into ascites tumor, and reaches the maximum in ascites as well as in tumor cell. Therefore, 125 I-MT can go through the membrane of tumor cell and reaches in the tumor cell

Distribution of 18F-5-fluorouracil in tumor-bearing mice and rats

International Nuclear Information System (INIS)

Shani, J.; Wolf, W.; Schlesinger, T.

1978-01-01

Extensive distribution studies of 18 F-5-fluorouracil ( 18 F-5-FU) in control and tumor-bearing mice (seven lines) and rats (eight lines) that have been shown or suspected to be responsive to 5-FU treatment were investigated with 18 F-5-FU. Studies were performed as a function of time, loading dose of 5-FU, and after a pretreatment regimen of 5-FU. Following the parenteral administration of 18 F-5-FU to tumor-bearing mice and rats there was slight preferential uptake by some of the tumor types, particularly subcutaneous leukemic tumors and breast adenocarcinomas. The degree of concentration in tumor tissue in comparison with surrounding tissues (blood, Muscle) was not such as to consider the radiopharmaceutical suitable for tumor localization. However, sufficient amounts of radioactivity localized in some tumors so that it might be possible to determine if a correlation exists between tumor uptake and anti-tumor effect of 5-fluorouracil. Another possible area of use might be in regulating the method of administration of the chemotherapeutic agent. (author)

Changes in VEGF expression and DNA synthesis in hepatocytes from hepatectomized and tumour-bearing mice.

Science.gov (United States)

García, Marcela N; Andrini, Laura B; Inda, Ana María; Ronderos, Jorge R; Hijano, Julio C; Errecalde, Ana Lía

2010-02-05

Transplanted tumours could modify the intensity and temporal distribution of the cellular proliferation in normal cell populations, and partial hepatectomy alters the serum concentrations of substances involved in cellular proliferation, leading to the compensatory liver hyperplasia. The following experiments were designed in order to study the SI (S-phase index) and VEGF (vascular endothelial growth factor) expression in regenerating liver (after partial hepatectomy) of adult male mice bearing a hepatocellular carcinoma, throughout one complete circadian cycle. We used adult male C3H/S-strain mice. After an appropriate period of synchronization, the C3H/S-histocompatible ES2a hepatocellular carcinoma was grafted into the subcutaneous tissue of each animal's flank. To determine the index of SI and VEGF expression of hepatocytes, we used immunohistochemistry. The animals were divided into two experimental groups: Group I, control, hepatectomized animals; Group II, hepatectomized tumour-bearing animals. The statistical analysis of SI and VEGF expression was performed using Anova and Tukey as a postcomparison test. The results show that in the second group, the curve of SI changes the time points for maximum and minimum activity, and the peak of VEGF expression appears before the first group. In conclusion, in the hepatectomized mice, the increases of hepatic proliferation, measured by the SI index, may produce a rise in VEGF expression with the object of generating a vascular network for hepatic regeneration. Lastly, as we have mentioned, in hepatectomized and tumour-bearing mice, the peak of VEGF expression appears before the one of DNA synthesis.

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

Science.gov (United States)

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.

Combination use of lentinan with x-ray therapy in mouse experimental tumor system, (2). Combination effect on MM102 syngeneic tumor

Energy Technology Data Exchange (ETDEWEB)

Shiio, Tsuyoshi; Ohishi, Kazuo; Tsuchiya, Yoshiharu; Niitsu, Iwayasu; Hayashibara, Hiromi; Yoshihama, Takashi; Moriyuki, Hirobumi

1988-03-01

C3H/He mice transplanted syngeneic MM102 tumor subcutaneously in the footpad were used to study the timing of administration of lentinan when combined with local irradiation of X-ray. In combination with 1,000 rads irradiation, the administration of lentinan after X-ray was not effective. When lentinan was administered in combination with 2,000 to 3,000 rads irradiation, the growth of tumor was decreased significantly in comparison with the groups which received radiotherapy alone and those that received lentinan alone. The administration of lentinan before irradiation was effective at the same degree in the group that received lentinan after irradiation. Life prolongation effect was also observed in the group that received lentinan before and after irradiation, and 4 mice among 8 tested mice were survived at 70th day after tumor transplantation.

The excretion of biotrace elements using the multitracer technique in tumour-bearing mice.

Science.gov (United States)

Wang, X; Tian, J; Yin, X M; Zhang, X; Wang, Q Z

2000-12-01

A radioactive multitracer solution obtained from the nuclear reaction of selenium with 25 MeV/nucleon 40Ar ions was used for investigation of trace element excretion into the faeces and urine of cancerous mice. The excretion rates of 22 elements (Na, K, Rb, Mg, Ca, Sr, Ga, As, Sc, V, Cr, Mn, Co, Fe, Y, Zr, Mo, Nb, Tc, Ru, Ag and In) were simultaneously measured under strictly identical experimental conditions, in order to clarify the excretion behavior of these elements in cancerous mice. The faecal and urinary excretion rates of Mg, Sr, Ga, As, Sc, V, Cr, Mn, Co, Fe, Y, Zr, Nb, Ru and Mo in cancerous mice, showed the in highest value at 0-8 hours. The accumulative excretion of Ca, Mo, Y and Zr was decreased and Na, Fe, Mn and Co increased in tumour-bearing mice, when compared to normal mice.

The excretion of biotrace elements using the multitracer technique in tumour-bearing mice

Energy Technology Data Exchange (ETDEWEB)

Wang, X.; Tian, J. E-mail: tianjun@public.lz.gs.cn; Yin, X.M.; Zhang, X.; Wang, Q.Z

2000-12-15

A radioactive multitracer solution obtained from the nuclear reaction of selenium with 25 MeV/nucleon {sup 40}Ar ions was used for investigation of trace element excretion into the faeces and urine of cancerous mice. The excretion rates of 22 elements (Na, K, Rb, Mg, Ca, Sr, Ga, As, Sc, V, Cr, Mn, Co, Fe, Y, Zr, Mo, Nb, Tc, Ru, Ag and In) were simultaneously measured under strictly identical experimental conditions, in order to clarify the excretion behavior of these elements in cancerous mice. The faecal and urinary excretion rates of Mg, Sr, Ga, As, Sc, V, Cr, Mn, Co, Fe, Y, Zr, Nb, Ru and Mo in cancerous mice, showed the in highest value at 0-8 hours. The accumulative excretion of Ca, Mo, Y and Zr was decreased and Na, Fe, Mn and Co increased in tumour-bearing mice, when compared to normal mice.

The excretion of biotrace elements using the multitracer technique in tumour-bearing mice

International Nuclear Information System (INIS)

Wang, X.; Tian, J.; Yin, X.M.; Zhang, X.; Wang, Q.Z.

2000-01-01

A radioactive multitracer solution obtained from the nuclear reaction of selenium with 25 MeV/nucleon 40 Ar ions was used for investigation of trace element excretion into the faeces and urine of cancerous mice. The excretion rates of 22 elements (Na, K, Rb, Mg, Ca, Sr, Ga, As, Sc, V, Cr, Mn, Co, Fe, Y, Zr, Mo, Nb, Tc, Ru, Ag and In) were simultaneously measured under strictly identical experimental conditions, in order to clarify the excretion behavior of these elements in cancerous mice. The faecal and urinary excretion rates of Mg, Sr, Ga, As, Sc, V, Cr, Mn, Co, Fe, Y, Zr, Nb, Ru and Mo in cancerous mice, showed the in highest value at 0-8 hours. The accumulative excretion of Ca, Mo, Y and Zr was decreased and Na, Fe, Mn and Co increased in tumour-bearing mice, when compared to normal mice

Syngeneic B16F10 Melanoma Causes Cachexia and Impaired Skeletal Muscle Strength and Locomotor Activity in Mice

Directory of Open Access Journals (Sweden)

Fabrício A. Voltarelli

2017-09-01

Full Text Available Muscle wasting has been emerging as one of the principal components of cancer cachexia, leading to progressive impairment of work capacity. Despite early stages melanomas rarely promotes weight loss, the appearance of metastatic and/or solid tumor melanoma can leads to cachexia development. Here, we investigated the B16F10 tumor-induced cachexia and its contribution to muscle strength and locomotor-like activity impairment. C57BL/6 mice were subcutaneously injected with 5 × 104 B16F10 melanoma cells or PBS as a Sham negative control. Tumor growth was monitored during a period of 28 days. Compared to Sham mice, tumor group depicts a loss of skeletal muscle, as well as significantly reduced muscle grip strength and epididymal fat mass. This data are in agreement with mild to severe catabolic host response promoted by elevated serum tumor necrosis factor-alpha (TNF-α, interleukin-6 (IL-6 and lactate dehydrogenase (LDH activity. Tumor implantation has also compromised general locomotor activity and decreased exploratory behavior. Likewise, muscle loss, and elevated inflammatory interleukin were associated to muscle strength loss and locomotor activity impairment. In conclusion, our data demonstrated that subcutaneous B16F10 melanoma tumor-driven catabolic state in response to a pro-inflammatory environment that is associated with impaired skeletal muscle strength and decreased locomotor activity in tumor-bearing mice.

Immunological tolerance and tumor rejection in embryo-aggregated chimeric mice – Lessons for tumor immunity

International Nuclear Information System (INIS)

Wagner, Alexander Y; Holle, Eric; Holle, Lori; Yu, Xianzhong; Schwamberger, Günter

2008-01-01

Rejection of transplanted tumors by the immune system is a rare event in syngeneic hosts, and is considered to be dependent on the local interaction of defensive immune reactions and tumor tolerance mechanisms. Here, we have enlisted the aid of a unique set of embryo-aggregated lineage chimeric mice derived from C57/BL6 and FVB donors to study the interplay between local and systemic tumor immunity and tolerance in rejection of mouse B16 melanoma cells, syngeneic to the C57/BL6 donor strain. Two variants of embryo-aggregated chimeric mice with either variable or no contribution of C57-derived cells to their skin were generated by the fusion of different ratios of morula stage blastomers. Chimeric mice were analyzed for s.c. growth of B16 tumors in comparison to their respective donor strains as well as normal F1 hybrids, and the relative frequencies of cellular components of the immune system by FACS analysis of peripheral blood or lymph node cells. B16 tumors grew significantly faster in mice with full chimerism in their skin as compared to syngeneic C57 or semi-syngeneic C57 × FVB F1 hosts. In contrast, s.c. tumor growth was either absent or significantly reduced in chimeric mice lacking C57-derived cells in their skin, but tolerant to C57 tissue in other organs. Comparison of the relative frequencies of various immune cells in the periphery via FACS-analysis did not reveal any significant differences between the two types of chimeric mice with respect to their donor strains. Our data suggest a complex interplay between mechanisms of local peripheral tolerance and innate antitumor mechanisms possibly involving NK cell allorecognition as a basis for the differential growth or rejection of B16 tumors in these unique chimeric mice, which we suggest to constitute a valuable new model system for the study of immune-mediated tumor rejection

Immunological tolerance and tumor rejection in embryo-aggregated chimeric mice – Lessons for tumor immunity

Directory of Open Access Journals (Sweden)

Yu Xianzhong

2008-12-01

Full Text Available Abstract Background Rejection of transplanted tumors by the immune system is a rare event in syngeneic hosts, and is considered to be dependent on the local interaction of defensive immune reactions and tumor tolerance mechanisms. Here, we have enlisted the aid of a unique set of embryo-aggregated lineage chimeric mice derived from C57/BL6 and FVB donors to study the interplay between local and systemic tumor immunity and tolerance in rejection of mouse B16 melanoma cells, syngeneic to the C57/BL6 donor strain. Methods Two variants of embryo-aggregated chimeric mice with either variable or no contribution of C57-derived cells to their skin were generated by the fusion of different ratios of morula stage blastomers. Chimeric mice were analyzed for s.c. growth of B16 tumors in comparison to their respective donor strains as well as normal F1 hybrids, and the relative frequencies of cellular components of the immune system by FACS analysis of peripheral blood or lymph node cells. Results B16 tumors grew significantly faster in mice with full chimerism in their skin as compared to syngeneic C57 or semi-syngeneic C57 × FVB F1 hosts. In contrast, s.c. tumor growth was either absent or significantly reduced in chimeric mice lacking C57-derived cells in their skin, but tolerant to C57 tissue in other organs. Comparison of the relative frequencies of various immune cells in the periphery via FACS-analysis did not reveal any significant differences between the two types of chimeric mice with respect to their donor strains. Conclusion Our data suggest a complex interplay between mechanisms of local peripheral tolerance and innate antitumor mechanisms possibly involving NK cell allorecognition as a basis for the differential growth or rejection of B16 tumors in these unique chimeric mice, which we suggest to constitute a valuable new model system for the study of immune-mediated tumor rejection.

Activation of antitumor immune responses by Ganoderma formosanum polysaccharides in tumor-bearing mice.

Science.gov (United States)

Wang, Cheng-Li; Lu, Chiu-Ying; Hsueh, Ying-Chao; Liu, Wen-Hsiung; Chen, Chun-Jen

2014-11-01

Fungi of the genus Ganoderma are basidiomycetes that have been used as traditional medicine in Asia and have been shown to exhibit various pharmacological activities. We recently found that PS-F2, a polysaccharide fraction purified from the submerged culture broth of Ganoderma formosanum, stimulates the maturation of dendritic cells and primes a T helper 1 (Th1)-polarized adaptive immune response in vivo. In this study, we investigated whether the immune adjuvant function of PS-F2 can stimulate antitumor immune responses in tumor-bearing mice. Continuous intraperitoneal or oral administration of PS-F2 effectively suppressed the growth of colon 26 (C26) adenocarcinoma, B16 melanoma, and sarcoma 180 (S180) tumor cells in mice without adverse effects on the animals' health. PS-F2 did not cause direct cytotoxicity on tumor cells, and it lost the antitumor effect in mice with severe combined immunodeficiency (SCID). CD4(+) T cells, CD8(+) T cells, and serum from PS-F2-treated tumor-bearing mice all exhibited antitumor activities when adoptively transferred to naïve animals, indicating that PS-F2 treatment stimulates tumor-specific cellular and humoral immune responses. These data demonstrate that continuous administration of G. formosanum polysaccharide PS-F2 can activate host immune responses against ongoing tumor growth, suggesting that PS-F2 can potentially be developed into a preventive/therapeutic agent for cancer immunotherapy.

Immunoglobulin leakiness in scid mice with CD4(+) T-cell-induced chronic colitis

DEFF Research Database (Denmark)

Brimnes, J; Reimann, J; Claesson, Mogens Helweg

2000-01-01

Inflammatory bowel disease in scid mice is initiated by transplantation of CD4(+) T-cells from immunocompetent syngenic donor mice. As the disease progresses, immunoglobulin (Ig)-containing cells appear in the gut lamina propria, suggesting that locally accumulating Ig may play a role in disease ...

Anti-bacterial immunity to Listeria monocytogenes in allogeneic bone marrow chimera in mice

International Nuclear Information System (INIS)

Onoe, K.; Good, R.A.; Yamamoto, K.

1986-01-01

Protection and delayed-type hypersensitivity (DTH) to the facultative intracellular bacterium Listeria monocytogenes (L.m.) were studied in allogeneic and syngeneic bone marrow chimeras. Lethally irradiated AKR (H-2k) mice were successfully reconstituted with marrow cells from C57BL/10 (B10) (H-2b), B10 H-2-recombinant strains or syngeneic mice. Irradiated AKR mice reconstituted with marrow cells from H-2-compatible B10.BR mice, [BR----AKR], as well as syngeneic marrow cells, [AKR----AKR], showed a normal level of responsiveness to the challenge stimulation with the listeria antigens when DTH was evaluated by footpad reactions. These mice also showed vigorous activities in acquired resistance to the L.m. By contrast, chimeric mice that had total or partial histoincompatibility at the H-2 determinants between donor and recipient, [B10----AKR], [B10.AQR----AKR], [B10.A(4R)----AKR], or [B10.A(5R)----AKR], were almost completely unresponsive in DTH and antibacterial immunity. However, when [B10----AKR] H-2-incompatible chimeras had been immunized with killed L.m. before challenge with live L.m., these mice manifested considerable DTH and resistance to L.m. These observations suggest that compatibility at the entire MHC between donor and recipient is required for bone marrow chimeras to be able to manifest DTH and protection against L.m. after a short-term immunization schedule. However, this requirement is overcome by a preceding or more prolonged period of immunization with L.m. antigens. These antigens, together with marrow-derived antigen-presenting cells, can then stimulate and expand cell populations that are restricted to the MHC (H-2) products of the donor type

Migration inhibition of immune mouse spleen cells by serum from x-irradiated tumor-bearing mice

International Nuclear Information System (INIS)

Moroson, H.

1978-01-01

Tumor-specific antigens of the chemically induced MC 429 mouse fibrosarcoma were detected in a 3 M KCl extract of tumor by the inhibition of migration of specifically immune spleen cells. Using this assay with serum from tumor-bearing mice no tumor antigen was detected in serum of mice bearing small tumors, unless the tumor was exposed to local x irradiation (3000 R) 1 day prior to collection of serum. It was concluded that local x irradiation of tumor caused increased concentration of tumor antigen in the serum. When the tumor was allowed to grow extremely large, with necrosis, then host serum did cause migration inhibition of both nonimmune and immune spleen cells. This migration-inhibition effect was not associated with tumor antigen, but with a nonspecific serum factor

Regorafenib inhibits tumor progression through suppression of ERK/NF-κB activation in hepatocellular carcinoma bearing mice.

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Weng, Mao-Chi; Wang, Mei-Hui; Tsai, Jai-Jen; Kuo, Yu-Cheng; Liu, Yu-Chang; Hsu, Fei-Ting; Wang, Hsin-Ell

2018-03-13

Regorafenib has been demonstrated in our previous study to trigger apoptosis through suppression of extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) activation in hepatocellular carcinoma (HCC) SK-Hep1 cells in vitro However, the effect of regorafenib on NF-κB-modulated tumor progression in HCC in vivo is ambiguous. The aim of the present study is to investigate the effect of regorafenib on NF-κB-modulated tumor progression in HCC bearing mouse model. pGL4.50 luciferase reporter vector transfected SK-Hep1 (SK-Hep1/ luc2 ) and Hep3B 2.1-7 tumor bearing mice were established and used for this study. Mice were treated with vehicle or regorafenib (20 mg/kg/day by gavage) for 14 days. Effects of regorafenib on tumor growth and protein expression together with toxicity of regorafenib were evaluated with digital caliper and bioluminescence imaging (BLI), ex vivo Western blotting immunohistochemistry (IHC) staining, and measurement of body weight and pathological examination of liver tissue, respectively, in SK-Hep1/ luc2 and Hep3B 2.1-7 tumor bearing mice. The results indicated regorafenib significantly reduced tumor growth and expression of phosphorylated ERK, NF-κB p65 (Ser536), phosphorylated AKT and tumor progression-associated proteins. In addition, we found regorafenib induced both extrinsic and intrinsic apoptotic pathways. Body weight and liver morphology were not affected by regorafenib treatment. Our findings present the mechanism of tumor progression inhibition by regorafenib is linked to suppression of ERK/NF-κB signaling in SK-Hep1/ luc2 and Hep3B 2.1-7 tumor-bearing mice. ©2018 The Author(s).

An Immune-Modulating Diet in Combination with Chemotherapy Prevents Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice.

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Nakamura, Kentaro; Sasayama, Akina; Takahashi, Takeshi; Yamaji, Taketo

2015-01-01

Cancer cachexia is characterized by muscle wasting caused partly by systemic inflammation. We previously demonstrated an immune-modulating diet (IMD), an enteral diet enriched with immunonutrition and whey-hydrolyzed peptides, to have antiinflammatory effects in some experimental models. Here, we investigated whether the IMD in combination with chemotherapy could prevent cancer cachexia in colon 26 tumor-bearing mice. Forty tumor-bearing mice were randomized into 5 groups: tumor-bearing control (TB), low dose 5-fluorouracil (5-FU) and standard diet (LF/ST), low dose 5-FU and IMD (LF/IMD), high dose 5-FU and standard diet (HF/ST) and high dose 5-FU and IMD (HF/IMD). The ST and IMD mice received a standard diet or the IMD ad libitum for 21 days. Muscle mass in the IMD mice was significantly higher than that in the ST mice. The LF/IMD in addition to the HF/ST and HF/IMD mice preserved their body and carcass weights. Plasma prostaglandin E2 levels were significantly lower in the IMD mice than in the ST mice. A combined effect was also observed in plasma interleukin-6, glucose, and vascular endothelial growth factor levels. Tumor weight was not affected by different diets. In conclusion, the IMD in combination with chemotherapy prevented cancer cachexia without suppressing chemotherapeutic efficacy.

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

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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.

In-111-oxine-labeled negative liposomes in tumor-bearing mice

International Nuclear Information System (INIS)

Chatal, J.F.; Guihard, D.; Bardy, A.; Pasqualini, R.

1983-01-01

The distribution of In-111-oxine-labelled liposomes in C 57 Bl 6 mice bearing a Lewis lung tumor and the variations contingent on modification of certain parameters have been studied. The distribution has been compared with that of Ga-67 citrate which is known for its affinity for lung tumors. In conclusion, it may be said that In-111-labeled negatively charged liposomes handled in oxygen-free conditions and having a size smaller than 80 nm make it possible to visualize a murine tumor as well, and even better, than does Ga-67 citrate

Ionizing radiation and autoimmunity: Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells

International Nuclear Information System (INIS)

Sakaguchi, N.; Sakaguchi, S.; Miyai, K.

1992-01-01

Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and the peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4 + T cells mediated the autoimmune prevention but CD8 + T cells did not. CD4 + T cells also appeared to mediate the TLI-induced autoimmune disease because CD4 + T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells. 62 refs., 9 figs., 2 tabs

Identification of Paramecium bursaria syngens through molecular markers--comparative analysis of three loci in the nuclear and mitochondrial DNA.

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Greczek-Stachura, Magdalena; Potekhin, Alexey; Przyboś, Ewa; Rautian, Maria; Skoblo, Inna; Tarcz, Sebastian

2012-09-01

This is the first attempt to resolve the phylogenetic relationship between different syngens of Paramecium bursaria and to investigate at a molecular level the intraspecific differentiation of strains originating from very distant geographical locations. Herein we introduce a new collection of five P. bursaria syngens maintained at St Petersburg State University, as the international collection of syngens was lost in the 1960s. To analyze the degree of speciation within Paramecium bursaria, we examined 26 strains belonging to five different syngens from distant and geographically isolated localities using rDNA (ITS1-5.8S-ITS2-5'LSU) fragments, mitochondrial cytochrome c oxidase subunit I (COI), and H4 gene fragments. It was shown that P. bursaria strains of the same syngens cluster together in all three inferred molecular phylogenies. The genetic diversity among the studied P. bursaria strains based on rDNA sequences was rather low. The COI divergence of Paramecium bursaria was also definitely lower than that observed in the Paramecium aurelia complex. The nucleotide sequences of the H4 gene analyzed in the present study indicate the extent of genetic differences between the syngens of Paramecium bursaria. Our study demonstrates the diagnostic value of molecular markers, which are important tools in the identification of Paramecium bursaria syngens. Copyright © 2011 Elsevier GmbH. All rights reserved.

Primary observation on the effect of APBMV on tumor weight and general physical condition of hepatoma 22-bearing mice after radiotherapy

International Nuclear Information System (INIS)

Kong Tianhan; Wei Ling; Han Xuefei; Dong Weihua

2000-01-01

Objective: To observe the effect of antineoplastic polypeptide from buthus martensii venom (APBMV) combined with radiotherapy on hepatoma-bearing mouse. Methods: Hundreds H22-bearing mice were used in this experiment. The tumor growth inhibiting rate (IR%), WBC count, hemoglobin content, activity of superoxide dismutase (SOD), level of lipid peroxide (LPO) and spleens index (SI) were used as the parameters. After radiotherapy (RT) or after administration of different dosage of APBMV combined with RT, the changes of these parameters were observed. Results: On the 6th and 9th day after radiotherapy, the tumor weights decreased after administrating APBMV combined with RT, in which IR were 78.29% and 70.45%, respectively (comparing with RT and APBMV group, P 0.05) among all groups. SOD activity was the lowest and LPO level was the highest in RT group (comparing with the control group, P 22 -bearing mice, SOD activity increased and LPO level decreased evidently (comparing with RT group, P 22 was stronger than radiation or APBMV alone. APBMV can also antagonize radiation injury on H 22 -bearing mice

A Ketogenic Formula Prevents Tumor Progression and Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice

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Kentaro Nakamura

2018-02-01

Full Text Available Low-carbohydrate, high-fat diets (ketogenic diets might prevent tumor progression and could be used as supportive therapy; however, few studies have addressed the effect of such diets on colorectal cancer. An infant formula with a ketogenic composition (ketogenic formula; KF is used to treat patients with refractory epilepsy. We investigated the effect of KF on cancer and cancer cachexia in colon tumor-bearing mice. Mice were randomized into normal (NR, tumor-bearing (TB, and ketogenic formula (KF groups. Colon 26 cells were inoculated subcutaneously into TB and KF mice. The NR and TB groups received a standard diet, and the KF mice received KF ad libitum. KF mice preserved their body, muscle, and carcass weights. Tumor weight and plasma IL-6 levels were significantly lower in KF mice than in TB mice. In the KF group, energy intake was significantly higher than that in the other two groups. Blood ketone body concentrations in KF mice were significantly elevated, and there was a significant negative correlation between blood ketone body concentration and tumor weight. Therefore, KF may suppress the progression of cancer and the accompanying systemic inflammation without adverse effects on weight gain, or muscle mass, which might help to prevent cancer cachexia.

Biodistribution and receptor imaging studies of insulin labelled with radioiodine in mice bearing H22 hepatocellular cacinoma

International Nuclear Information System (INIS)

Tang Gongshun; Kuang Anren; Liang Zenlu

2004-01-01

Objectives: It has been demonstrated that insulin receptor of hepatocellular carcinoma cells is overexpression. The biodistribution of 125I-insulin and receptor imaging studies of 131I-insulin in mice bearing solid liver tumor comprised of hepatic carcinoma H22 cells were performed to develop insulin as a carder of radioiodine. Methods: 1 )Insulin was radiolabeled with iodine-125 or iodine-131 using a Chloramines T method. Twenty mice bearing tumor were divided into 4 groups (n = 5 each) randomly. They were killed at 5, 15, 30, 60 min after 125I-insulin administered intravenously. The percentage of injected dose of 125I-insulin per gram of tissue(%ID/gdis) in mice bearing tumor were determined. 2) Another ten mice bearing tumor were selected to be as a inhibition group. They received cold insulin 2 mg intravenously 2 min ahead of administration of 125I-insulin and they were killed at 30 min (n=5) and 60 rain (n=5) randomly post 125I-insulin injection. The %ID/ginh and the inhibited rates[(%ID/gdis-%iD/ginh) %ID/gdis 100%] were obtained. 3) One tumor-mouse received 7.4 Mbq 13II-insulin intravenously, another received cold insulin 2 mg injection before 13II-insulin injection. Whole body images were carded out and the radioactivity ratios of tumor/normal were accounted at 60 min. Results: 1) The radiochemical purities of 125I-insulin and 13II-insulin were 96.7%-98.9%. The tumors uptake of the 125I-insulin increased gradually, its peak (%ID/gdis) was 3.44% 0.42% at 30 min, when the normal tissues uptake decreased sharply post-injection. The radioactivity ratio of the tumor/blood and tumor/muscle reached to 1.44 and 3.62 respectively at 60 min. 2)The tumor-inhibition rate was 32.07% at 30 min and 37.42% at 60 min. 3) A high radioactivity accumulation in tumor region could be seen in the mouse at 60 min post 131I-insulin injection. The radioactivity ratio of the tumor/normal tissue was 2.13 and it declined to 1.37 after received insulin 2 mg intervention. Conclusions

Synthesis and preliminary biodistribution studies of [131I]SIB-PEG4-CHC in tumor-bearing mice

International Nuclear Information System (INIS)

Xiaobei Zheng; Jing Yang; Xiaojiang Duan; Tingting Niu; Wangsuo Wu; Jianjun Wang; Feng Dong

2011-01-01

This work reports the synthesis and preliminary biodistribution results of [ 131 I]SIB-PEG 4 -CHC in tumor-bearing mice. The tributylstannyl precursor ATE-PEG 4 -CHC was synthesized by conjugation of ATE to amino pegylated colchicine NH 2 -PEG 4 -CHC. [ 131 I]SIB-PEG 4 -CHC was radiosynthesized by electrophilic destannylation of the precursor with a yield of ∼44%. The radiochemical purity (RCP) appeared to be >95% by a Sep-Pak cartridge purification. [ 131 I]SIB-PEG 4 -CHC was lipophilic and was stable at room temperature. Biodistribution studies in tumor-bearing mice showed that [ 131 I]SIB-PEG 4 -CHC cleared from background rapidly, and didn't deiodinate in vivo. However, the poor tumor localization excluded it from further investigations as a tumor-targeted radiopharmaceuticals. (author)

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

Science.gov (United States)

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.

Establishment and characterization of murine small cell lung carcinoma cell lines derived from HPV-16 E6/E7 transgenic mice.

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Carraresi, Laura; Martinelli, Rosanna; Vannoni, Alessandro; Riccio, Massimo; Dembic, Maja; Tripodi, Sergio; Cintorino, Marcella; Santi, Spartaco; Bigliardi, Elisa; Carmellini, Mario; Rossini, Mara

2006-01-08

We have established two murine cell lines derived from Small Cell Lung Carcinomas (SCLCs) developed by HPV-E6/E7 transgenic mice. These cells named PPAP-9 and PPAP-10 were isolated from mice bearing tumors, 9 and 10 months old, respectively. The cells, 5 microm in diameter, express HPV oncoproteins and sustain tumor formation after subcutaneous injection in syngenic mice. A detailed analysis indicated the epithelial origin and the neuroendocrine differentiation of these cells. We showed by confocal immunofluorescence the expression of the epithelial marker cytokeratin 5, whose gene promoter was used to direct the expression of HPV E6/E. Cells express several neuroendocrine markers such as CGRP, MAP-2, Ash1, CgrA, Scg2. The neuroendocrine differentiation of these cells was further confirmed by electron microscopy demonstrating neuropeptides secreting granules in their cytoplasm. Furthermore, in agreement with the altered expression observed in the majority of human SCLC we showed in these cells the absence of both p53 and pRB and a dramatic reduction in the expression of Caveolin-1.

IDENTIFICATION OF PARAMECIUM BURSARIA SYNGENS THROUGH MOLECULAR MARKERS – COMPARATIVE ANALYSIS OF MITOCHONDRIAL CYTOCHROME C OXIDASE SUBUNIT I (COI

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Patrycja Zagata

2014-08-01

Full Text Available The aim of this study is an identification of Paramecium bursaria syngens originating from different geographical locations and proving the correlation between distributions and belonging to any of five syngens. Ten strains of Paramecium bursaria belonging to five different syngens and strain of Paramecium multimicronucleatum were investigated using molecular marker — mitochondrial cytochrome c oxidase subunit I (COI. According to results, obtained in this study, using phylogenetic methods like Neighbor Joining (NJ and Maximum Likelihood (ML, relationship between analyzing strains through their clustering in clusters and correlation between strains belonging to any syngen and syngen’s distribution was confirmed. Phylograms constructed using NJ and ML methods revealed strains’ grouping in five clusters. Results which were obtained revealed usefulness of COI as a biomarker, which is important in identification of Paramecium bursaria syngens. This reports to a great potential of COI as a molecular marker and obtaining dependable results through combination of molecular methods with classical ones.

Distribution of Selenium and Oxidative Stress in Breast Tumor-Bearing Mice

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Pei-Chung Chen

2013-02-01

Full Text Available The present study investigated the effects of breast tumors on the blood and tissue distribution of essential trace mineral selenium (Se, and oxidative stress status of mice. Female 10-week-old BALB/cByJNarl mice were randomly assigned into control (CNL and breast tumor-bearing (TB groups. TB mice were injected subcutaneously into the right hind thigh with 5 × 106 EMT6 mouse mammary tumor cells. After 22 days, we measured Se concentrations, Se-dependent glutathione peroxidase (GPx activities, and malondialdehyde (MDA products (indicator of oxidative stress in plasma, various tissues, and plasma vascular endothelial growth factor (VEGF concentrations. There were no significant differences in body weights and daily intake between both groups. Compared with the CNL group, TB mice have decreases in plasma Se concentrations and GPx activities, as well as higher plasma VEGF and MDA concentrations. Plasma Se concentrations were also negatively correlated with plasma MDA and VEGF concentrations. Furthermore, tissue Se concentrations and GPx activities in TB animals were lower; whereas the MDA concentrations higher in various tissues including liver, kidney, brain, lung, spleen, and thymic tissues. In conclusion, disruption of Se homeostasis critically reflects oxidative stress in target tissues, thus may increase the risk for progression of breast cancer and metastasis.

Macrophage inhibitory cytokine-1 (MIC-1/GDF15 slows cancer development but increases metastases in TRAMP prostate cancer prone mice.

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Yasmin Husaini

Full Text Available Macrophage inhibitory cytokine-1 (MIC-1/GDF15, a divergent member of the TGF-β superfamily, is over-expressed by many common cancers including those of the prostate (PCa and its expression is linked to cancer outcome. We have evaluated the effect of MIC-1/GDF15 overexpression on PCa development and spread in the TRAMP transgenic model of spontaneous prostate cancer. TRAMP mice were crossed with MIC-1/GDF15 overexpressing mice (MIC-1(fms to produce syngeneic TRAMP(fmsmic-1 mice. Survival rate, prostate tumor size, histopathological grades and extent of distant organ metastases were compared. Metastasis of TC1-T5, an androgen independent TRAMP cell line that lacks MIC-1/GDF15 expression, was compared by injecting intravenously into MIC-1(fms and syngeneic C57BL/6 mice. Whilst TRAMP(fmsmic-1 survived on average 7.4 weeks longer, had significantly smaller genitourinary (GU tumors and lower PCa histopathological grades than TRAMP mice, more of these mice developed distant organ metastases. Additionally, a higher number of TC1-T5 lung tumor colonies were observed in MIC-1(fms mice than syngeneic WT C57BL/6 mice. Our studies strongly suggest that MIC-1/GDF15 has complex actions on tumor behavior: it limits local tumor growth but may with advancing disease, promote metastases. As MIC-1/GDF15 is induced by all cancer treatments and metastasis is the major cause of cancer treatment failure and cancer deaths, these results, if applicable to humans, may have a direct impact on patient care.

Preparation and Identification of HER2 Radioactive Ligands and Imaging Study of Breast Cancer-Bearing Nude Mice

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Meng-zhi Zhang

2017-08-01

Full Text Available OBJECTIVE: A micro-molecule peptide TP1623 of 99mTc-human epithelial growth factor receptor 2 (HER2 was prepared and the feasibility of using it as a HER2-positive molecular imaging agent for breast cancer was evaluated. METHODS: TP1623 was chemically synthesized and labeled with 99mTc. The labeling ratio and stability were detected. HER2 expression levels of breast cancer cells (SKBR3 and MDA-MB-231 and cell binding activity were measured. Biodistribution of 99mTC-TP1623 in normal mice was detected. SKBR3/MDA-MB-231-bearing nude mice models with high/low expressions of HER2 were established. Tumor tissues were stained with hematoxylin–eosin (HE and measured by immunohistochemistry to confirm the formation of tumors and HER2 expression. SPECT imaging was conducted for HER2-overexpressing SKBR3-bearing nude mice. The T/NT ratio was calculated and compared with that of MDA-MB-231-bearing nude mice with low HER2 expression. The competitive inhibition image was used to discuss the specific binding of 99mTc- TP1623 and the tumor. RESULTS: The labeling ratio of 99mTc-TP1623, specific activity, and radiochemical purity (RCP after 6 h at room temperature were (97.39 ± 0.23%, (24.61 ± 0.06 TBq/mmol, and (93.25 ± 0.06%, respectively. HER2 of SKBR3 and MDA-MB-231 cells showed high and low expression levels by immunohistochemistry, respectively. The in vitro receptor assays indicated that specific binding of TP1623 and HER2 was retained. Radioactivity in the brain was always at the lowest level, while the clearance rate of blood and the excretion rate of the kidneys were fast. HE staining showed that tumor cells were observed in SKBR3- and MDA-MB-231-bearing nude mice, with significant heteromorphism and increased mitotic count. The imaging of mice showed that targeted images could be made of 99mTc-TP1623 in high HER2-expressing tumors, while no obvious development was shown in tumors in low HER2-expressing nude mice. No development was visible in

Salmonella Immunotherapy Improves the Outcome of CHOP Chemotherapy in Non-Hodgkin Lymphoma-Bearing Mice

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Bascuas, Thais; Moreno, María; Grille, Sofía; Chabalgoity, José A.

2018-01-01

We have previously shown that Salmonella immunotherapy is effective to treat B-cell non-Hodgkin lymphoma (B-NHL) in mice. However, this model involves animals with high tumor burden, whereas in the clinics B-NHL patients are usually treated with chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line therapy prior to immunotherapy. Recently, we have described a NHL-B preclinical model using CHOP chemotherapy to achieve MRD in immunocompetent animals that closely resemble patients’ conditions. In this work, we assessed the efficacy of Salmonella immunotherapy in B-NHL-bearing mice undergoing chemotherapy. Salmonella administration significantly delayed tumor growth and prolonged survival of chemotherapy-treated NHL-bearing animals. Mice receiving the CHOP–Salmonella combined therapy showed increased numbers of tumor-infiltrating leukocytes and a different profile of cytokines and chemokines expressed in the tumor microenvironment. Further, Salmonella immunotherapy in CHOP-treated animals also enhanced NK cells cytotoxic activity as well as induced systemic lymphoma-specific humoral and cellular responses. Chemotherapy treatment profoundly impacted on the general health status of recipient animals, but those receiving Salmonella showed significantly better overall body condition. Altogether, the results clearly demonstrated that Salmonella immunotherapy could be safely used in individuals under CHOP treatment, resulting in a better prognosis. These results give strong support to consider Salmonella as a neoadjuvant therapy in a clinical setting. PMID:29410666

Local control of murine melanoma xenografts in nude mice by neutron capture therapy

International Nuclear Information System (INIS)

Allen, B.J.; Corderoy-Buck, S.; Moore, D.E.; Mishima, Y.; Ichihashi, M.

1992-01-01

In recent years considerable progress has been made in the development and implementation of neutron capture therapy (NCT) for the treatment of cancer. In particular, the boron analogue of the melanin precursor phenylalanine, i.e., DL-p-boronophenylalanine (BPA), has been used to demonstrate the regression and cure of Harding-Passey (HP) melanoma in syngeneic mice. However, 18 to 25% cures were obtained for neutron irradiations without boron, suggesting that the neutron dose alone plays an important role. Neutron capture therapy of B-16 melanoma xenografts in nude mice showed substantial tumor regression over 35 days, but the survival rate of NCT treated mice after 7 weeks was only 40-60%. In this paper the authors demonstrate the equivalence of the nude mouse model with a syngeneic model, using the same Harding-Passey murine melanoma line, and delineate the conditions required for maximum differential response between neutron irradiation with and without BPA administration, with complete local control as the end point

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

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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.

Protease-Sensitive Liposomes in Chemotherapy & Chemoradiotherapy: From Material Development to In Vivo Application in Tumor-Bearing Mice

DEFF Research Database (Denmark)

Brogaard, Rikke Yding; Melander, Fredrik

to enhance therapeutic efficacies. In this thesis, the development, characterization, and evaluation of an advanced liposomal DDS and its potential in chemoradiotherapy is presented from material development to in vivo application in tumor*bearing mice. In the first part of the thesis, we report the design...... concept of the liposomal DDS, which leads to rapid cellular uptake. Various lipid compositions are tested in uptake and cytotoxicity experiments in vitro, followed by in vivo experiments where the ability of the liposomal DDS to accumulate in tumors together with its anti*cancer activity is explored...... in tumor*bearing mice. The in vivo data demonstrates superior anti*cancer activity relative to the free drug and to conventional, long circulating liposomes. This indicates that the MMP*sensitive liposomal DDS holds potential in therapeutic applications. In the second part of the thesis, the potential...

The production of IL-1, IL-3, CSA by bone marrow nuclears during bone marrow haemopoiesis after lethal irradiation and syngenic bone marrow transplantation

International Nuclear Information System (INIS)

Dygaj, A.M.; Buznik, D.V.; Bogdashin, I.V.; Agafonov, V.I.

1994-01-01

The production of haemopoietic factors (IL-1, IL-3, CSA) by adherent and unadherent cells of lethally irradiate CBA mice bone marrow and after syngenic myelokaryocyte transplantation was studied. Radioresistant myelokaryocytes capable to produce haemopoetic factors IL-1, CSA as early as 24 hr after irradiation were found in adherent cell fraction. The synthesis of humoral factors (IL-3, CSA) by unadherent bone marrow elements was realised in a late of experiment (3-6 days) that was connected with forming of functionally valuable cell forms from transplanted or viable stem cells

Immunological tolerance to lymphocytic choriomeningitis virus in neonatally infected virus carrier mice: evidence supporting a clonal inactivation mechanism

International Nuclear Information System (INIS)

Cihak, J.; Lehmann-Grube, F.

1978-01-01

Experiments are described aimed at analysing the mechanism responsible for the absence of cell-mediated immunity against LCM virus-infected cells in neonatally established LCM virus carrier mice. Virus-specific cell-mediated immunity was assessed by 51 Cr release and target cell reduction assays. Attempts to demonstrate cells in spleens of CBA/J carrier mice able to suppress in syngeneic recipients the induction or the effector phase of the cytotoxic T-cell response against LCM virus-infected cells were unsuccessful. Also, no factors were detected in CBA/J and C57BL/6J carrier mice, either spleen cell-associated or free in the circulation, which would block the activity of cytotoxic T-lymphocytes against LCM virus-infected syngeneic target cells. The results indicate that inability of LCM virus carrier mice to act immunologically against virus-infected target cells is due to deletion or irreversible inactivation of T lymphocytes carrying receptors for virally altered cell membrane antigens. (author)

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

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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...

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

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Li HY

2016-06-01

Full Text Available Huaiyu Li,1,* Longlong Gu,1,2,* Yuanyuan Zhong,1 Yajuan Chen,1 Lei Zhang,1 Annie R Zhang,3 Robert W Sobol,4,5 Tong Chen,1,6 Jianfeng Li4,5 1Yunnan Key Laboratory of Pharmacology for Natural Products, School of Pharmaceutical Sciences, 2Haiyuan College, Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 3Graduate School of Applied and Professional Psychology, Rutgers, The State University of New Jersey, Piscataway, NJ, 4Department of Oncologic Sciences, 5Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA; 6Yunnan Panax notoginseng (Burk F.H. Chen Biotechnology and Pharmaceutical Engineering Research Center, Kunming, Yunnan, People’s Republic of China *These authors contributed equally to this work 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. Keywords: polysaccharide, Panax notoginseng, liver cancer, immunotherapy, IL-2

The research on biodistribution of bearing sarcoma mice and rabbit SPECT imaging of 177Lu-DOTMP

International Nuclear Information System (INIS)

Deng Xinrong; Xiang Xueqin; Li Fenglin; Fan Caiyun; Liu Zihua; Luo Zhifu; Chen Yang

2012-01-01

Cyclen (1, 4, 7, 10-tetraazacyclododecane) and H 3 PO 3 were used to synthesis DOTMP (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-Tetraaminomethylenephosphonate), and then DOTMP was labelled with 177 Lu. The research of biodistribution of 177 Lu-DOTMP in model mice bearing S180 sarcoma and SPECT imaging in Japanese white rabbit were also carried out. The results of biodistribution of bearing S180 mice indicated that 177 Lu-DOTMP cleared rapidly from blood and was selectively delivered to target bone. The radioactivity uptake was mainly in bone and less in other organs and tissues. The results of SPECT imaging of Japanese white rabbit showed that the radioactivity was accumulated in bladder. 177 Lu-DOTMP was mainly excreted by kidney. The uptake of the activity in the skeleton was observed significantly within 22 h post-injection and it became quite significant at 46 h post-injection. It indicated that 177 Lu-DOTMP has good bone targeting and is worthy of further study. (authors)

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

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Yang Z

2017-01-01

Full Text Available Zhaoshuo Yang,1 Jianhua Liu,2 Qingqing Huang,3 Zhouji Zhang,1 Jiawei Zhang,1 Yanjia Pan,1 Yunke Yang,1 Dengfeng Cheng4 1Department of Chinese Traditional Medicine, Zhongshan Hospital, Fudan University, 2School of Medicine, Shanghai Jiao Tong University, 3Department of Nuclear Medicine, Shanghai 10th People’s Hospital, Tongji University School of Medicine, 4Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China 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�

Differentiation of bone marrow cells to functional T lymphocytes following implantation of thymus grafts and thymic stroma in nude and ATxBM mice

International Nuclear Information System (INIS)

Splitter, G.A.; McGuire, T.C.; Davis, W.C.

1977-01-01

Cardiac allografts were used to compare the immunologic capacity of nude mice and adult, thymectomized, lethally irradiated, bone marrow-reconstituted (AT x BM) mice. Neither nude nor AT x BM mice were able to reject cardiac allografts of any party. However, both rejected grafts of any party following implantation of neonatal thymus or thymus from 3-week-old syngeneic mice. Irradiated syngeneic thymus grafts (800 R) were equally effective in restoring host responsiveness against allografts. In contrast, allogeneic thymus grafts restored the capacity to reject second-party heart grafts only in AT x BM mice. Second-party grafts persisted indefintely when placed on nude mice implanted with an allogeneic, unirradiated thymus graft. Third-party grafts transplanted 17 weeks after reconstitution, however, were rejected. Irradiated nude mice given normal littermate bone marrow and simultaneously grafted with second-party thymus and heart allografts also failed to reject their second-party heart grafts. The difference in ultimate capacity to respond between AT x BM and nude mice suggests that a maturational defect exists in the nude mouse environment which impedes development of precursor T lymphocytes

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

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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.

Anti-idiotypic antibodies against UV-induced tumor-specific CTL clones. Preparation in syngeneic combination

International Nuclear Information System (INIS)

Kuribayashi, K.; Tanaka, C.; Matsubayashi, Y.; Masuda, T.; Udono, H.; Abe, M.; Nakayama, E.; Shiku, H.

1988-01-01

In this study, we first established several CTL clones of (BALB/c x C57BL/6)F1 origin that were specific for either syngeneic UV female 1 or UV male 1 fibrosarcoma cell lines. All the CTL clones had Thy-1+ Lyt-2+ L3T4- phenotypes and showed Kd restriction when lysing the corresponding target cells. Sera obtained from syngeneic animals immunized with three CTL clones, 10B-5 for UV female 1, and CTL9 and CTL10 for UV male 1, showed specific inhibition of target cell lysis with the corresponding CTL clones. The inhibitory activities were found in sera of the majority of immunized animals. Because the inhibitory activity resides in protein A-binding fraction, mAb were produced by hybridizing spleen cells of hyperimmune animals. N1-56 was thus obtained from a mouse immunized with 10B-5 CTL clone reactive with UV female 1. N1-56 was clonotype specific, reacting with 10B-5 but not with other CTL lines or leukemia cell lines. No N1-56+ cells were detectable in thymocytes, lymph node cells, or spleen cells of either naive or UV female 1-immune CB6F1 mice. Immunoprecipitation showed that N1-56 reacts with 90,000 Mr molecules on 10B-5 CTL clone under nonreducing conditions and 45,000 Mr molecules under reducing conditions, indicating its reactivities with idiotypic determinants of TCR on the CTL clone. N1-56 inhibited lytic activity of 10B-5, but neither N1-56 nor alpha-10B-5 hyperimmune serum inhibited that of alpha-UV female 1 mixed lymphocyte tumor cell culture cells. N1-56 induced proliferation of 10B-5 without addition of Ag

Increased hypoxia-inducible factor-1α in striated muscle of tumor-bearing mice.

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Devine, Raymond D; Bicer, Sabahattin; Reiser, Peter J; Wold, Loren E

2017-06-01

Cancer cachexia is a progressive wasting disease resulting in significant effects on the quality of life and high mortality. Most studies on cancer cachexia have focused on skeletal muscle; however, the heart is now recognized as a major site of cachexia-related effects. To elucidate possible mechanisms, a proteomic study was performed on the left ventricles of colon-26 (C26) adenocarcinoma tumor-bearing mice. The results revealed several changes in proteins involved in metabolism. An integrated pathway analysis of the results revealed a common mediator in hypoxia-inducible factor-1α (HIF-1α). Work by other laboratories has shown that extensive metabolic restructuring in the C26 mouse model causes changes in gene expression that may be affected directly by HIF-1α, such as glucose metabolic genes. M-mode echocardiography showed progressive decline in heart function by day 19 , exhibited by significantly decreased ejection fraction and fractional shortening, along with posterior wall thickness. Using Western blot analysis, we confirmed that HIF-1α is significantly upregulated in the heart, whereas there were no changes in its regulatory proteins, prolyl hydroxylase domain-containing protein 2 (PHD2) and von Hippel-Lindau protein (VHL). PHD2 requires both oxygen and iron as cofactors for the hydroxylation of HIF-1α, marking it for ubiquination via VHL and subsequent destruction by the proteasome complex. We examined venous blood gas values in the tumor-bearing mice and found significantly lower oxygen concentration compared with control animals in the third week after tumor inoculation. We also examined select skeletal muscles to determine whether they are similarly affected. In the diaphragm, extensor digitorum longus, and soleus, we found significantly increased HIF-1α in tumor-bearing mice, indicating a hypoxic response, not only in the heart, but also in skeletal muscle. These results indicate that HIF-1α may contribute, in part, to the metabolic changes

Malignant myoepithelial cells are associated with the differentiated papillary structure and metastatic ability of a syngeneic murine mammary adenocarcinoma model

International Nuclear Information System (INIS)

Bumaschny, Viviana; Urtreger, Alejandro; Diament, Miriam; Krasnapolski, Martín; Fiszman, Gabriel; Klein, Slobodanka; Joffé, Elisa Bal de Kier

2004-01-01

The normal duct and lobular system of the mammary gland is lined with luminal and myoepithelial cell types. Although evidence suggests that myoepithelial cells might suppress tumor growth, invasion and angiogenesis, their role remains a major enigma in breast cancer biology and few models are currently available for exploring their influence. Several years ago a spontaneous transplantable mammary adenocarcinoma (M38) arose in our BALB/c colony; it contains a malignant myoepithelial cell component and is able to metastasize to draining lymph nodes and lung. To characterize this tumor further, primary M38 cultures were established. The low-passage LM38-LP subline contained two main cell components up to the 30th subculture, whereas the higher passage LM38-HP subline was mainly composed of small spindle-shaped cells. In addition, a large spindle cell clone (LM38-D2) was established by dilutional cloning of the low-passage MM38-LP cells. These cell lines were studied by immunocytochemistry, electron microscopy and ploidy, and syngeneic mice were inoculated subcutaneously and intravenously with the different cell lines, either singly or combined to establish their tumorigenic and metastatic capacity. The two subpopulations of LM38-LP cultures were characterized as luminal and myoepithelium-like cells, whereas LM38-HP was mainly composed of small, spindle-shaped epithelial cells and LM38-D2 contained only large myoepithelial cells. All of them were tumorigenic when inoculated into syngeneic mice, but only LM38-LP cultures containing both conserved luminal and myoepithelial malignant cells developed aggressive papillary adenocarcinomas that spread to lung and regional lymph nodes. The differentiated histopathology and metastatic ability of the spontaneous transplantable M38 murine mammary tumor is associated with the presence and/or interaction of both luminal and myoepithelial tumor cell types

Experimental study of hypoxia-imaging agent 99mTc-HL91 in mice bearing glioblastoma G422

International Nuclear Information System (INIS)

Zhou Ying; Qu Wanying; Yao Zhiming; Chen Fang; Zhu Ming; Zhu Lin

1999-01-01

Objective: To evaluate the ability of detecting cerebral tumor by 99m Tc-HL91 in mice bearing glioblastoma G422. Methods: Six model mice underwent static whole body planar imagings at once and at 1,2,3,4,6,7,8 h postinjection of 99m Tc-HL91. Three mice each were killed at 4 h and 8 h, respectively. the tumor, blood and organs were removed, weighted and the radioactivity was measured. ROIs were drawn around tumor, head, contralateral axilla and chest in whole body planar images, and the radioactivity ratios of tumor to head (T/H), contralateral axilla (T/A) and chest (T/C) were calculated. Results: Increased tumor activity was identified in static whole body planar images since 1 h postinjection. At 2h postinjection, T/H, T/A and T/C were 2.93 +- 0.51, 4.86 +- 0.79 and 2.00 +- 0.35 respectively, which were significantly higher than those at once and at 1h postinjection (P 99m Tc-HL91 in tumor tissue of mice bearing glioblastoma G422 is increased and clearance rate is decreased. 99m Tc-HL91 imaging is suitable for glioblastoma at 2 h postinjection. It is appropriate to image tumors in head, neck, thorax, bone and soft tissues, but not in abdominal area

A Color-coded Imageable Syngeneic Mouse Model of Stromal-cell Recruitment by Metastatic Lymphoma.

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Matsumoto, Takuro; Suetsugu, Atsushi; Shibata, Yuhei; Nakamura, Nobuhiko; Aoki, Hitomi; Kunisada, Takahiro; Tsurumi, Hisashi; Shimizu, Masahito; Hoffman, Robert M

2015-09-01

A syngeneic color-coded imageable lymphoma model has been developed to visualize recruitment of host stromal cells by malignant lymphoma during metastasis. The EL4 cell line was previously derived from a lymphoma induced in a C57/BL6 mouse by 9,10-dimethyl-1,2-benzanthracene. EL4 lymphoma cells expressing red fluorescent protein (EL4-RFP) were initially established. EL4-RFP cells were subsequently injected into the tail vein of C57/BL6-GFP transgenic mice. EL4-RFP metastasis was observed in the lymph nodes of the upper mediastinum and in the liver 28 days after cell injection. Large EL4-RFP liver metastases in C57/BL6-GFP mice contained GFP-expressing stromal cells derived from the host. In addition, EL4-RFP lymphoma metastasis was formed in peri-gastric lymph nodes, which were also enriched in host GFP-expressing cells. Furthermore, EL4-RFP lymphoma cells were also observed in the peripheral blood and bone marrow of C57/BL6-GFP transgenic mice, where they were associated with GFP-expressing host cells. Lymph node, liver and bone marrow metastases were found approximately 4 weeks after transplantation and all RFP-expressing metastases were highly enriched in GFP-expressing host stromal cells. This model of malignant lymphoma can be used to study early tumor development, metastasis, and the role of the stroma, as well as for discovery and evaluation of novel therapeutics for this treatment-resistant disease. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

[Protective effect of polysaccharides extracts from corn silk against cyclophosphamide induced host damages in mice bearing H22 tumors].

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Wu, Xian-chuang; Du, Gang-jun; Song, Xiao-yong; Zhang, Yong-zhou; Liu, Yu-xin

2014-10-01

To study the protective effect of polysaccharides from corn silk (PCS) against cyclophosphamide (CTX) induced host damages in mice bearing H22 tumors. The ascitic and solid tumor bearing mice model were established to investigate the anti-tumor effects of different dose of PCS (100, 200 and 300 mg/kg). The effects of PCS alone and with combination of CTX on tumor weight, survival time, thymus and spleen index, white blood cell, nucleated cell of marrow, serum ALT and AST level were tested. The high-dose PCS (300 mg/kg) had significant inhibitory effects on tumor. After combination with CTX, the tumor inhibitory ratio was enhanced to 68.71%, the survival time of tumor-burdened ascites tumor mice was significantly prolonged to 72.07% compared with CTX group. The Q value of combination group was 0.997. Thymus and spleen index, white blood cell, nucleated cell of marrow decreased by CTX were ameliorated significantly. The level of ALT and AST increased by CTX were reduced by combination with PCS. PCS has a potent inhibitory effect on the growth of implanted H22 tumors in mice and has a synergetic effect and an attenuated toxic effect in combination with CTX.

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

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Ramon eGarcia-Areas

2014-02-01

Full Text Available Semaphorins, a large family of molecules involved in the axonal guidance and development of the nervous system, 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 via it binding to α1β1integrins. Additionally, SEMA7A has been shown to promote chemotaxis of monocytes, inducing them to produce proinflammatory mediators. In this study we explored the role of SEMA7A in the tumoral context. We show that SEMA7A is highly expressed by DA-3 murine mammary tumor cells in comparison to normal mammary cells (EpH4, and that peritoneal macrophages from mammary tumor-bearing mice also express SEMA7A at higher levels compared to peritoneal macrophages derived from normal control mice. We also show that murine macrophages treated with recombinant murine SEMA7A significantly increased their expression of proangiogenic molecules, such as CXCL2/MIP-2. Gene silencing of SEMA7A in peritoneal elicited macrophages from DA-3 tumor-bearing mice resulted in decreased CXCL2 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 MIP-2, CXCL1 and MMP-9, compared to macrophages from control DA-3 mammary tumors. We postulate that SEMA7A derived from mammary carcinomas may serve as a monocyte chemoattractant and skew monocytes into a pro-tumorigenic phenotype. A putative relationship between tumor-derived SEMA7A and monocytes could prove valuable in establishing new research avenues towards unraveling important tumor-host immune interactions in breast cancer patients.

Transfer of in vitro expanded T lymphocytes after activation with dendritomas prolonged survival of mice challenged with EL4 tumor cells.

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Li, Jinhua; Theofanous, Leigh; Stickel, Sara; Bouton-Verville, Hilary; Burgin, Kelly E; Jakubchak, Susan; Wagner, Thomas E; Wei, Yanzhang

2007-07-01

Adoptive T cell transfer after in vitro expansion represents an attractive cancer immunotherapy. The majority of studies so far have been focusing on the expansion of tumor infiltrated lymphocytes (TIL) and some have shown very encouraging results. Recently, we have developed a unique tumor immune response activator, dendritomas, by fusion of dendritic cells and tumor cells. Animal studies and early clinical trials have shown that dendritomas are able to activate tumor specific immune responses. In this study, we hypothesized that naïve T cells can be primed with dendritomas and expanded in vitro to develop an adoptive transfer therapy for patients who do not have solid tumors, such as leukemia. T cells were isolated and purified from lymph nodes of mice. The cells were then incubated with dendritomas made from syngeneic DCs and tumor cells and expanded in vitro using Dynabeads mouse CD3/CD28 T cell expander for approximately three weeks. The in vitro primed and expanded T cells showed tumor cell specific CTL activity and increased secretion of IFN-gamma. Tumor bearing mice receiving the in vitro expanded T cells survived significantly longer than control mice. Furthermore, the depletion of regulator T cells enhanced the survival of the mice that received the adoptive transfer therapy.

Tetrandrine Suppresses Cancer Angiogenesis and Metastasis in 4T1 Tumor Bearing Mice

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Jian-Li Gao

2013-01-01

Full Text Available Metastasis remains the most deadly aspect of cancer and still evades direct treatment. Thus, there is a great need to develop new treatment regimens to suppress tumor cells that have escaped surgical removal or that may have already disseminated. We have found that tetrandrine (TET exhibits anticolon cancer activity. Here, we investigate the inhibition effect of TET to breast cancer metastasis, angiogenesis and its molecular basis underlying TET’s anticancer activity. We compare TET with chemotherapy drug doxorubicin in 4T1 tumor bearing BALB/c mice model and find that TET exhibits an anticancer metastatic and antiangiogenic activities better than those of doxorubicin. The lung metastatic sites were decreased by TET, which is confirmed by bioluminescence imaging in vivo. On the other hand, laser doppler perfusion imaging (LDI was used for measuring the blood flow of tumor in 4T1-tumor bearing mice. As a result, the local blood perfusion of tumor was markedly decreased by TET after 3 weeks. Mechanistically, TET treatment leads to a decrease in p-ERK level and an increase in NF-κB levels in HUVECs. TET also regulated metastatic and angiogenic related proteins, including vascular endothelial growth factor, hypoxia-inducible factor-1α, integrin β5, endothelial cell specific molecule-1, and intercellular adhesion molecule-1 in vivo.

Lactobacillus casei ssp.casei induced Th1 cytokine profile and natural killer cells activity in invasive ductal carcinoma bearing mice.

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Soltan Dallal, Mohammad Mehdi; Yazdi, Mohammad Hossein; Holakuyee, Marzieh; Hassan, Zuhair Mohammad; Abolhassani, Mohsen; Mahdavi, Mehdi

2012-06-01

Lactic acid bacteria which are used as probiotics have ability to modulate immune responses and modify immune mechanisms. It has also been indicated that some strains of this family can affect the immune responses against solid tumors. In the present work, we proposed to study the effects of oral administration of L.cacesi ssp casei on the NK cells cytotoxicity and also production of cytokines in spleen cells culture of BALB/c mice bearing invasive ductal carcinoma. 30 female In-bred BALB/c mice, were used and divided in two groups of test and control each containing 15 mice. Every day from 2 weeks before tumor transplantation 0.5 ml of PBS containing 2.7×108 CFU/ml of L.casei spp casei was orally administered to the test mice and it was followed 3 weeks after transplantation as well with 3 days interval between each week. Control mice received an equal volume of PBS in a same manner. Results showed that oral administration of L. casei significantly increased the production of IL-12 and IFN-γ (Psurvival was significantly prolonged in comparison to the controls. Our findings suggest that daily intake of L.casei can improve immune responses in mice bearing invasive ductal carcinoma, but further studies are needed to investigate the other involving mechanisms in this case.

Radiolabeled F(ab')2-cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models.

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Bellaye, P-S; Moreau, M; Raguin, O; Oudot, A; Bernhard, C; Vrigneaud, J-M; Dumont, L; Vandroux, D; Denat, F; Cochet, A; Brunotte, F; Collin, B

2018-05-17

This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111 In and 177 Lu, respectively. We designed F(ab') 2 -fragments of cetuximab radiolabeled with 111 In and 177 Lu. 111 In-F(ab') 2 -cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111 In-F(ab') 2 -cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177 Lu-F(ab') 2 -cetuximab was evaluated in SWISS nude mice bearing A431 tumors. Radiolabeling procedure did not change F(ab') 2 -cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111 In-DOTAGA-F(ab') 2 -cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab') 2 -cetuximab. SPECT imaging of 111 In-DOTAGA-F(ab') 2 -cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177 Lu-DOTAGA-F(ab') 2 -cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. 111 In-DOTAGA-F(ab') 2 -cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177 Lu-DOTAGA-F(ab') 2 -cetuximab is an interesting theranostic tool allowing therapy and imaging.

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

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

2009-01-01

Abstract 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 ...

Protection of lethally irradiated mice with allogeneic fetal liver cells: influence of irradiation dose on immunologic reconstitution

International Nuclear Information System (INIS)

Tulunay, O.; Good, R.A.; Yunis, E.J.

1975-01-01

After lethal irradiation long-lived, immunologically vigorous C3Hf mice were produced by treatment with syngeneic fetal liver cells or syngeneic newborn or adult spleen cells. Treatment of lethally irradiated mice with syngeneic or allogeneic newborn thymus cells or allogeneic newborn or adult spleen cells regularly led to fatal secondary disease or graft-versus-host reactions. Treatment of the lethally irradiated mice with fetal liver cells regularly yielded long-lived, immunologically vigorous chimeras. The introduction of the fetal liver cells into the irradiated mice appeared to be followed by development of immunological tolerance of the donor cells. The findings suggest that T-cells at an early stage of differentiation are more susceptible to tolerance induction than are T-lymphocytes at later stages of differentiation. These investigations turned up a perplexing paradox which suggests that high doses of irradiation may injure the thymic stroma, rendering it less capable of supporting certain T-cell populations in the peripheral lymphoid tissue. Alternatively, the higher and not the lower dose of irradiation may have eliminated a host cell not readily derived from fetal liver precursors which represents an important helper cell in certain cell-mediated immune functions, e.g., graft-versus-host reactions, but which is not important in others, e.g., allograft rejections. The higher dose of lethal irradiation did not permit development or maintenance of a population of spleen cells that could initiate graft-versus-host reactions but did permit the development of a population of donor cells capable of achieving vigorous allograft rejection

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice

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Shoya Shiromizu

2018-04-01

Full Text Available Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Keywords: l-asparaginase, Asparagine, Solid tumor, Chrono-pharmacotherapy

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.

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Shiromizu, Shoya; Kusunose, Naoki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

2018-04-01

Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

The immunomodulatory activities of licorice polysaccharides (Glycyrrhiza uralensis Fisch.) in CT 26 tumor-bearing mice.

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Ayeka, Peter Amwoga; Bian, YuHong; Githaiga, Peter Mwitari; Zhao, Ying

2017-12-15

The increasing use of complementary and alternative medicine (CAM) has kindled the need for scientific evaluation of the mechanism of action of CAMs. Although, licorice, a common ingredient in many Traditional Chinese medicine (TCM) has attracted great attention for its antitumor and immunomodulatory activities, the mechanism of action of its polysaccharides is still unclear. Here we report the immunomodulatory activity of licorice polysaccharides in vivo. The differential anticancer activities of licorice polysaccharides by tumorigenesis and immunomodulation was evaluated in vivo. Six weeks old, 120 CT-26 tumor bearing BALB/c mice, weighing 20 ± 2 g were used. They were randomly divided into six groups, three groups receiving high molecular weight (fraction A), low molecular weight (fraction B) polysaccharides and crude extract (fraction C); positive, negative and normal groups receiving cytoxin, saline and normal diet respectively. Weight of mice and tumors was determined and tumorigenicity assay calculated to determine the anticancer effects. Immunomodulatory potential was determined by immune organ indices, immune cell population and serum cytokine levels using immune organ weight and index, flow cytometry and cytokine/chemokine bead panel kit respectively. Licorice polysaccharides exhibited immunomodulatory activities in CT 26 tumor bearing BALB/c mice. The polysaccharides significantly suppressed tumor growth and increased immune organ index. Furthermore, the immunomodulatory effect was evident with activation of CD4 + and CD8 + immune cells population. The polysaccharides also affected the production of various cytokines, by increasing IL 2, IL 6, IL 7 levels and a decreasing TNFα levels. In summary, licorice polysaccharide especially of low molecular weight exhibit anticancer and immunomodulatory activities by suppressing tumor growth and improving general health of mice. They also augment the thymus/spleen index and population of T lymphocytes

Biodistribution and SPECT imaging of 99Tcm labeling NGR peptide in nude mice bearing human HePG2 hepatoma

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Ma Wenhui; Wang Jing; Yang Weidong; Li Guiyu; Ma Xiaowei; Wang Zhe

2012-01-01

A peptide containing the Asn-Gly-Arg (NGR) sequence was radiolabeled by 99 Tc m and its radiochemical characteristics, biodistribution and SPECT imaging in nude mice bearing human HePG2 hepatoma were evaluated. 99 Tc m -NGR was prepared directly with a labeling yield higher than 90%, and the radiochemical purity (RCP) higher than 95%. Nude mice bearing human HePG2 hepatoma were randomly divided into 6 groups with 3 mice in each group. The control group mice were blocked by injecting 100 μg unlabeled NGR 0.5 h before 99 Tc m -NGR injection. The mice were sacrificed at 1, 2, 4, 8, 12 h after caudal intravenous injection of 7.4 MBq 99 Tc m -NGR. The uptakes of kidney and liver were very high. Tumor uptake was (2.52±0.62)% ID/g at 1 h, with the highest uptake of (7.26±2.71) %ID/g. At 12 h, the uptake was still (3.93±1.93) %ID/g. In comparison, the uptake of the blocked control group was (1.29±0.85) %ID/g. The SPECT static images of 3 mice and the tumor/muscle (T/NT) value were obtained. The highest T/NT value was 3.25 at 4 h. The xenografted tumor became visible at 1 h and the clearest image of the tumor was observed at 12 h. Results from this work shows that 99 Tc m -NGR can be efficiently prepared, can favorably target tumor angiogenesis, and should be a potential probe in tumor therapy. (authors)

Effect of all-trans retinoic acid combined with trichostatin A on the nude mice bearing human follicular thyroid carcinoma

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Yu Libo; Yuan Gengbiao

2011-01-01

Objective: To study the changes of iodine uptake of the follicular thyroid carcinoma cell line (FTC-133) and nude mice bearing human follicular thyroid carcinoma after the induction with all-trans retinoic acid (ATRA), trichostatin A (TSA) or ATRA combined with TSA. Methods: After the induction with ATRA, TSA, or ATRA combined with TSA in different concentrations for 96 h, the iodine uptake of FTC-133 cells was observed. The concentrations for different groups were as follows: ATRA 1.0 ×10 -6 mol/L(A low group), ATRA 1.0 × 10 -4 mol/L (A high group), TSA 1.65 ×10 -7 mol/L (T group), A low + T group, A high + T group and ethanol (control group). Cell quantities and morphology were observed by HE staining. FTC-133 cells were subcutaneously injected into nude mice. Twelve nude mice were randomly divided into 4 groups after tumor formation: ATRA group (2 mg/kg, intragastric administration), TSA group (10 mg/kg, intraperitoneal injection), combined therapy group (ATRA + TSA, the same doses as above) and saline control group (10 ml/kg, intragastric and intraperitoneal administration, respectively). Drugs were administered to the tumor-bearing mice according to the mouse body mass daily. At the 22nd day, the tumor-bearing mice were injected with 37 MBq 131 I intraperitoneally. The biodistribution of 131 I and gamma imaging were performed at 4, 6, 12 and 24 h after the injection respectively. Histopathological examinations of the tumor samples were taken after imaging completion. The results were analyzed by analysis of variance (ANOVA) with SPSS 13.0. Results: The cellular iodine uptake were (23 885 ± 616.0) and (13 849 ±728.2) counts · min -1 · 10 -6 cells in the A low + T group and A high + T group respectively, and the data were (985 ± 84.2) - (17 600 ± 782.7) counts · min -1 · 10 -6 in the other groups (F=600.879, P<0.001). The % ID/g of tumor at 6 h was 6.17 ±0.46 in the combined group and it increased to 9.34 ±0.61 at 12 h and 11.19 ± 0.98 at 24 h. The

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

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

1991-01-01

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

Syngeneic peripheral blood stem cell transplantation with immunosuppression for hepatitis-associated severe aplastic anemia

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Aleksandar Savic

2010-12-01

Full Text Available Hepatitis-associated aplastic anemia occurs in up to 10% of all aplastic anemia cases. Syngeneic bone marrow transplantation is rare in patients with severe aplastic anemia and usually requires pre-transplant conditioning to provide engraftment. We report on a 29-year-old male patient with hepatitis-associated severe aplastic anemia who had a series of severe infectious conditions before transplantation, including tracheal inflammation. Life-threatening bleeding, which developed after bronchoscopy, was successfully treated with activated recombinant factor VII and platelet transfusions. Syngeneic peripheral blood stem cell transplantation using immunosuppressive treatment with antithymocyte globulin and cyclosporin A without high-dose pre-transplant conditioning was performed, followed by complete hematologic and hepatic recovery.

Muscle wasting and impaired myogenesis in tumor bearing mice are prevented by ERK inhibition.

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Fabio Penna

Full Text Available BACKGROUND: The onset of cachexia is a frequent feature in cancer patients. Prominent characteristic of this syndrome is the loss of body and muscle weight, this latter being mainly supported by increased protein breakdown rates. While the signaling pathways dependent on IGF-1 or myostatin were causally involved in muscle atrophy, the role of the Mitogen-Activated-Protein-Kinases is still largely debated. The present study investigated this point on mice bearing the C26 colon adenocarcinoma. METHODOLOGY/PRINCIPAL FINDINGS: C26-bearing mice display a marked loss of body weight and muscle mass, this latter associated with increased phosphorylated (p-ERK. Administration of the ERK inhibitor PD98059 to tumor bearers attenuates muscle depletion and weakness, while restoring normal atrogin-1 expression. In C26 hosts, muscle wasting is also associated with increased Pax7 expression and reduced myogenin levels. Such pattern, suggestive of impaired myogenesis, is reversed by PD98059. Increased p-ERK and reduced myosin heavy chain content can be observed in TNFα-treated C2C12 myotubes, while decreased myogenin and MyoD levels occur in differentiating myoblasts exposed to the cytokine. All these changes are prevented by PD98059. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that ERK is involved in the pathogenesis of muscle wasting in cancer cachexia and could thus be proposed as a therapeutic target.

In vivo distribution of Mn-hematoporphyrin derivative in tumor bearing mice54

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Crone Escanye, M.C.; Anghilleri, L.T.; Robert, J.

1988-01-01

This paper presents results of preliminary studies of the in vivo uptake and biodistribution of manganese labbelled hematoporphyrin derivative (HpD). The results indicate that: (1) Mn-HpD 54 is crhomatographically very similar to HpD; (2) the tissue distribution of Mn-HpD 54 are overal compareble to that reported by other. Authors for C 14 -HpD and H 3 -HpD in tumor bearing mice. It seems therefore that maanganese labelled HpD for the non invasivequantitation of HpD concetration in tumor and normal tissues and may be hepful in assessing the potential usefulness of Mn-HpD in NMR imaging of living animals

Cross-immunity between syngeneic tumors in mice immunized with gamma-irradiated ascites tumors

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Kudo, Hajime; Waga, Takashi; Sato, Tatsusuke; Ogasawara, Masamichi; Ito, Izumi

1980-01-01

C3H/He mice immunized repeatedly with irradiated (13,000 rads 60 Co) MM46 or MM48, both transplantable ascites mammary carcinomas of the same strain, were subcutaneously challenged with the identical or the different tumor. In mice immunized with irradiated MM46, the growth of challenges of not only MM46 but also MM48 was inhibited. On the other hand, in mice immunized with irradiated MM48, the growth of challenges of MM48 was inhibited, but the inhibition of the growth of MM46 was not observed. Cross-immunity, therefore, was shown by immunization with MM46 but not with MM48. These findings were considered to indicate that MM46 expressed cross-immunity against MM48 because of its high resistance to the irradiation, and that MM48 did not show cross-immunity to MM46 because of its low resistance to the irradiation. (author)

Experimental study of the function of the sodium/iodide symporter (nis) in the nude mice bearing breast cancer

International Nuclear Information System (INIS)

Fan Wei; Wang Guohui; Zhang Weiguang; Dai Junjin; Yang Xiaochun

2004-01-01

Objective: To investigate the function of the sodium / iodide symporter (NIS) and the feasibility of treating breast cancer by studying the distribution and imaging of the nude mice bearing breast cancer. Methods: The animal model of MCF-7/ER(+)-bearing and MCF-7/ER(-)-bearing human breast cancer nude mice were prepared before experiments. The mice were intraperitoneally injected with 131I when tumor grown to 0.8-1 cm . The distribution of 131I in different tissues was detected at different time ( 6, 12, and 24h ). The percentage of the injected dose per gram of tissue (%D/g) and the ratio of Tumor/Non-tumor were calculated. Meanwhile, the nude mice were imaged at different time. Results: The 131I in tumor tissue in the MCF-7/ER(+)group was higher than that of MCF- 7/ER(-) group at 6h after injection, and the %ID/g were 6.13% and 2.37% respectively. The %lD/g at 12 h of two groups were 9.31 and 3.12, and were 11.21 and 3.47 at 24 h. There was a distinguish difference between them (p<0.05). At 12 h, the values of T/NT of blood, heart, lung, intestine and muscle were 2.39,3.06,3.94, 7.69 and 7.60 and were 5.15, 5.47, 5.29, 11.44 and 10.99 at 24 h. The values of T/NT of MCF-7/ER(-) group were much lower than those of MCF-7/ER(+) group. The imaging results showed that there was much radioactivity in tumor tissue in the MCF-7/ER(+) group at 12 h . The control groups has no obvious radioactivity in the tumor tissue all the time. Conclusion: Sodium/iodide symporter expressed in the estrogen-receptor-positive breast cancer tissue could transformed actively 131I into tumor tissue, which suggests 1311 therapy might become a promising way to treat breast cancer. (authors)

Combined Use of α‐Difluoromethylornithine and an Inhibitor of S‐Adenosylmethionine Decarboxylase in Mice Bearing P388 Leukemia or Lewis Lung Carcinoma

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Nakaike, Shiro; Kashiwagi, Keiko; Terao, Kiyoshi; Iio, Kokoro

1988-01-01

The antitumor and antimetastatic effects of α‐difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, combined with an inhibitor of S‐adenosylmethionine decarboxylase, either methylglyoxal bis(guanylhydrazone) (MGBG) or ethylglyoxal bis(guanylhydrazone) (EGBG), were studied in mice bearing P388 leukemia or Lewis lung carcinoma. Although EGBG is a more specific inhibitor of polyamine biosynthesis than the widely used MGBG, the antitumor effect of the DFMO‐EGBG combination on P388 leukemia‐bearing mice was less than that of the DFMO‐MGBG combination. The prolongation of survival time by the DFMOC1000 mg/kg)‐MGBG(25 mg/kg) combination was 2.65‐fold, while that of the DFMO(1000 mg/kg)‐EGBG(50 mg/kg) combination was 1.34‐fold. When mice were fed a polyamine‐deficient diet, stronger antitumor effects were exerted; the prolongation of survival time by the DFMO‐MGBG and the DFMO‐EGBG combinations was 2.89‐fold and 2.03‐fold, respectively. The antitumor effect of combined use of the two polyamine antimetabolites with mice on normal and polyamine‐deficient diets correlated with a decrease of polyamine charge contents in the tumor cells. The above in vivo results were confirmed clearly in the KB cell culture system. The antimetastatic activity of DFMO on Lewis lung carcinoma‐bearing mice was strengthened by the addition of MGBG or EGBG. The antimetastatic activity of the DFMO‐MGBG or DFMO‐EGBG combination did not parallel the polyamine charge contents in the primary tumor and blood. PMID:3133338

Distribution of a boronated porphyrin (BTPP) in osteosarcoma bearing nude mice

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Takeuchi, Akira; Ojima, N.; Kadosawa, T.; Hatanaka, H.

1992-01-01

Osteosarcoma is known as one of the malignant tumor which is highly resistant to the ordinary irradiation therapy, and amputation of the affected limb at an early stage has been a treatment of choice for long years. The authors final goal in this study is to find out a possibility to treat the osteosarcoma conserving the affected limb by irradiating high dose to the tumor specifically using the characteristics of boron-neutron capture therapy (BNCT). For the success of this study, the development of the boron carrier with specific affinity to tumor or osteosarcoma is essential. In this paper, a recently developed boronated derivative, boronotetraphenylporphyrin (BTPP) was studied for its distribution in osteosarcoma bearing nude mice by means of whole body alfa-track autoradiography

Characteristics of DTH suppressor cells in mice infected with Candida albicans.

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Valdez, J C; Mesón, O E; Sirena, A; de Alderete, N G

1987-05-01

Inoculation of 10(8) C. albicans intraperitoneally into Balb/c mice at given dosage was reported to induce suppression of antigen-specific delayed-type hypersensitivity. Adoptive transfer of spleen cells into normal syngeneic mice pre-treated with Cyclophosphamide confirmed the existence of suppressor cells in mice. Such cells were sensitive to treatment with anti-theta serum and complement, non-adherent to Sephadex G-10. A pretreatment of the mice with Cyclophosphamide eliminated DTH suppression. Treatment with antimacrophage agents via intraperitoneal abrogated suppression only if being effected before inoculation of alive 10(8) Candida albicans. It is concluded that the spleen suppressor cell is a T-lymphocyte whose precursor is Cyclophosphamide-sensitive, requiring the macrophage to be induced.

Molecular Identification of Paramecium bursaria Syngens and Studies on Geographic Distribution using Mitochondrial Cytochrome C Oxidase Subunit I (COI).

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Zagata, Patrycja; Greczek-Stachura, Magdalena; Tarcz, Sebastian; Rautian, Maria

2015-01-01

Paramecium bursaria is composed of five syngens that are morphologically indistinguishable but sexually isolated. The aim of the present study was to confirm by molecular methods (analyses of mitochondrial COI) the identification of P. bursaria syngens originating from different geographical locations. Phylograms constructed using both the neighbor-joining and maximum-likelihood methods based on a comparison of 34 sequences of P. bursaria strains and P. multimicronucleatum, P. caudatum and P.calkinsi strains used as outgroups revealed five clusters which correspond to results obtained previously by mating reaction. Our analysis shows the existence of 24 haplotypes for the COI gene sequence in the studied strains. The interspecies haplotype diversity was Hd = 0.967. We confirmed genetic differentiation between strains of P. bursaria and the occurrence of a correlation between geographical distribution and the correspondent syngen.

Radioimmunoimaging of nude mice bearing human lung adenocarcinoma xenografts after injecting 131I-McAbs

International Nuclear Information System (INIS)

Liu Liang

1992-01-01

Monoclonal antibodies (Lc86a-C5, Lc86a-H8) directed against human lung adenocarcinoma cell line LTEP-a-2 and normal BALB/c IgG were labelled with iodine-131 by chloramine T. The 131 I-McAbs and 131 I-IgG were respectively injected into the peritoneal cavities of nude mice bearing transplanted human lung adenocarcinoma cell line LTEP-a-2. After 72 h, the tumor tissue in nude mice injected with 131 I-McAbs was distinguishable from normal tissues as a very clear image obtained during gamma scintigraphy. No difference was found between tumor and normal tissues in the nude mice injected with 131 I-IgG. The tumor: blood ration was 3.1:1 in nude injected with 131 I McAb(H8) and 0.9:1 in nude mice injected with 131 I-IgG respectively. This indicates that the tumor tissue image was the result of specific binding of the 131 I-McAbs, which have high specificity and affinity both in vitro and in vivo, to tumor cells, and these monoclonal antibodies may serve as potential agents in tumor diagnosis and treatment

Restoring Ovarian Endocrine Function with Encapsulated Ovarian Allograft in Immune Competent Mice.

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David, Anu; Day, James Ronald; Cichon, Alexa Leigh; Lefferts, Adam; Cascalho, Marilia; Shikanov, Ariella

2017-07-01

Premature ovarian insufficiency (POI) is a major complication of cytotoxic treatments due to extreme ovarian sensitivity to chemotherapy and radiation. In pediatric cancer patients modern therapy has improved the long-term survival to over 80% in the United States. However, these cancer survivors face long-term health problems related to treatment toxicity. In female cancer survivors POI leads to sterility, along with the consequences of estrogen deficiency such as premature osteopenia, muscle wasting, accelerated cardiovascular diseases and a vast array of other health and developmental problems. These long-lasting effects are particularly significant for young girls reaching puberty. As such, restoring ovarian endocrine function is paramount in this population. In the present study, we evaluated the feasibility of restoring ovarian endocrine function in ovariectomized mice by transplanting syngeneic and allogeneic ovarian tissue encapsulated in alginate capsules or TheraCyte ® . Histological analysis of the implants retrieved after 7 and 30 days' post implantation showed follicular development up to the secondary and antral stages in both syngeneic and allogeneic implants. Implantation of syngeneic and allogeneic ovarian grafts encapsulated in TheraCyte devices restored ovarian endocrine function, which was confirmed by decreased serum FSH levels from 60 to 70 ng/mL in ovariectomized mice to 30-40 ng/mL 30 days after implantation. Absence of allo-MHC-specific IgG and IgM antibodies in the sera of implanted mice with allogeneic ovarian tissue encapsulated in TheraCyte indicate that the implants did not evoke an allo-immune response, while the allogeneic controls were rejected 21 days after implantation. Our results show that TheraCyte effectively isolates the graft from immune recognition but also supports follicular growth.

Enhancement of radiomodulatory effect through liposome encapsulated radio-modifier on cancer bearing mice

International Nuclear Information System (INIS)

Alam, A.; Chakraborty, S.; Rapthap, C.; Sharan, R.N.

1999-01-01

Efficacy of a radioprotective drug, 2-mercaptopropionylglycine (MPG), in its free form and after its encapsulation into liposomes have been studied in normal and cancer bearing mice. Cancer was induced in micy by oral administration of aqueous extract of betel nut (AEBN) for 3 months. Radioprotection afforded by free MPG and liposome encapsulated MPG (LEM) in normal and cancerous tissue were evaluated by monitoring levels of glutathione (GSH) and γ-glutamyltranspeptidase (GGT) enzyme and state of structural organization of chromatin. The results of our studies reveal that in cancerous tissues LEM afforded better radioprotection than the free form of MPG. (orig.)

Enhancement of radiomodulatory effect through liposome encapsulated radio-modifier on cancer bearing mice

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Alam, A.; Chakraborty, S.; Rapthap, C. [North-Eastern Hill Univ., Shillong (India). Immunology Lab.; Srivastava, P.N. [Jawaharlal Nehru Univ., New Delhi (India); Sharan, R.N. [North-Eastern Hill Univ., Shillong (India). Dept. of Biochemistry

1999-07-01

Efficacy of a radioprotective drug, 2-mercaptopropionylglycine (MPG), in its free form and after its encapsulation into liposomes have been studied in normal and cancer bearing mice. Cancer was induced in micy by oral administration of aqueous extract of betel nut (AEBN) for 3 months. Radioprotection afforded by free MPG and liposome encapsulated MPG (LEM) in normal and cancerous tissue were evaluated by monitoring levels of glutathione (GSH) and {gamma}-glutamyltranspeptidase (GGT) enzyme and state of structural organization of chromatin. The results of our studies reveal that in cancerous tissues LEM afforded better radioprotection than the free form of MPG. (orig.)

CPP2-p16MIS treatment–induced colon carcinoma cell death in vitro and prolonged lifespan of tumor-bearing mice

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Wang, Lifeng; Chen, Haijin; Yu, Jinlong; Lin, Xiaohua; Qi, Jia; Cui, Chunhui; Xie, Lang; Huang, Shuxin

2016-01-01

Cell-penetrating peptides (CPPs) are a research hotspot due to their noninvasive delivery ability. Among the identified CPPs, the TAT and R8 peptides have been preferentially applied to transduction into different cells. However, this process is nonselective among various cells. Recent research suggested that CPP2 could selectively penetrate human colorectal cancer (CRC) cells. Using in vitro experiments, the mean fluorescence intensity of fluorescein isothiocyanate–labeled CPPs (CPPs-FITC) incubated with different cell lines was compared to corroborate the colon tumor targeting ability of CPP2. The targeting ability of CPP2 was determined in the same way in tumor-bearing mice. We synthesized antitumor peptides by fusing CPP2 to the minimal inhibitory sequence of p16 (p16MIS), which had the ability to restore the function of lost p16, the expression of which was absent in tumor cell lines of various origins. The antitumor effect of the combined peptide was tested in both CRC cell lines and tumor-bearing mice. In each CRC cell line, the mean fluorescence intensity of CPP2-FITC was higher than that of the TAT-FITC (p < 0.001) and R8-FITC (p < 0.001) groups. CPP2-p16MIS, the targeting carrier, showed a higher antitumor response in the in vitro cell research. CPP2-p16MIS showed a prolonged mean lifespan of tumor-bearing mice, further characterizing its role in specific tumor-targeting ability in vivo. Survival analysis showed that the mice treated with CPP2-p16MIS had significantly longer survival than the mice treated with phosphate-buffered saline (p < 0.05) or those treated with control peptides, including the CPP2 (p < 0.05) and p16MIS (p < 0.05) groups. CPP2 could more selectively penetrate CRC cells than TAT or R8 as well as effectively deliver the p16MIS to the tumor

Effect of hGC-MSCs from human gastric cancer tissue on cell proliferation, invasion and epithelial-mesenchymal transition in tumor tissue of gastric cancer tumor-bearing mice.

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Song, Lin; Zhou, Xin; Jia, Hong-Jun; Du, Mei; Zhang, Jin-Ling; Li, Liang

2016-08-01

To study the effect of hGC-MSCs from human gastric cancer tissue on cell proliferation, invasion and epithelial-mesenchymal transition in tumor tissue of gastric cancer tumor-bearing mice. BABL/c nude mice were selected as experimental animals and gastric cancer tumor-bearing mice model were established by subcutaneous injection of gastric cancer cells, randomly divided into different intervention groups. hGC-MSCs group were given different amounts of gastric cancer cells for subcutaneous injection, PBS group was given equal volume of PBS for subcutaneous injection. Then tumor tissue volume were determined, tumor-bearing mice were killed and tumor tissues were collected, mRNA expression of proliferation, invasion, EMT-related molecules were determined. 4, 8, 12, 16, 20 d after intervention, tumor tissue volume of hGC-MSCs group were significantly higher than those of PBS group and the more the number of hGC-MSCs, the higher the tumor tissue volume; mRNA contents of Ki-67, PCNA, Bcl-2, MMP-2, MMP-7, MMP-9, MMP-14, N-cadherin, vimentin, Snail and Twist in tumor tissue of hGC-MSCs group were higher than those of PBS group, and mRNA contents of Bax, TIMP1, TIMP2 and E-cadherin were lower than those of PBS group. hGC-MSCs from human gastric cancer tissue can promote the tumor growth in gastric cancer tumor-bearing mice, and the molecular mechanism includes promoting cell proliferation, invasion and epithelial-mesenchymal transition. Copyright © 2016 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

Study on the toxic side effect of 131I-17-AAG treatment in ovarian cancer-bearing nude mice

International Nuclear Information System (INIS)

Gao Wen

2007-01-01

Objective: To investigate the toixc side effect on bone marrow and hepatic function of 131 I-17-allylamino-17-demethoxy geldanamycin ( 131 I-17 AAG) treatment for ovarian-cancer-bearing nude mice models. Methods: Ovarian-cancer- bearing nude mice models (n=40) were prepared with cancer cell inoculation. 131 I labelled 17 AAG originally prepared in this laboratory was used intravenously for treatment at a single dose of 3 mCi in 20 models and the remain 20 models were used as controls. Rontine bllod examination (CBC, Hgb, platalet) and liver function test (ALT, AST, ALP and r-GT) were performed in these models at lwk and 2wk after treatment. Results: CBC and Hgb in the treated models were not much different from those in controls at 2wk with the exception of a higher platalet count (P 0.05). Conclusion: Toxic side-effect of 131 I-17-AAG treatment on hematologyical and hepatic function in the models was rather mild and there was a tendency toward recovery at 2wk after treatment. (authors)

The observation about the change of the body weight for tumor patients and the bearing tumor mice in radiotherapy

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Wu Dijun; Ju Yongjian; Ning Liyan; Wu Hong; Wang Gaoren; Gao Xuan; Tang Yahong

2010-01-01

Objective: To observe the change of the body weight for tumor patients and the bearing tumor mice in radiotherapy. Methods: For 63 tumor patients, the body weight (BW) were measured before and after radiotherapy respectively, and then the change of BW were compared and analyzed with that of 23 healthy volunteers at the median treatment period. Also 45 mice bearing human galactophore tumor cells SK-BR-3 were divided into irradiation and non-irradiation groups, and the change of BW for these two groups were measured and analyzed. Results: The average BW decreases in the irradiation groups' mice but increase in the non-irradiation groups' mice, and the change of BW in these two groups has the statistical significance respectively, also the difference between these two groups has the statistical significance. For the four groups' tumor patients including 63 tumor patients as a whole, the nasopharynx cancer, esophagus cancer and lung cancer, the average BW decreases, but only in nasopharynx cancer and lung cancer groups the statistical significance are found. And at the same period, the BW of healthy volunteers are maintained. Compared change of BW in the four tumor groups with that in the healthy volunteers respectively, except the esophagus cancer group, the statistical significance are found in the other three groups. Conclusion: For tumor patients,perhaps the BW will lose in the period of radiotherapy, so the effect of lose of BW must be cared about. (authors)

The effect of pentoxifylline on L-1 sarcoma tumor growth and angiogenesis in Balb/c mice

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Barbara Joanna Bałan

2017-07-01

Full Text Available Methyloxantines are present in many herbs and vegetal foods, among them in tea, coffee and chocolate. Previous studies revealed that theophylline and theobromine have anti-angiogenic properties. Anti-tumor properties of theobromine were also described. Pentoxifylline (3,7-dimethyl-1-(5-oxohexylxanthine, PTX is a synthetic xanthine derivative. It is a phosphodiesterase inhibitor and has various anti-inflammatory abilities. Pentoxifylline is widely used in therapy of inflammatory arterial diseases such as intermittent claudication of upper and lower limbs as well as in coronary heart disease. The aim of our research was to evaluate the effect of pentoxifylline (individually and in combination with non-steroidal anti-inflammatory drug sulindac, on L-1 sarcoma angiogenic activity and tumor formation in syngeneic Balb/c mice. Pre-incubation of tumor cells for 90 min with various PTX concentrations resulted in dose-dependent decrease of their ability to induce newly-formed blood vessels after transplantation into the skin of recipient mice. Administration of PTX to mice, recipients of tumor cells, slows tumor growth and reduces its volume. Synergistic inhibitory effect of PTX and sulindac, expressed as % of tumors sixth and thirteen day after subcutaneous grafting of L-1 sarcoma into syngeneic Balb/c mice, was observed.

Determination of liposomal boron biodistribution in tumor bearing mice by using neutron capture autoradiography

International Nuclear Information System (INIS)

Yanagie, H.; Yasuhara, H.; Ogura, K.; Maruyama, K.; Matsumoto, T.; Skvarc, J.; Ilic, R.; Kuhne, G.; Eriguchi, M.; Kobayashi, H.

2001-01-01

It is necessary to accumulate the 10 B atoms selectively to the tumor cells for effective boron neutron capture therapy (BNCT). In order to achieve accurate measurements of 10 B concentrations in biological samples, we employ a technique of neutron capture autoradiography (NCAR) of the sliced whole body samples of tumor bearing mice using CR- 39 plastic track detectors. The CR-39 detectors attached with samples were exposed to thermal neutrons in the thermal column of the TRIGA II reactor at the Institute for Atomic Energy, Rikkyo University. We obtained NCAR images for mice injected intraveneously by 10 B-polyethylene-glycol (PEG) binding liposome or 10 B-bare liposome. The 10 B concentrations in the tumor tissue of mice were estimated by means of alpha and lithium track density measurements. In this study, we increased the accumulation of 10 B atoms in the tumor tissues by binding PEG chains to the surface of liposome, which increase the retension in the blood flow and escape the phagocytosis by reticulo-endotherial systems. Therefore, 10 B-PEG liposome is a candidate for an effective 10 B carrier in BNCT.(author)

Blockade of Notch Signaling in Tumor-Bearing Mice May Lead to Tumor Regression, Progression, or Metastasis, Depending on Tumor Cell Types

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Xing-Bin Hu

2009-01-01

Full Text Available It has been reported that blocking Notch signaling in tumor-bearing mice results in abortive angiogenesis and tumor regression. However, given that Notch signaling influences numerous cellular processes in vivo, a comprehensive evaluation of the effect of Notch inactivation on tumor growth would be favorable. In this study, we inoculated four cancer cell lines in mice with the conditional inactivation of recombination signal-binding protein-Jκ (RBP-J, which mediates signaling from all four mammalian Notch receptors. We found that whereas three tumors including hepatocarcinoma, lung cancer, and osteogenic sarcoma grew slower in the RBP-J-deficient mice, at least a melanoma, B16, grew significantly faster in the RBP-J-deficient mice than in the controls, suggesting that the RBP-J-deficient hosts could provide permissive cues for tumor growth. All these tumors showed increased microvessels and up-regulated hypoxia-inducible factor 1α, suggesting that whereas defective angiogenesis resulted in hypoxia, different tumors might grow differentially in the RBP-J-deleted mice. Similarly, increased infiltration of Gr1+/Mac1+ cells were noticed in tumors grown in the RBP-J-inactivated mice. Moreover, we found that when inoculated in the RBP-J knockout hosts, the H22 hepatoma cells had a high frequency of metastasis and lethality, suggesting that at least for H22, deficiency of environmental Notch signaling favored tumor metastasis. Our findings suggested that the general blockade of Notch signaling in tumor-bearing mice could lead to defective angiogenesis in tumors, but depending on tumor cell types, general inhibition of Notch signaling might result in tumor regression, progression, or metastasis.

Migration of human antigen-presenting cells in a human skin graft onto nude mice model after contact sensitization

NARCIS (Netherlands)

Hoefakker, S.; Balk, H.P.; Boersma, W.J.A.; Joost, T. van; Notten, W.R.F.; Claassen, E.

1995-01-01

Fluorescent contact chemical allergens provoke sensitization after application on both syngeneic and allogeneic skin grafts in mice. We attempted to determine whether the functional activity in a contact sensitization response of human skin graft was affected at the level of antigen uptake and

Eosinophilic spleen colonies are produced in rat-marrow-transplanted but not in murine-marrow-transplanted mice

International Nuclear Information System (INIS)

Szabo, L.G.; Kelemen, E.

1988-01-01

Differential counts of about 5000 splenic clusters and colonies developing in whole-body-irradiated mice and rats were made, using semi-serial histological sections prepared 9 to 12 d after transplantation with bone marrow haemopoietic cells. The investigated mouse and rat spleens were from syngeneically, allogeneically, or xenogeneically transplanted recipients. Splenic eosinophil clusters were always found when rat eosinophil-producing progenitors were present in the inoculum, whereas murine inocula failed to produce splenic eosinophilic clusters even in the syngeneic mouse. The limiting factor in the production pf splenic eosinophilic clusters was the appropriate donor progenitor/committed stem cell itself. Changes in the percentages of eosinophil clusters with the number of injected cells and with increased doses of irradiation, as well as formation of rat eosinophil colonies in mice, as against mainly clusters in rats, themselves show that regulatory mechanisms of the recipients also play a role. These regulatory mechanisms cannot be attributed to the splenic microenvironment. (author)

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

International Nuclear Information System (INIS)

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

1990-01-01

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

Graft-versus-leukemia, donor selection for adoptive immunotherapy in mice

International Nuclear Information System (INIS)

LeFeber, W.P.; Truitt, R.L.; Rose, W.C.; Bortin, M.M.

1977-01-01

The optimal donor for adoptive immunotherapy would exhibit great antitumor reactivity and no antihost reactivity. Immunocompetent cells from 11 strains of mice were tested in vivo for their reactivity against a long-passage AKR acute lymphoblastic leukemia and against immunosuppressed nonleukemic AKR mice. Donor mice were syngeneic, unprimed H-2 compatible, primed H-2 compatible, congenic, or H-2 incompatible with AKR. Bioassays were used to evaluate the relative graft-vs.-leukemia (GvL) reactivity and the relative graft-vs.-host (GvH) reactivity of transplanted bone marrow and lymph-node cells from the panel of donors. No significant GvL reactivity was found when cells from syngeneic, unprimed H-2 compatible, or congenic donors were tested. H-2 compatible donors that were immunized with γ-irradiated AKR leukemic spleen cells showed modest GvL reactivity, but associated with the immunization was a disproportionate increase in acute and delayed GvH mortality. Among the H-2 mismatched donors, mice of the SJL strain appeared to most closely approach the ideal because of least intense GvH reactivity and maximal GvL reactivity. As measured in these experiments there was no correlation between the severity of GvH disease and the efficacy of the GvL reaction; GvL reactivity in unprimed donors was always associated with H-2 incompatibility; disparity between donor and recipient at H-2 did not guarantee an effective GvL reaction; and the increase in GvL reactivity obtained by immunizing H-2 compatible donors was overshadowed by the increase in GvH disease

Effects of low dose radiation on tumor apoptosis, cell cycle progression and changes of apoptosis-related protein bcl-2 in tumor-bearing mice

International Nuclear Information System (INIS)

Yu Hongsheng; Fei Conghe; Shen Fangzhen; Liang Jun

2003-01-01

Objective: To study the effect of low dose radiation (LDR) on tumor apoptosis, cell cycle progression and changes of apoptosis-related protein bcl-2 in tumor-bearing mice. Methods: Kunming stain male mice were implanted with S180 sarcoma cells in the left inguen subcutaneously as an in situ experimental animal model. Seven days after implantation, the mice were given 75 mGy whole-body γ-irradiation. At 24 and 48 h after irradiation, all mice were sacrificed to measure the tumor volume, and tumor cell apoptosis, cell cycle progression were analyzed by flow cytometry. The expression of apoptosis-related protein bcl-2 and the apoptotic rate of tumor cells were observed by immunohistochemistry and electron microscopy. Results: Tumor growth was significantly slowed down after LDR (P 1 phase and the expression of bcl-2 protein decreased at 24 h. Apoptotic rate of tumor cells increased significantly at 48 h after LDR. Conclusion: LDR could cause a G 1 -phase arrest and increase the apoptosis of tumor cells through the low level of apoptosis-related protein bcl-2 in the tumor-bearing mice. The organized immune function and anti-tumor ability are markedly increased after LDR. The study provides practical evidence of clinical application to cancer treatment

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

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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

Doxil Synergizes with Cancer Immunotherapies to Enhance Antitumor Responses in Syngeneic Mouse Models

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Jonathan Rios-Doria

2015-08-01

Full Text Available Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti–PD-L1, PD-1, and CTLA-4 mAbs and TNF receptor agonists (OX40 and GITR ligand fusion proteins in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti–PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system. Using established tumors and maximally efficacious doses of Doxil and cancer immunotherapies in either CT26 or MCA205 tumor models, combination groups produced strong synergistic antitumor effects, a larger percentage of complete responders, and increased survival. In vivo pharmacodynamic studies showed that Doxil treatment decreased the percentage of tumor-infiltrating regulatory T cells and, in combination with anti–PD-L1, increased the percentage of tumor-infiltrating CD8+ T cells. In the tumor, Doxil administration increased CD80 expression on mature dendritic cells. CD80 expression was also increased on both monocytic and granulocytic myeloid cells, suggesting that Doxil may induce these tumor-infiltrating cells to elicit a costimulatory phenotype capable of activating an antitumor T-cell response. These results uncover a novel role for Doxil in immunomodulation and support the use of Doxil in combination with checkpoint blockade or TNFR agonists to increase response rates and antitumor activity.

Immunological response in mice bearing LM3 breast tumor undergoing Pulchellin treatment

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de Matos Djamile

2012-07-01

Full Text Available Abstract Background Ribosome-inactivating proteins (RIP have been studied in the search for toxins that could be used as immunotoxins for cancer treatment. Pulchellin, a type 2 RIP, is suggested to induce immune responses that have a role in controlling cancer. Methods The percentage of dendritic cells and CD4+ and CD8+ T cells in the spleen (flow cytometry, cytokines’ release by PECs and splenocytes (ELISA and nitric oxide production by PECs (Griess assay were determined from tumor-bearing mice injected intratumorally with 0.1 ml of pulchellin at 0.75 μg/kg of body weight. Statistical analysis was performed by one-way ANOVA with Tukey’s post hoc test. Results Pulchellin-treated mice showed significant immune system activation, characterized by increased release of IFN-γ and Th2 cytokines (IL-4 and IL-10, while IL-6 and TGF-β levels were decreased. There was also an increase in macrophage’s activation, as denoted by the higher percentage of macrophages expressing adhesion and costimulatory molecules (CD54 and CD80, respectively. Conclusions Our results suggest that pulchellin is promising as an adjuvant in breast cancer treatment.

Experimental study of 99Tcm-HL91 and 99Tcm-MIBI in mice bearing Lewis lung cancer

International Nuclear Information System (INIS)

Han Chunqi; Li Yaming; Ren Yangang; Yi Lijie

2000-01-01

Objective: To evaluate the ability of detecting lung cancer by 99 Tc m -HL91 and 99 Tc m -MIBI in mice bearing Lewis lung cancer. Methods: Four model mice underwent whole body planar imaging at 2 h, 4 h after injection of 99 Tc m -MIBI; four mice underwent whole body planar imaging at 2 h and 4 h after injection of 99 Tc m -HL91, and the mice of the 99 Tc m -HL91 group were then killed, the tumor, blood and organs were removed, weighted and the radioactivity was measured. ROIs were drawn around the tumor, head and chest in whole body planar images, and radioactivity ratios of tumor to head (T/H), chest (T/C) and contralateral limbs (T/L) were calculated. Results: No significant tumor radioactivity in 2 h and 4 h images of 99 Tc m -MIBI mice (T/C: 0.20 +- 0.08 and 0.14 +- 0.07) was found; increased tumor radioactivity was identified in images of 99 Tc m -HL91 mice (T/C: 3.25 +- 1.25 and 2.44 +- 1.07), and there was significant difference (t = 4.8 - 7.5, P 99 Tc m -HL91 in tumor tissue of mice is higher and clearance rate is slower. 99 Tc m -HL91 is a valuable tumor imaging agent for clinical diagnosis for the cancer

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

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Zhu Y

2014-12-01

Full Text Available Yin Zhu,1,* Ming Cheng,2,* Zhen Yang,3 Chun-Yan Zeng,3 Jiang Chen,3 Yong Xie,3 Shi-Wen Luo,3 Kun-He Zhang,3 Shu-Feng Zhou,4 Nong-Hua Lu1,31Department of Gastroenterology, 2Department of Orthopedics, 3Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China; 4Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA*These authors contributed equally to this workAbstract: 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

Sialic acid changes in Dalton's lymphoma-bearing mice after cyclophosphamide and cisplatin treatment

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Nicol B.M.

2002-01-01

Full Text Available Sialic acid changes in Dalton's lymphoma cells and other tissues of 10-12-week-old Swiss albino mice were investigated in relation to tumour growth in vivo and following cyclophosphamide (ip, 200 mg/kg body weight or cisplatin (ip, 8 mg/kg body weight treatment. Three to four animals of both sexes were used in each experimental group. The sialic acid level of tumour cells (0.88 µmol/g increased with tumour progression (1.44-1.59 µmol/g; P<=0.05 in mice. Sialic acid concentration in other tissues (liver, kidney, testes and brain also increased (~40, 10, 30 and 58%, respectively in the tumour-bearing hosts as compared with that in the respective tissues of normal mice. In vivo cyclophosphamide or cisplatin treatment resulted in an overall decrease of sialic acid contents in the tissues. Cyclophosphamide was more efficient in lowering tissue sialic acid than cisplatin (P<=0.01, ANOVA. It is suggested that sialic acid residues could be an important factor contributing to the manifestation of malignant properties in cancer cells in general and Dalton's lymphoma cells in particular. A significant decrease in the sialic acid content of Dalton's lymphoma cells after cisplatin or cyclophosphamide treatment may bring about specific changes in tumour cells which could be associated with tumour regression.

Cellular radiation response as a function of tumor size, host hematocrit, and erythrokinetics in CA755 tumor-bearing mice

International Nuclear Information System (INIS)

Jirtle, R.L.

1977-01-01

Experiments were performed which both characterized the kinetics of host anemia when CA755 mammary adenocarcinomas were grown in either preirradiated or unirradiated host tissue of C57B1/2J (BDF 1 ) mice, and determined whether a correlation exists between the extent of host anemia and the cellular radiosensitivity of the grossly viable tumor tissue. The red cell destruction rate and the total red cell volume (TRCV) were simultaneously measured throughout tumor growth, and from this information the erythrocyte production per day could be estimated. Increased erythrocyte production was accompanied by a corresponding increase in circulating reticulocytes. The application of these methods to a tumor-bearing mouse system demonstrated that the erythrocyte production rates increased to a maximum of 6 to 10 times normal in mice bearing tumors growing in either preirradiated or unirradiated graft sites. It was concluded that tumor host anemia was due to accelerated random loss of erythrocytes and the nearly simultaneous decrease in erythrocyte potential life span rather than to a decrease in the erythrocyte production

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

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Hong-Mei Yang

2017-02-01

Full Text Available 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.

Macrophages support splenic erythropoiesis in 4T1 tumor-bearing mice.

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Min Liu

Full Text Available Anemia is a common complication of cancer; a role of spleen in tumor-stress erythropoiesis has been suggested. However, the molecular mechanisms involved in the splenic erythropoiesis following tumor maintenance remain poorly understood. Here we show that tumor development blocks medullar erythropoiesis by granulocyte colony-stimulating factor (G-CSF and then causes anemia in murine 4T1 breast tumor-bearing mice. Meanwhile, tumor-stress promotes splenic erythropoiesis. Splenectomy worsened tumor-induced anemia, and reduced tumor volume and tumor weight, indicating the essential role of spleen in tumor-stress erythropoiesis and tumor growth. Tumor progression of these mice led to increased amounts of bone morphogenetic protein 4 (BMP4 in spleen. The in vivo role of macrophages in splenic erythropoiesis under tumor-stress conditions was investigated. Macrophage depletion by injecting liposomal clodronate decreased the expression of BMP4, inhibited splenic erythropoiesis, aggravated the tumor-induced anemia and suppressed tumor growth. Our results provide insight that macrophages and BMP4 are positive regulators of splenic erythropoiesis in tumor pathological situations. These findings reveal that during the tumor-stress period, the microenvironment of the spleen is undergoing changes, which contributes to adopt a stress erythropoietic fate and supports the expansion and differentiation of stress erythroid progenitors, thereby replenishing red blood cells and promoting tumor growth.

Anti-tumour immune effect of oral administration of Lactobacillus plantarum to CT26 tumour-bearing mice.

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Hu, Jingtao; Wang, Chunfeng; Ye, Liping; Yang, Wentao; Huang, Haibin; Meng, Fei; Shi, Shaohua; Ding, Zhuang

2015-06-01

Colorectal cancer (CRC) is one of the most prevalent forms of cancer that shows a high mortality and increasing incidence. There are numerous successful treatment options for CRC, including surgery, chemotherapy, radiotherapy and immunotherapy; however, their side effects and limitations are considerable. Probiotics may be an effective strategy for preventing and inhibiting tumour growth through stimulation of host innate and adaptive immunity. We investigated and compared potential anti-tumour immune responses induced by two isolated Lactobacillus strains, Lactobacillus plantarum A and Lactobacillus rhamnosus b, by pre-inoculating mice with lactobacilli for 14 days. Subsequently, subcutaneous and orthotopic intestinal tumours were generated in the pre-inoculated mice using CT26 murine adenocarcinoma cells and were assessed for response against the tumour. Our results indicated that oral administration with L. plantarum inhibited CT26 cell growth in BALB/c mice and prolonged the survival time of tumour-bearing mice compared with mice administered L. rhamnosus. L. plantarum produced protective immunity against the challenge with CT26 cells by increasing the effector functions of CD8+ and natural killer (NK) cell infiltration into tumour tissue, up-regulation of IFN-gamma (but not IL-4 or IL-17) production, and promotion of Th1-type CD4+ T differentiation. Consequently, our results suggest that L. plantarum can enhance the anti-tumour immune response and delay tumour formation.

Study on therapy of 188Re labelled stannic sulfur suspension in nude mice bearing human colon tumor

International Nuclear Information System (INIS)

Li Huiyuan; Wu Yuanfang; Dong Mo

2003-01-01

The effect of therapy, tissue distribution and stability are studied in nude mice bearing human colon tumor after injections of 188 Re labelled stannic sulfur suspension. The tissues are observed with electric microscope. The results show that 188 Re labelled stannic sulfur suspension is stabilized in the tumor and its inhibitive effects on human colon tumor cells are obvious. 188 Re labelled stannic sulfur suspension is a potential radiopharmaceuticals for therapy of human tumor

Mechanism of stimulation of antibody-forming ability of bone marrow cells of mice immunized with staphylococci

International Nuclear Information System (INIS)

Lyashchenko, K.P.; Golovanova, T.A.; Bobrovnik, S.A.

1987-01-01

The purpose of this paper is to study the formation of the ability of the bone marrow cells of mice immunized with staphylococci to create antibodies to this antigen. The research includes a study of the effect of the irradiation in vitro of the bone marrow cells on their stimulating activity and the role played by the thymus and spleen in the formation of this activity. Experiments were carried out on CBA and BALB/c mice as well as on mice with congenital absence of the thymus. The bone marrow cell donors were immunized intravenously with staphylococcal corpuscular antigen. Receptor mice were irradiated with cobalt 60 gamma radiation and injected intravenously with bone marrow cell extract from the immunized donors and were immunized with the antigen. Spleen cells were labelled with chromium 51 and injected intravenously into intact syngeneic recipients together with as well as without the antigen. Three days later the level of radioactivity in the spleen and femora of the animals was determined by scintillation counting. Total radioactivity of the bone marrow was calculated. Irradiation of the bone marrow cells of immunized animals was shown to abolish their stimulating effect on the humoral immune response of intact syngeneic recipients to the staphylococcal corpuscular antigen. Consequently, the immunostimulating effect of bone marrow cells is realized through the proliferating and radiosensitive lymphoid cells rather than through the macrophages

Oral beta-glucan adjuvant therapy converts nonprotective Th2 response to protective Th1 cell-mediated immune response in mammary tumor-bearing mice.

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Gordon D Ross

2007-06-01

Full Text Available Beta (1-3-D-glucans were identified almost 40 years ago as biological response modifiers that stimulated tumor rejection. In vitro studies have shown that beta-glucans bind to a lectin domain within complement receptor type 3 (CR3, or to, more recently described dectin-1 a beta-glucan specific receptor, acting mainly on phagocytic cells. In this study, we assessed the intracellular cytokine profiles of peripheral blood lymphocytes from mice bearing mammary tumors receiving i.v. anti-tumor mAbs combined or not with whole glucan particle suspension given orally (WGP, 400 microg every 24 hours. The proportions of T cells producing IL-4 and IFNgamma were determined by flow cytometry. The proportion of T cells producing IL-4 was significantly higher in tumor-bearing mice not receiving beta-glucan-enhanced therapy. Conversely, T cells from mice undergoing beta-glucan-enhanced therapy showed increased production of the Th1 cytokine IFNgamma. The switch from a Th2 to a Th1 response after WGP therapy was possibly mediated by intestinal mucosal macrophages releasing IL-12.

The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer

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Miller Andrew F

2008-11-01

Full Text Available Abstract Background Pancreatic cancer continues to have a 5-year survival of less than 5%. Therefore, more effective therapies are necessary to improve prognosis in this disease. Angiogenesis is required for tumor growth, and subsequently, mediators of angiogenesis are attractive targets for therapy. Vascular endothelial growth factor (VEGF is a well-characterized mediator of tumor angiogenesis that functions primarily by binding and activating VEGF receptor 2 (VEGFR2. In this study, we evaluate the use of CT-322, a novel biologic (Adnectin. This small protein is based on a human fibronectin domain and has beneficial properties in that it is fully human, stable, and is produced in bacteria. CT-322 binds to and inhibits activation of VEGFR2. Methods The efficacy of CT-322 was evaluated in vivo using two orthotopic pancreatic tumor models. The first model was a human tumor xenograft where MiaPaCa-2 cells were injected into the tail of the pancreas of nude mice. The second model was a syngeneic tumor using Pan02 cells injected into pancreas of C57BL/6J mice. In both models, therapy was initiated once primary tumors were established. Mice bearing MiaPaCa-2 tumors were treated with vehicle or CT-322 alone. Gemcitabine alone or in combination with CT-322 was added to the treatment regimen of mice bearing Pan02 tumors. Therapy was given twice a week for six weeks, after which the animals were sacrificed and evaluated (grossly and histologically for primary and metastatic tumor burden. Primary tumors were also evaluated by immunohistochemistry for the level of apoptosis (TUNEL, microvessel density (MECA-32, and VEGF-activated blood vessels (Gv39M. Results Treatment with CT-322 was effective at preventing pancreatic tumor growth and metastasis in orthotopic xenograft and syngeneic models of pancreatic cancer. Additionally, CT-322 treatment increased apoptosis, reduced microvessel density and reduced the number of VEGF-activated blood vessels in tumors

Fate of bone marrow stromal cells in a syngenic model of bone formation.

Science.gov (United States)

Boukhechba, Florian; Balaguer, Thierry; Bouvet-Gerbettaz, Sébastien; Michiels, Jean-François; Bouler, Jean-Michel; Carle, Georges F; Scimeca, Jean-Claude; Rochet, Nathalie

2011-09-01

Bone marrow stromal cells (BMSCs) have been demonstrated to induce bone formation when associated to osteoconductive biomaterials and implanted in vivo. Nevertheless, their role in bone reconstruction is not fully understood and rare studies have been conducted to follow their destiny after implantation in syngenic models. The aim of the present work was to use sensitive and quantitative methods to track donor and recipient cells after implantation of BMSCs in a syngenic model of ectopic bone formation. Using polymerase chain reaction (PCR) amplification of the Sex determining Region Y (Sry) gene and in situ hybridization of the Y chromosome in parallel to histological analysis, we have quantified within the implants the survival of the donor cells and the colonization by the recipient cells. The putative migration of the BMSCs in peripheral organs was also analyzed. We show here that grafted cells do not survive more than 3 weeks after implantation and might migrate in peripheral lymphoid organs. These cells are responsible for the attraction of host cells within the implants, leading to the centripetal colonization of the biomaterial by new bone.

Genetic control of cell-mediated lympholysis to trinitrophenyl (TNP)-modified murine syngeneic cells. Expression of Ir gene function at the cytotoxic precursor and helper cell

International Nuclear Information System (INIS)

Fujiwara, H.; Shearer, G.M.

1981-01-01

The present study investigates some of the cellular mechanisms responsible for the defect in cytotoxic T lymphocyte (CTL) response to trinitrophenyl (TNP)-modified H-2/sup b/ self components in C57Bl/6(H-2/sup b/) or (C57BL/6 x C3H/He)(H-2/sup b/ x H-2/sup k/)F 1 mice. C3H/He, C57BL/6, and (C57BL/6 x C3H/He)F 1 mice were immunized to TNP-modified self by skin painting with trinitrochlorobenzene, and their spleen cells were used a) for in vitro secondary sensitization to syngeneic spleen cells conjugated with limiting concentrations of trinitrobenzene sulfonate (TNP-self) or b) as a source of radioresistant helper cells for augmenting the TNP-self CTL response generated by spleen cells from unimmunized C3H/He, C57Bl/6, and F 1 mice. The results indicate that strong or weak in vitro secondary CTL responses could be obtained in the H-2/sup k/ or H-2/sup b/ strain, respectively. This strain-dependent genetic difference was also observed in (H-2/sup b/ x H-2/sup k/)F 1 mice. These results permit the detection of the Ir gene defect in the anti-TNP-H-2/sup b/ self CTL response at both the helper and cytotoxic precursor cell levels

Plasmodium chabaudi in mice. Adoptive transfer of immunity with enriched populations of spleen T and B lymphocytes

International Nuclear Information System (INIS)

McDonald, V.; Phillips, R.S.

1978-01-01

Thymectomized NIH and C57BL mice were more susceptible to Plasmodium chabaudi than controls, indicating a role for T cells in acquired immunity to the parasite. Enriched populations of T and B cells were prepared from the spleens of immune mice using nylon-wool columns, and were adoptively transferred to syngeneic non-irradiated mice or mice irradiated with 600 or 800 rad. Some immunity could usually be transferred with immune T, B and glass-wool (g.w.) filtered spleen cell populations. In the heavily irradiated mice g.w. filtered immune spleen cells gave the best protection and the immune T cells the least. Preliminary attempts to show synergistic activity between immune T and B cells in irradiated mice were not successful. (author)

Increased intracellular Th1 cytokines in scid mice with inflammatory bowel disease

DEFF Research Database (Denmark)

Bregenholt, S; Claesson, Mogens Helweg

1998-01-01

Severe combined immunodeficient (scid) mice engrafted with small pieces of full thickness gut wall from immunocompetent syngenic donors develop a chronic and lethal colitis. Lymphocytes from the lamina propria of engrafted mice were analyzed for phorbol ester/ionomycin-induced cytokine production...... by intracellular staining. A 4-5-fold increase in the fraction of IFN-gamma-producing CD4+ lamina propria T cells was found in moderately and severely diseased mice when compared to healthy congenic C.B-17 control mice. The number of IL-2-producing T cells was increased by approximately 2-fold when comparing mice...... suffering from severe disease to healthy control mice. The fraction of TNF-alpha positive CD4+ T cells was increased by a factor of two in both moderately and severely diseased mice. When analyzing Th2 cytokines, it was found that the levels of IL-4-producing CD4+ T cells was not altered in diseased animals...

Preparation and evaluation of 99Tcm-(HYNIC-[Lys3] -bombesin) (tricine) (TPPTS) for imaging the Balb/c nude mice bearing human pancreatic cancer

International Nuclear Information System (INIS)

Tian Wei; Wang Feng; Li Shaohua; Shao Guoqiang; Hou Yanjie; Wang Zizheng

2011-01-01

Objective: To synthesize 99 Tc m - (hydrazinonictinamide- [Lys 3 ] -bombesin) (tricine)(trisodium triphenylphosphine-3,3',3 - trisulfonate) ((HYNIC-[Lys 3 ]-BBS) (tricine) (TPPTS)) and evaluate its biodistribution and binding capability with tumor tissue in Balb/c nude mice bearing human pancreatic cancer xenografts. Methods: HYNIC was conjugated to the [Lys 3 ] -BBS at pH=9.0 with SnCl 2 as reducing agent and both tricine and TPPTS as coligands for 99 Tc m -labeling. 99 Tc m -HYNIC-[Lys 3 ]-BBS)(tricine) (TPPTS) was purified by Sep-Pak C18 cartridge and was analysed by HPLC. The radiochemical purity and radiolabeling yield were measured. The stability of 99 Tc m -(HYNIC-[Lys 3 ]-BBS) (tricine)(TPPTS) in serum, biodistribution (% ID/g) in the normal mice and imaging of the Balb/c nude mice bearing human pancreatic cancer xenografts in vivo were studied. Results: The radiolabeling yield was (90±2)% and the radiochemical purity was over 95%. The radiochemical purity after 4 h in serum was over 85%. The distribution in normal mice showed rapid clearance from blood (the uptake was (0.07±0.01) %ID/g at 2 h postinjection). 99 Tc m -(HYNIC-[Lys 3 ]-BBS) (tricine) (TPPTS) was excreted mainly via the kidney with little radioactivity accumulation in the liver and gastrointestinal tract (the uptake of liver, stomach, intestine was (0.27±0.03), (0.06±0.03), (0.04±0.00) %ID/g at 2 h postinjection). Marked uptake of radioactivity was found in tumor tissue of the Balb/c nude mice bearing human pancreatic cancer with maximum T/NT ratio of 3.71±0.57 at 2 h postinjection. Conclusions: 99 Tc m -(HYNIC-[Lys 3 ]-BBS)(tricine) (TPPTS) can be easily prepared with high radiolabeling yield and radiochemical purity. The stability in serum and good biodistribution characteristics make it useful for the diagnosis of human pancreatic cancer with over-expression of the gastric-releasing peptide(GRP) receptor. (authors)

Adoptively transferred dendritic cells restore primary cell-mediated inflammatory competence to acutely malnourished weanling mice.

Science.gov (United States)

Hillyer, Lyn; Whitley, Charlene; Olver, Amy; Webster, Michelle; Steevels, Tessa; Woodward, Bill

2008-02-01

Immune depression associated with prepubescent malnutrition underlies a staggering burden of infection-related morbidity. This investigation centered on dendritic cells as potentially decisive in this phenomenon. C57BL/6J mice, initially 19 days old, had free access for 14 days to a complete diet or to a low-protein formulation that induced wasting deficits of protein and energy. Mice were sensitized by i.p. injection of sheep red blood cells on day 9, at which time one-half of the animals in each dietary group received a simultaneous injection of 10(6) syngeneic dendritic cells (JAWS II). All mice were challenged with the immunizing antigen in the right hind footpad on day 13, and the 24-hour delayed hypersensitivity response was assessed as percentage increase in footpad thickness. The low-protein diet reduced the inflammatory immune response, but JAWS cells, which exhibited immature phenotypic and functional characteristics, increased the response of both the malnourished group and the controls. By contrast, i.p. injection of 10(6) syngeneic T cells did not influence the inflammatory immune response of mice subjected to the low-protein protocol. Antigen-presenting cell numbers limited primary inflammatory cell-mediated competence in this model of wasting malnutrition, an outcome that challenges the prevailing multifactorial model of malnutrition-associated immune depression. Thus, a new dendritic cell-centered perspective emerges regarding the cellular mechanism underlying immune depression in acute pediatric protein and energy deficit.

Anti-tumor effect of 131I labeled 17-allylamino-17-demethoxygeldanamycin on human non-small cell lung cancer in xenograft-bearing nude mice

International Nuclear Information System (INIS)

Sun Jin; Liu Lu; Zhu Xiaoli; Chen Daozhen; Gao Wen; Jiang Xinyu; Huang Ying

2008-01-01

Objective: 17-allylamino-17-demethoxygeldanamycin (17-AAG) has been developed as a novel heat shock protein 90 (HSP90) inhibitor being used in clinical trials. HSP90 is known as a molecular target for tumor therapy. The goal of this study was to investigate the inhibitive effects of 131 I labeled 17-AAG on human non-small cell lung cancer in xenograft-bearing nude mice. Methods: 17-AAG was labeled with 131 I. Twenty-eight BALB/c nude mice bearing H460 human non-small cell lung carcinoma tumor xenograft were randomly divided into seven groups, one control group and six treatment groups according to the route of administration (via tail vein injection or intratumoral injection) and the doses of injected radio-activity (5.5 MBq x 2 with 8 d interval, 11.0 MBq and 5.5 MBq). Two additional mice were treated with intratumoral injection of Na 131 I solution that was served as seintigraphic imaging controls. In each group two mice underwent scintigraphy at 2 h, 6 h, 24 h, 2 d, 3 d, 7 d, 10 d and 16 d. After 16 d the tumor inhibition rate was calculated. Then all of the mice were sacrificed and the tumor tissues were obtained for histological examination and immunohistochemical assay. Results: Persistent accumulation of 131 I-17-AAG in the tumors was seen on seintigraphic images. Tumor inhibiting effect was demonstrated in all treatment groups with varying degrees. The highest tumor inhibition rate (86.77 ± 4.57)% was shown in the group with interval intratumoral injection (5.5 MBq x 2). There was no significant difference of tumor inhibition rates between 5.5 MBq x 2 group (via tail vein injection) and 11.0 MBq group( via tail vein injection, q=1.67, P>0.05). While among the other treatment groups, there was significant difference in tumor inhibition rates( q=3.16-24.34, all P 131 I-17-AAG may effectively inhibit the tumor growth and expression of HSP90α antigen expression in non-small cell lung cancer bearing nude mice. The more prominent anti-tumor effect may be

The biodistribution study of 99mTc labelled anti-CEA monoclonal antibody in tumor bearing nude mice

International Nuclear Information System (INIS)

Lou Zongxin

1992-01-01

The author report the optimal condition of 99m Tc labelling with anti-CEA monoclonal antibody using chelating of 99m Tc with dimethylformamide. The labelling rate of this method is 60%-80%, the radiochemical purity of labelling antibody over 90% and maintain its better immuno activity. The biodistribution of the tumor bearing nude mice demonstrates that as compared with the control group, 24 hours after the intraperitoneal injection the injected labelled antibody has its specific concentration in tumor tissue

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

International Nuclear Information System (INIS)

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

2010-01-01

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.

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

Science.gov (United States)

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.

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

Energy Technology Data Exchange (ETDEWEB)

Jie, Meng; Man, Yang; Fumin, Jia; Hua, Kong; Weiqi, Zhang; Haiyan, Xu [Department of Biomedical Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005 (China); Chaoying, Wang; Sishen, Xie [Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, 8 Nan San Jie, Zhongguancun, Beijing100080 (China); Xing Jianmin, E-mail: xuhy@pumc.edu.cn [Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029 (China)

2010-04-09

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.

Antineoplastic Activities of MT81 and Its Structural Analogue in Ehrlich Ascites Carcinoma-Bearing Swiss Albino Mice

Directory of Open Access Journals (Sweden)

Sujata Maiti Choudhury

2010-01-01

Full Text Available Many fungal toxins exhibit in vitro and in vivo antineoplastic effects on various cancer cell types. Luteoskyrin, a hydroxyanthraquinone has been proved to be a potent inhibitor against Ehrlich ascites tumor cells. The comparative antitumor activity and antioxidant status of MT81 and its structural analogue [Acetic acid-MT81 (Aa-MT81] having polyhydroxyanthraquinone structure were assessed against Ehrlich ascites carcinoma (EAC tumor in mice. The in vitro cytotoxicity was measured by the viability of EAC cells after direct treatment of the said compounds. In in vivo study, MT81 and its structural analogue were administered (i.p. at the two different doses (5, 7 mg MT81; 8.93, 11.48 mg Aa-MT81/kg body weight for 7 days after 24 hrs. of tumor inoculation. The activities were assessed using mean survival time (MST, increased life span (ILS, tumor volume, viable tumor cell count, peritoneal cell count, protein percentage and hematological parameters. Antioxidant status was determined by malondialdehyde (MDA and reduced glutathione (GSH content, and by the activity of superoxide dismutase (SOD and catalase (CA T. MT81 and its structural analogues increased the mean survival time, normal peritoneal cell count. They decreased the tumor volume, viable tumor cell count, hemoglobin percentage and packed cell volume. Differential counts of WBC, total counts of RBC & WBC that altered by EAC inoculation, were restored in a dose-dependent manner. Increased MDA and decreased GSH content and reduced activity of SOD, and catalase in EAC bearing mice were returned towards normal after the treatment of MT81 and its structural analogue. Being less toxic than parent toxin MT81, the structural analogue showed more prominent antineoplastic activities against EAC cells compared to MT81. At the same time, both compounds exhibit to some extent antioxidant potential for the EAC-bearing mice.

[Establishment of EL4 tumor-bearing mouse models and investigation on immunological mechanisms of anti-tumor effect of melphalan].

Science.gov (United States)

Li, Mo-lin; Li, Chuan-gang; Shu, Xiao-hong; Jia, Yu-jie; Qin, Zhi-hai

2006-03-01

To establish mouse lymphoma EL4 tumor-bearing mouse models in wild type C57BL/6 mice and nude C57BL/6 mice respectively, and to further investigate the immunological mechanisms of anti-tumor effect of melphalan. Mouse lymphoma EL4 cells were inoculated subcutaneously into wild type C57BL/6 mice (immune-competent mice). Twelve days later, melphalan of different doses were administered intraperitoneally to treat these wild type C57BL/6 tuomr-bearing mice. Tumor sizes were observed and recorded subsequently to find out the minimal dose of melphalan that could cure the tuomr-bearing mice. Then the same amount of EL4 tumor cells were inoculated subcutaneously into wild type C57BL/6 mice and nude C57BL/6 mice (T cell-deficient mice) simultaneously, which had the same genetic background of C57BL/6. Twelve days later, melphalan of the minimal dose was given intraperitoneally to treat both the wild type and nude C57BL/6 tuomr-bearing mice. Tumor sizes were observed and recorded in these two different types of mice subsequently. A single dose of melphalan (7.5 mg/kg) could cure EL4 tumor-bearing wild type C57BL/6 mice, but could not induce tumor regression in EL4 tumor-bearing nude C57BL/6 mice. A single dose of melphalan has obvious anti-tumor effect on mouse lymphoma EL4 tumor-bearing wild type C57BL/6mice, which requires the involvement of T lymphocytes in the host probably related to their killing functions.

Prolonged minor allograft survival in intravenously primed mice--a test of the veto hypothesis

International Nuclear Information System (INIS)

Johnson, L.L.

1987-01-01

Experiments were performed to test the hypothesis that veto cells are responsible for the prolonged survival of minor allografts of skin that is observed in recipients primed intravenously with spleen cells from mice syngeneic with the skin donors. This prolonged survival was observed for each of several minor histocompatibility (H) antigens and is antigen-specific. Gamma radiation (3300 rads) abolished the ability of male spleen cells infused i.v. to delay the rejection of male skin grafts (H-Y antigen) on female recipients. However, depletion of Thy-1+ cells from the i.v. infusion failed to abolish the ability to prolong male skin graft survival. Furthermore, the prolonged survival accorded to B6 (H-2b) male skin grafts on CB6F1 (H-2b/H-2d) female recipients given i.v. infusions of B6 male spleen cells extended to BALB/c (H-2d) male skin grafts as well, indicating a lack of MHC restriction. Thus, prolongation of minor allograft survival by i.v. infusion of minor H antigen-bearing spleen cells appears not to depend on veto T cells that others have found to be responsible for the suppression of CTL generation

Inhibition of Tumor Growth and Immunomodulatory Effects of Flavonoids and Scutebarbatines of Scutellaria barbata D. Don in Lewis-Bearing C57BL/6 Mice

Directory of Open Access Journals (Sweden)

Tao Gong

2015-01-01

Full Text Available Immunomodulatory effect has been found to be an important therapeutic measure for immune responses against cancer. In this study, we evaluated the inhibition of Scutellaria barbata D. Don (SB, an anti-inflammatory and an antitumor Chinese herb, including flavonoids and scutebarbatines on tumor growth and its immunomodulatory effects in vivo. HPLC and LC/MS/MS methods were conducted for the analysis of flavonoids and scutebarbatines in SB. Lewis-bearing C57BL/6 mice model was established and tumor volume was evaluated by high frequency color ultrasound experiment. ELISA and western blot analysis were performed for the determination of immunomodulatory factors. SB treatment at the dose of 10, 6.67, and 3.33 g crude drug/kg/d significantly inhibited tumor growth of Lewis-bearing C57BL/6 mice with the inhibition rates of 44.41±5.44%, 33.56±4.85%, and 27.57±4.96%, respectively. More importantly, the spleen and thymus indexes were increased remarkably by SB treatment. SB could decrease IL-17, IL-10, FOXP3, TGF-β1, RORγt, and IL-6 levels whereas it could increase remarkably IL-2 and IFN-γ levels. Our results demonstrated that SB could inhibit tumor growth in vivo through regulating immune function in tumor-bearing mice and suggested that the immunomodulatory function of SB had a potential therapeutic effect in lung cancer.

Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft.

Science.gov (United States)

Ukon, Naoyuki; Zhao, Songji; Yu, Wenwen; Shimizu, Yoichi; Nishijima, Ken-Ichi; Kubo, Naoki; Kitagawa, Yoshimasa; Tamaki, Nagara; Higashikawa, Kei; Yasui, Hironobu; Kuge, Yuji

2016-12-01

Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl- 3 H(N)]-3'-fluoro-3'-deoxythythymidine ([ 3 H]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3'-[ 18 F]fluoro-3'-deoxythymidine ([ 18 F]FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498). The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [ 18 F]FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [ 18 F]FLT. The dynamic pattern of [ 18 F]FLT levels in the tumor significantly changed after the treatment. The rate constant of [ 18 F]FLT phosphorylation (k 3 ) was significantly higher in the treatment group (0.111 ± 0.027 [1/min]) than in the control group (0.082 ± 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [ 18 F]FLT forward transport (K 1 ) to reverse transport (k 2 ), between the two groups (0.556 ± 0.073 and 0.641 ± 0.052 [mL/g] in the control group). Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic

Systemic agonistic anti-CD40 treatment of tumor bearing mice modulates hepatic myeloid suppressive cells and causes immune-mediated liver damage

Science.gov (United States)

Medina-Echeverz, José; Ma, Chi; Duffy, Austin; Eggert, Tobias; Hawk, Nga; Kleiner, David E.; Korangy, Firouzeh; Greten, Tim F.

2015-01-01

Immune stimulatory monoclonal antibodies are currently evaluated as anti tumor agents. Although overall toxicity appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in liver and spleen, serum transaminases and liver histologies were analyzed after antibody administration. Nox2−/−, Cd40−/− as well as bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid derived suppressive cells was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras we demonstrated that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80 and CD40 positive liver CD11b+Gr-1+ immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14+HLA-DRlow PBMC from cancer patients reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced, myeloid cells, caused myeloid dependent hepatotoxicity and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggests that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC. PMID:25637366

Immunovirotherapy with measles virus strains in combination with anti-PD-1 antibody blockade enhances antitumor activity in glioblastoma treatment.

Science.gov (United States)

Hardcastle, Jayson; Mills, Lisa; Malo, Courtney S; Jin, Fang; Kurokawa, Cheyne; Geekiyanage, Hirosha; Schroeder, Mark; Sarkaria, Jann; Johnson, Aaron J; Galanis, Evanthia

2017-04-01

Glioblastoma (GBM) is the most common primary malignant brain tumor and has a dismal prognosis. Measles virus (MV) therapy of GBM is a promising strategy due to preclinical efficacy, excellent clinical safety, and its ability to evoke antitumor pro-inflammatory responses. We hypothesized that combining anti- programmed cell death protein 1 (anti-PD-1) blockade and MV therapy can overcome immunosuppression and enhance immune effector cell responses against GBM, thus improving therapeutic outcome. In vitro assays of MV infection of glioma cells and infected glioma cells with mouse microglia ± aPD-1 blockade were established to assess damage associated molecular pattern (DAMP) molecule production, migration, and pro-inflammatory effects. C57BL/6 or athymic mice bearing syngeneic orthotopic GL261 gliomas were treated with MV, aPD-1, and combination treatment. T2* weighted immune cell-specific MRI and fluorescence activated cell sorting (FACS) analysis of treated mouse brains was used to examine adaptive immune responses following therapy. In vitro, MV infection induced human GBM cell secretion of DAMP (high-mobility group protein 1, heat shock protein 90) and upregulated programmed cell death ligand 1 (PD-L1). MV infection of GL261 murine glioma cells resulted in a pro-inflammatory response and increased migration of BV2 microglia. In vivo, MV+aPD-1 therapy synergistically enhanced survival of C57BL/6 mice bearing syngeneic orthotopic GL261 gliomas. MRI showed increased inflammatory cell influx into the brains of mice treated with MV+aPD-1; FACS analysis confirmed increased T-cell influx predominantly consisting of activated CD8+ T cells. This report demonstrates that oncolytic measles virotherapy in combination with aPD-1 blockade significantly improves survival outcome in a syngeneic GBM model and supports the potential of clinical/translational strategies combining MV with αPD-1 therapy in GBM treatment. © The Author(s) 2016. Published by Oxford University Press

[Study of the immunological mechanism of anti-tumor effects of 5-FU by establishing EL4 tumor-bearing mouse models].

Science.gov (United States)

Li, Mo-Lin; Li, Chuan-Gang; Shu, Xiao-Hong; Li, Ming-Xia; Jia, Yu-Jie; Qin, Zhi-Hai

2007-11-01

To investigate the immunological mechanism of anti-tumor effect of 5-FU by establishing lymphoma EL4 tumor-bearing mouse models in wild type C57BL/6 mice and nude C57BL/6 mice, respectively. The mouse lymphoma EL4 cells were inoculated subcutaneously into wild type C57BL/6 mice (immune-competent mice). Twelve days later, 5-FU of different doses was administered intraperitoneally to treat these wild type C57BL/6 tumor-bearing mice. The size of tumors in the wild type C57BL/6 mice was observed and recorded to explore the minimal dose of 5-FU that could cure the tumor-bearing mice. Then the same amount of EL4 tumor cells was inoculated subcutaneously into wild type C57BL/6 mice and nude C57BL/6 mice (T cell-deficient mice) simultaneously, which had the same genetic background of C57BL/6. Twelve days later, 5-FU of the minimal dose was given intraperitoneally to treat both the wild type and nude C57BL/6 tumor-bearing mice. The size of tumors in the two different types of mice was observed and recorded. A single dose of 5-FU (75 mg/kg) cured both the EL4 tumor-bearing wild type C57BL/6 mice and the EL4 tumor-bearing nude C57BL/6 mice in the first week. Two weeks after 5-FU treatment, all of the nude mice died of tumor relapse while most of the wild type C57BL/6 mice were fully recovered. A single dose of 5-FU has marked anti-tumor effects on lymphoma EL4 tumor-bearing C57BL/6 mice with or without T lymphocytes. The relapse of tumors after 5-FU treatment might be related to the function of T lymphocytes.

Hyperactivity and learning deficits in transgenic mice bearing a human mutant thyroid hormone beta1 receptor gene.

Science.gov (United States)

McDonald, M P; Wong, R; Goldstein, G; Weintraub, B; Cheng, S Y; Crawley, J N

1998-01-01

Resistance to thyroid hormone (RTH) is a human syndrome mapped to the thyroid receptor beta (TRbeta) gene on chromosome 3, representing a mutation of the ligand-binding domain of the TRbeta gene. The syndrome is characterized by reduced tissue responsiveness to thyroid hormone and elevated serum levels of thyroid hormones. A common behavioral phenotype associated with RTH is attention deficit hyperactivity disorder (ADHD). To test the hypothesis that RTH produces attention deficits and/or hyperactivity, transgenic mice expressing a mutant TRbeta gene were generated. The present experiment tested RTH transgenic mice from the PV kindred on behavioral tasks relevant to the primary features of ADHD: hyperactivity, sustained attention (vigilance), learning, and impulsivity. Male transgenic mice showed elevated locomotor activity in an open field compared to male wild-type littermate controls. Both male and female transgenic mice exhibited impaired learning of an autoshaping task, compared to wild-type controls. On a vigilance task in an operant chamber, there were no differences between transgenics and controls on the proportion of hits, response latency, or duration of stimulus tolerated. On an operant go/no-go task measuring sustained attention and impulsivity, there were no differences between controls and transgenics. These results indicate that transgenic mice bearing a mutant human TRbeta gene demonstrate several behavioral characteristics of ADHD and may serve a valuable heuristic role in elucidating possible candidate genes in converging pathways for other causes of ADHD.

Hyperactivity and Learning Deficits in Transgenic Mice Bearing a Human Mutant Thyroid Hormone β1 Receptor Gene

Science.gov (United States)

McDonald, Michael P.; Wong, Rosemary; Goldstein, Gregory; Weintraub, Bruce; Cheng, Sheue-yann; Crawley, Jacqueline N.

1998-01-01

Resistance to thyroid hormone (RTH) is a human syndrome mapped to the thyroid receptor β (TRβ) gene on chromosome 3, representing a mutation of the ligandbinding domain of the TRβ gene. The syndrome is characterized by reduced tissue responsiveness to thyroid hormone and elevated serum levels of thyroid hormones. A common behavioral phenotype associated with RTH is attention deficit hyperactivity disorder (ADHD). To test the hypothesis that RTH produces attention deficits and/or hyperactivity, transgenic mice expressing a mutant TRβ gene were generated. The present experiment tested RTH transgenic mice from the PV kindred on behavioral tasks relevant to the primary features of ADHD: hyperactivity, sustained attention (vigilance), learning, and impulsivity. Male transgenic mice showed elevated locomotor activity in an open field compared to male wild-type littermate controls. Both male and female transgenic mice exhibited impaired learning of an autoshaping task, compared to wild-type controls. On a vigilance task in an operant chamber, there were no differences between transgenics and controls on the proportion of hits, response latency, or duration of stimulus tolerated. On an operant go/no-go task measuring sustained attention and impulsivity, there were no differences between controls and transgenics. These results indicate that transgenic mice bearing a mutant human TRβ gene demonstrate several behavioral characteristics of ADHD and may serve a valuable heuristic role in elucidating possible candidate genes in converging pathways for other causes of ADHD. PMID:10454355

Radioiodination and biodistribution of NBNPQD ( 2-benzyl-1-oxo-1-2-dihydropyrido (4,3-b) quinoxaline 5,10- dioxide) in tumor bearing mice

International Nuclear Information System (INIS)

Ibrahim, I. T.; Habib, S. A.; Wally, H. A.; El-Shishtawy, M. M.

2012-12-01

NBNPQD (2-benzyl-1-oxo-1,2 dihydropyrido (quinoxaline 5,10-dioxide) is a new synthesized quinoxaline derivative. It could be labeled with Auger emitter iodine-125 successfully with yield about 90%. The labeled product was evaluated by electrophoresis and studied. 1 23I - NBNPQD was stable up to 48 h post labeling. Biodistribution study of 1 23I - NBNPQD in normal and tumor bearing mice was also conducted. The biodistribution data revealed that 1 23I -NBNPQD diffused rapidly to tumor sites in to both ascites and solid tumor bearing mice. 1 23I -NBNPQD was decline rapidly from most of organs but slowly from tumor sites. In-vitro radiotoxicity of 1 23I - NBNPQD increased with the increase of its radioactivity. This study encourages the possible use of 1 23I - NBNPQD in tumor imaging and treatment. It also encourages further studies on the chemotherapeutic activity of NBNPQD hoping to get a new potent antitumor agent. (Author)

Facilitation of syngeneic stem cell engraftment by anti-class I monoclonal antibody pretreatment of unirradiated recipients

International Nuclear Information System (INIS)

Voralia, M.; Semeluk, A.; Wegmann, T.G.

1987-01-01

We have established a murine model of syngeneic bone marrow transplantation based on the use of monoclonal antibody as the sole conditioning regimen in unirradiated recipients. Administration of a single injection of monoclonal antibody directed against major histocompatibility complex-encoded class I determinants facilitated permanent hemopoietic stem cell engraftment without any apparent side-effects. Whereas untreated hosts exhibited a maximal chimerism of 15% at donor cell doses of up to 12 X 10(7) bone marrow cells, pretreatment by 2 mg of anti-class I antibody one week prior to transplantation of 3 X 10(7) syngeneic bone marrow cells resulted in a mean donor representation of about 80%. The antibody can be given up to four weeks prior to transplantation, and the degree of donor engraftment observed is a function of the dose of antibody administered. The fact that specific antibody enhanced engraftment in two strain combinations indicates that antibody is the active agent in facilitating engraftment and that facilitation is not strain-restricted. Anti-class I antibodies of the IgG2a, but not IgG1, isotype are effective in promoting engraftment. Although the isotype requirement suggests a role for antibody-mediated cytotoxicity in promoting stem cell engraftment, the extensive time-frame of facilitation suggests that other effects of the antibody may also be involved. The model of syngeneic bone marrow transplantation we describe here will be useful in studying the mechanisms regulating stem cell engraftment and may have potential clinical application as an approach to autologous marrow transplantation

CD40 dependent exacerbation of immune mediated hepatitis by hepatic CD11b+ Gr-1+ myeloid derived suppressor cells in tumor bearing mice

Science.gov (United States)

Kapanadze, Tamar; Medina-Echeverz, José; Gamrekelashvili, Jaba; Weiss, Jonathan M.; Wiltrout, Robert H.; Kapoor, Veena; Hawk, Nga; Terabe, Masaki; Berzofsky, Jay A.; Manns, Michael P.; Wang, Ena; Marincola, Francesco M.; Korangy, Firouzeh; Greten, Tim F.

2015-01-01

Immunosuppressive CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) accumulate in the livers of tumor-bearing mice. We studied hepatic MDSC in two murine models of immune mediated hepatitis. Unexpectedly, treatment of tumor bearing mice with Concanavalin A or α-Galactosylceramide resulted in increased ALT and AST serum levels in comparison to tumor free mice. Adoptive transfer of hepatic MDSC into naïve mice exacerbated Concanavalin A induced liver damage. Hepatic CD11b+Gr-1+ cells revealed a polarized pro-inflammatory gene signature after Concanavalin A treatment. An interferon gamma- dependent up-regulation of CD40 on hepatic CD11b+Gr-1+ cells along with an up-regulation of CD80, CD86, and CD1d after Concanavalin A treatment was observed. Concanavalin A treatment resulted in a loss of suppressor function by tumor-induced CD11b+Gr-1+ MDSC as well as enhanced reactive oxygen species-mediated hepatotoxicity. CD40 knockdown in hepatic MDSC led to increased arginase activity upon Concanavalin A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40−/− tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased reactive oxygen species production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSC act as pro-inflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner. PMID:25616156

Transfer of adoptive immunity to tuberculosis in mice

International Nuclear Information System (INIS)

Lefford, M.J.

1975-01-01

A system is described for studying adoptive immunity to tuberculosis in syngeneic mice. Donor mice were immunized with 10 4 BCG intravenously, and lymphoid cells were harvested 28 days later. Adoptive immunity was measured in recipient mice in terms of the inhibition of growth of BCG in the liver and spleen following intravenous injection. Adoptive immunity was expressed optimally when recipients were sublethally irradiated (500 R), challenged with 10 4 to 10 5 viable organisms, and given sensitized lymphoid cells intravenously. Adoptive immunity was not manifest until 14 days after challenge and was effective against Mycobacterium tuberculosis H37Rv as well as BCG. Immunity could be conferred by spleen, lymph node, peritoneal exudate, and resident peritoneal (washout) cells. The lymphoid cells conferring immunity were shown to be thymus-dependent lymphocytes by virtue of their nonadherence to glass wool and sensitivity to anti-theta serum plus complement. The sensitized cells were relatively susceptible to both in vitro and in vivo x irradiation

Two types of T helper cells in mice: Differences in cellular immune functions and cytokine secretion - selective reduction of one type after total lymphoid irradiation

International Nuclear Information System (INIS)

Bass, H.Z.

1989-01-01

As observed from a large panel of mouse T helper clones, there are at least two subsets of CD4 + T cells that both differ in function and demonstrate distinct patterns of cytokine secretion after antigen or mitogen stimulation. Th1 cells synthesize IL-2, INF-γ and lymphotoxin. They produce a DTH reaction in the footpads of naive mice. In addition, Th1 cells are required for the generation of CTL, and they appear to augment IgG2a antibody production. In contrast, by secreting IL-4, IL-5, and IL-6, Th2 cells play an essential role in humoral immunity. TLI consists of high dose, fractionated irradiation delivered selectively to the major lymphoid tissues. Four to six weeks after TLI, the CD4 + cells of the treated mice (counted as a percentage of the total spleen lymphocytes) recover to the similar levels as those in normal BALB/c mice. These CD4 + cells can help normal syngeneic B cells to produce a vigorous antibody response to TNP-KLH in adoptive cell transfer experiments, but the same cells are inactive in the MLR, and they fail to transfer DTH in TNP-KLH primed syngeneic BALB/c mice

Targeted inhibition of osteosarcoma tumor growth by bone marrow-derived mesenchymal stem cells expressing cytosine deaminase/5-fluorocytosine in tumor-bearing mice.

Science.gov (United States)

NguyenThai, Quynh-Anh; Sharma, Neelesh; Luong, Do Huynh; Sodhi, Simrinder Singh; Kim, Jeong-Hyun; Kim, Nameun; Oh, Sung-Jong; Jeong, Dong Kee

2015-01-01

Mesenchymal stem cells (MSCs) are considered as an attractive approach for gene or drug delivery in cancer therapy. In the present study, the ability of human bone marrow-derived MSCs expressing the cytosine deaminase/5-fluorocytosine prodrug (CD/5-FC MSCs) to target the human osteosarcoma cell line Cal72 was evaluated. The stable CD/5-FC MSC cell line was established by transfection of pEGFP containing the cytosine deaminase gene into MSCs with G418 selection. The anti-tumor effect was verified by a bystander effect assay in vitro and co-injection of Cal72 and CD/5-FC MSCs in cancer-bearing mice. The therapeutic CD/5-FC MSCs retained the characteristics of multipotent cells, such as differentiation into adipocytes/osteocytes and expression of mesenchymal markers (CD90 and CD44), and showed migration toward Cal72 cells to a greater extent than the native MSCs. The bystander effect assay showed that the CD/5-FC MSCs significantly augmented Cal72 cytotoxicity in direct co-culture and in the presence of 5-FC through the application of conditioned medium. In osteosarcoma-bearing mice, the CD/5-FC MSCs inhibited tumor growth compared to control mice subcutaneously injected with only Cal72 cells. Taken together, these findings suggest that CD/5-FC MSCs may be suitable for targeting human osteosarcoma. Copyright © 2015 John Wiley & Sons, Ltd.

Tumor-Targeting Salmonella typhimurium A1-R Promotes Tumoricidal CD8+ T Cell Tumor Infiltration and Arrests Growth and Metastasis in a Syngeneic Pancreatic-Cancer Orthotopic Mouse Model.

Science.gov (United States)

Murakami, Takashi; Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Kiyuna, Tasuku; Hwang, Ho Kyoung; Miyake, Kentaro; Homma, Yuki; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Ichikawa, Yasushi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

2018-01-01

The present study determined the effect of the tumor-targeting strain Salmonella typhimurium A1-R (S. typhimurium A1-R) on CD8 + tumor-infiltrating lymphocytes (TILs) in a syngeneic pancreatic-cancer orthotopic mouse model. The effect of tumor-targeting S. typhimurium A1-R on CD8 + TILs was determined on the Pan02 murine pancreatic-adenocarcinoma implanted orthotopically in the pancreatic tail of C57BL/6 immunocompromised mice. Three weeks after orthotopic implantation, mice were randomized as follows G1: untreated control group (n = 8); and G2: S. typhimurium A1-R-treatment group (n = 8, 1 × 10 7 colony forming units [CFU]/body, iv, weekly, 3 weeks). On the 22nd day from initial treatment, all mice were sacrificed and tumors were harvested. The tumor-volume ratio was defined as ratio of tumor volume on the 22nd day relative to the 1st day. The tumor volume ratio was significantly lower in the S. typhimurium A1-R-treated group (G2) (3.0 ± 2.8) than the untreated control (G1) (39.9 ± 30.7, P R-treated mice (G2). Six mice in G1 had peritoneal dissemination, whereas no mice showed peritoneal dissemination in G2 (P R promotes CD8 + T cell infiltration and inhibition of tumor growth and metastasis. J. Cell. Biochem. 119: 634-639, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Cell-extrinsic defective lymphocyte development in Lmna(-/- mice.

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J Scott Hale

2010-04-01

Full Text Available Mutations in the LMNA gene, which encodes all A-type lamins, result in a variety of human diseases termed laminopathies. Lmna(-/- mice appear normal at birth but become runted as early as 2 weeks of age and develop multiple tissue defects that mimic some aspects of human laminopathies. Lmna(-/- mice also display smaller spleens and thymuses. In this study, we investigated whether altered lymphoid organ sizes are correlated with specific defects in lymphocyte development.Lmna(-/- mice displayed severe age-dependent defects in T and B cell development which coincided with runting. Lmna(-/- bone marrow reconstituted normal T and B cell development in irradiated wild-type recipients, driving generation of functional and self-MHC restricted CD4(+ and CD8(+ T cells. Transplantation of Lmna(-/- neonatal thymus lobes into syngeneic wild-type recipients resulted in good engraftment of thymic tissue and normal thymocyte development.Collectively, these data demonstrate that the severe defects in lymphocyte development that characterize Lmna(-/- mice do not result directly from the loss of A-type lamin function in lymphocytes or thymic stroma. Instead, the immune defects in Lmna(-/- mice likely reflect indirect damage, perhaps resulting from prolonged stress due to the striated muscle dystrophies that occur in these mice.

Combination of Albendazole and 2-Methoxyestradiol significantly improves the survival of HCT-116 tumor-bearing nude mice

International Nuclear Information System (INIS)

Ehteda, Anahid; Galettis, Peter; Pillai, Krishna; Morris, David L

2013-01-01

Albendazole (ABZ) is a microtubule-targeting anthelmintic with a remarkable activity against a variety of human cancer cells. In this study, we examined if the antitumor activity of ABZ could be enhanced by its combination with other microtubule-binding agents. The interactions between ABZ and microtubule-binding agents, paclitaxel, vinblastine, colchicine, and 2-methoxyestradiol were characterized using median effect analysis method in HCT-116 colorectal cancer cells and DU145 prostate cancer cell line. The mechanism underlying the synergistic interaction related to tubulin polymerization and apoptosis was then investigated. Finally, the effect of the combination therapy on the survival of HCT-116 tumor-bearing nude mice was evaluated. Among the tested drugs, a synergistic anti-proliferative effect was observed with the combination of low concentrations of ABZ plus colchicine and ABZ plus 2-methoxyestradiol (2ME). Exploring the mechanism of the interaction between ABZ and 2ME revealed that the combination therapy synergistically activated the extrinsic pathway of apoptosis. Consistent with in vitro results, the combination of low concentration of ABZ with 2ME prolonged the survival of mice-bearing HCT-116 tumors. High concentration of ABZ in combination with 2ME, however, proved to be less effective than ABZ alone. The combination of low doses of ABZ and 2ME has shown promising results in our pre-clinical model. Additionally, the finding that the combination of two microtubule-binding agents that share the same binding site can act synergistically may lead to the development of new therapeutic strategies in cancer treatment

Exploring the role of CHI3L1 in pre-metastatic lungs of mammary tumor-bearing mice

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Stephania eLibreros

2013-12-01

Full Text Available Elevated levels of chitinase-3-like-1 (CHI3L1 are associated with poor prognosis, shorter recurrence-free intervals and low survival in breast cancer patients. Breast cancer often metastasizes to the lung. We hypothesized that molecules expressed in the pre-metastatic lung microenvironment could support the newly immigrant tumor cells by providing growth and angiogenic factors. Macrophages are known to play an important role in tumor growth by releasing pro-angiogenic molecules. Using mouse mammary tumor models, we have previously shown that during neoplastic progression both the mammary tumor cells and splenic macrophages from tumor-bearing mice express higher levels of CHI3L1 compared to normal control mice. However, the role of CHI3L1 in inducing angiogenesis by macrophages at the pulmonary microenvironment to support newly arriving breast cancer cells is not yet known. In this study, we determined the expression of CHI3L1 in bronchoalveolar lavage macrophages and interstitial macrophages in regulating angiogenesis that could support the growth of newly immigrant mammary tumor cells into the lung. Here we show that in vitro treatment of pulmonary macrophages with recombinant murine CHI3L1 resulted in enhanced expression of pro-angiogenic molecules including CCL2, CXCL2 and MMP-9. We and others have previously shown that inhibition of CHI3L1 decreases the production of angiogenic molecules. In this study, we explored if in vivo administration of chitin microparticles has an effect on the expression of CHI3L1 and pro-angiogenic molecules in the lungs of mammary tumor-bearing mice. We show that treatment with chitin microparticles decreases the expression of CHI3L1 and pro-angiogenic molecules in the metastatic lung. These studies suggest that targeting CHI3L1 may serve as a potential therapeutic agent to inhibit angiogenesis and thus possibly tumor growth and metastasis.

Loss of Ia-bearing splenic adherent cells after whole body ultraviolet irradiation

International Nuclear Information System (INIS)

Letvin, N.L.; Nepom, J.T.; Greene, M.I.; Benacerraf, B.; Germain, R.N.

1980-01-01

Daily uv irradiation of mice results in a marked decrease in the antigen-presenting capability of SAC from these mice after 1 wk of uv exposure. To directly examine this cell population, we developed a technique for purifying SAC that involves passing mouse splenocytes through two cycles of glass adherence with an intervening incubation on rabbit anti-mouse Ig-coated dishes. SAC from externally uv irradiated mice prepared by this method, when pulsed with antigen, activate primed T cells to proliferate much less efficiently than SAC from normal mice. Both the proportion and absolute number of Ia-bearing cells in this purified SAC population from uv irradiated mice are considerably smaller than that seen in similarly prepared populations from normal mice. Previous adjuvant immunization was shown to override functional defects elicited by external uv irradiation. This demonstration of a uv irradiation induced selective loss of Ia bearing splenic adherent cells and the functional consequences of this loss provide further evidence for the importance of Ia-bearing accessory cells in antigen presentation of T dependent antigens, and provides insight into the origin of the immunologic defects induced by whole body uv irradiation

Characterization of regulatory dendritic cells that mitigate acute graft-versus-host disease in older mice following allogeneic bone marrow transplantation.

Science.gov (United States)

Scroggins, Sabrina M; Olivier, Alicia K; Meyerholz, David K; Schlueter, Annette J

2013-01-01

Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD) is often a fatal complication following hematopoietic stem cell transplant (HSCT). Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg) in young bone marrow transplanted (BMT) mice has been shown to decrease GVHD-associated mortality. To evaluate this approach in older BMT recipients, young (3-4 months) and older (14-18 months) DCreg were generated using GM-CSF, IL-10, and TGFβ. Analysis of young versus older DCreg following culture revealed no differences in phenotype. The efficacy of DCreg treatment in older BMT mice was evaluated in a BALB/c→C57Bl/6 model of GVHD; on day 2 post-BMT (d +2), mice received syngeneic, age-matched DCreg. Although older DCreg-treated BMT mice showed decreased morbidity and mortality compared to untreated BMT mice (all of which died), there was a small but significant decrease in the survival of older DCreg-treated BMT mice (75% survival) compared to young DCreg-treated BMT mice (90% survival). To investigate differences between dendritic cells (DC) in young and older DCreg-treated BMT mice that may play a role in DCreg function in vivo, DC phenotypes were assessed following DCreg adoptive transfer. Transferred DCreg identified in older DCreg-treated BMT mice at d +3 showed significantly lower expression of PD-L1 and PIR B compared to DCreg from young DCreg-treated BMT mice. In addition, donor DC identified in d +21 DCreg-treated BMT mice displayed increased inhibitory molecule and decreased co-stimulatory molecule expression compared to d +3, suggesting induction of a regulatory phenotype on the donor DC. In conclusion, these data indicate DCreg treatment is effective in the modulation of GVHD in older BMT recipients and provide evidence for inhibitory pathways that DCreg and donor DC may

Characterization of regulatory dendritic cells that mitigate acute graft-versus-host disease in older mice following allogeneic bone marrow transplantation.

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Sabrina M Scroggins

Full Text Available Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD is often a fatal complication following hematopoietic stem cell transplant (HSCT. Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg in young bone marrow transplanted (BMT mice has been shown to decrease GVHD-associated mortality. To evaluate this approach in older BMT recipients, young (3-4 months and older (14-18 months DCreg were generated using GM-CSF, IL-10, and TGFβ. Analysis of young versus older DCreg following culture revealed no differences in phenotype. The efficacy of DCreg treatment in older BMT mice was evaluated in a BALB/c→C57Bl/6 model of GVHD; on day 2 post-BMT (d +2, mice received syngeneic, age-matched DCreg. Although older DCreg-treated BMT mice showed decreased morbidity and mortality compared to untreated BMT mice (all of which died, there was a small but significant decrease in the survival of older DCreg-treated BMT mice (75% survival compared to young DCreg-treated BMT mice (90% survival. To investigate differences between dendritic cells (DC in young and older DCreg-treated BMT mice that may play a role in DCreg function in vivo, DC phenotypes were assessed following DCreg adoptive transfer. Transferred DCreg identified in older DCreg-treated BMT mice at d +3 showed significantly lower expression of PD-L1 and PIR B compared to DCreg from young DCreg-treated BMT mice. In addition, donor DC identified in d +21 DCreg-treated BMT mice displayed increased inhibitory molecule and decreased co-stimulatory molecule expression compared to d +3, suggesting induction of a regulatory phenotype on the donor DC. In conclusion, these data indicate DCreg treatment is effective in the modulation of GVHD in older BMT recipients and provide evidence for inhibitory pathways that DCreg and

Intrathymic selection of NK1.1+α/β T cell antigen receptor (TCR)+ cells in transgenic mice bearing TCR specific for chicken ovalbumin and restricted to I-Ad

OpenAIRE

Iwabuchi, Chikako; Iwabuchi, Kazuya; Nakagawa, Ken-ichi; Takayanagi, Toshiaki; Nishihori, Hiroki; Tone, Saori; Ogasawara, Kazumasa; Good, Robert A.; Onoé, Kazunori

1998-01-01

Generation and negative selection of NK1.1+α/β T cell receptor (TCR)+ thymocytes were analyzed using TCR-transgenic (B10.D2 × DO10)F1 and (C57BL/6 × DO10)F1 mice and Rag-1−/−/DO10 mice, which had been established by breeding and backcrossing between Rag-1−/− and DO10 mice. Almost all T cells from these mice were shown to bear Vα13/Vβ8.2 that is specific for chicken ovalbumin (cOVA) and restricted to I-Ad. A normal proportion of the NK1.1+ Vα13/Vβ8.2+ thymocytes was generated in these mice. Ho...

Cytoplasmic transfer of heritable elements other than mtDNA from SAMP1 mice into mouse tumor cells suppresses their ability to form tumors in C57BL6 mice.

Science.gov (United States)

Shimizu, Akinori; Tani, Haruna; Takibuchi, Gaku; Ishikawa, Kaori; Sakurazawa, Ryota; Inoue, Takafumi; Hashimoto, Tetsuo; Nakada, Kazuto; Takenaga, Keizo; Hayashi, Jun-Ichi

2017-11-04

In a previous study, we generated transmitochondrial P29mtSAMP1 cybrids, which had nuclear DNA from the C57BL6 (referred to as B6) mouse strain-derived P29 tumor cells and mitochondrial DNA (mtDNA) exogenously-transferred from the allogeneic strain SAMP1. Because P29mtSAMP1 cybrids did not form tumors in syngeneic B6 mice, we proposed that allogeneic SAMP1 mtDNA suppressed tumor formation of P29mtSAMP1 cybrids. To test this hypothesis, current study generated P29mt(sp)B6 cybrids carrying all genomes (nuclear DNA and mtDNA) from syngeneic B6 mice by eliminating SAMP1 mtDNA from P29mtSAMP1 cybrids and reintroducing B6 mtDNA. However, the P29mt(sp)B6 cybrids did not form tumors in B6 mice, even though they had no SAMP1 mtDNA, suggesting that SAMP1 mtDNA is not involved in tumor suppression. Then, we examined another possibility of whether SAMP1 mtDNA fragments potentially integrated into the nuclear DNA of P29mtSAMP1 cybrids are responsible for tumor suppression. We generated P29 H (sp)B6 cybrids by eliminating nuclear DNA from P29mt(sp)B6 cybrids and reintroducing nuclear DNA with no integrated SAMP1 mtDNA fragment from mtDNA-less P29 cells resistant to hygromycin in selection medium containing hygromycin. However, the P29 H (sp)B6 cybrids did not form tumors in B6 mice, even though they carried neither SAMP1 mtDNA nor nuclear DNA with integrated SAMP1 mtDNA fragments. Moreover, overproduction of reactive oxygen species (ROS) and bacterial infection were not involved in tumor suppression. These observations suggest that tumor suppression was caused not by mtDNA with polymorphic mutations or infection of cytozoic bacteria but by hypothetical heritable cytoplasmic elements other than mtDNA from SAMP1 mice. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Cellular intrinsic mechanism affecting the outcome of AML treated with Ara-C in a syngeneic mouse model.

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Wenjun Zhao

Full Text Available The mechanisms underlying acute myeloid leukemia (AML treatment failure are not clear. Here, we established a mouse model of AML by syngeneic transplantation of BXH-2 derived myeloid leukemic cells and developed an efficacious Ara-C-based regimen for treatment of these mice. We proved that leukemic cell load was correlated with survival. We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival. To examine the molecular alterations in cells with different sensitivity, genome-wide expression of the leukemic cells was profiled, revealing that overall 366 and 212 genes became upregulated or downregulated, respectively, in the resistant cells. Many of these genes are involved in the regulation of cell cycle, cellular proliferation, and apoptosis. Some of them were further validated by quantitative PCR. Interestingly, the Ara-C resistant cells retained the sensitivity to ABT-737, an inhibitor of anti-apoptosis proteins, and treatment with ABT-737 prolonged the life span of mice engrafted with resistant cells. These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C. Incorporation of apoptosis inhibitors, such as ABT-737, into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C.

Whole-Retina Reduced Electrophysiological Activity in Mice Bearing Retina-Specific Deletion of Vesicular Acetylcholine Transporter.

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Jake Bedore

Full Text Available Despite rigorous characterization of the role of acetylcholine in retinal development, long-term effects of its absence as a neurotransmitter are unknown. One of the unanswered questions is how acetylcholine contributes to the functional capacity of mature retinal circuits. The current study investigates the effects of disrupting cholinergic signalling in mice, through deletion of vesicular acetylcholine transporter (VAChT in the developing retina, pigmented epithelium, optic nerve and optic stalk, on electrophysiology and structure of the mature retina.A combination of electroretinography, optical coherence tomography imaging and histological evaluation assessed retinal integrity in mice bearing retina- targeted (embryonic day 12.5 deletion of VAChT (VAChTSix3-Cre-flox/flox and littermate controls at 5 and 12 months of age. VAChTSix3-Cre-flox/flox mice did not show any gross changes in nuclear layer cellularity or synaptic layer thickness. However, VAChTSix3-Cre-flox/flox mice showed reduced electrophysiological response of the retina to light stimulus under scotopic conditions at 5 and 12 months of age, including reduced a-wave, b-wave, and oscillatory potential (OP amplitudes and decreased OP peak power and total energy. Reduced a-wave amplitude was proportional to the reduction in b-wave amplitude and not associated with altered a-wave 10%-90% rise time or inner and outer segment thicknesses.This study used a novel genetic model in the first examination of function and structure of the mature mouse retina with disruption of cholinergic signalling. Reduced amplitude across the electroretinogram wave form does not suggest dysfunction in specific retinal cell types and could reflect underlying changes in the retinal and/or extraretinal microenvironment. Our findings suggest that release of acetylcholine by VAChT is essential for the normal electrophysiological response of the mature mouse retina.

Proliferation and apoptosis of lamina propria CD4+ T cells from scid mice with inflammatory bowel disease

DEFF Research Database (Denmark)

Bregenholt, S; Reimann, J; Claesson, Mogens Helweg

1998-01-01

Scid mice transplanted with low numbers of syngeneic CD4+ T cells, develop a chronic and lethal inflammatory bowel disease (IBD) within 4-6 months. We have used in vivo 5-bromo2-deoxy-uridine (BrdU) labeling to assess the proliferation of lamina propria-derived CD4+ T cells in diseased scid mice....... The hourly rate of renewal of colonic lamina propria CD4+ T cells in diseased mice was 7% compared with 1.5% in normal BALB/c control mice. Transplantation of scid mice with in vitro activated CD4+ T cells accelerated the disease onset and development in a cell dose-dependent fashion when compared with non......-activated CD4+ T cells. In pulse-chase experiments it was shown that BrdU-labeled cells disappeared rapidly from the lamina propria of diseased mice. DNA analysis revealed that this was due to the presence of nearly four times as many apoptotic CD4+ T cells in diseased than in control mice. Further analyses...

Comparison of Allogeneic and Syngeneic Rat Glioma Models by Using MRI and Histopathologic Evaluation.

Science.gov (United States)

Biasibetti, Elena; Valazza, Alberto; Capucchio, Maria T; Annovazzi, Laura; Battaglia, Luigi; Chirio, Daniela; Gallarate, Marina; Mellai, Marta; Muntoni, Elisabetta; Peira, Elena; Riganti, Chiara; Schiffer, Davide; Panciani, Pierpaolo; Lanotte, Michele

2017-03-01

Research in neurooncology traditionally requires appropriate in vivo animal models, on which therapeutic strategies are tested before human trials are designed and proceed. Several reproducible animal experimental models, in which human physiologic conditions can be mimicked, are available for studying glioblastoma multiforme. In an ideal rat model, the tumor is of glial origin, grows in predictable and reproducible patterns, closely resembles human gliomas histopathologically, and is weakly or nonimmunogenic. In the current study, we used MRI and histopathologic evaluation to compare the most widely used allogeneic rat glioma model, C6-Wistar, with the F98-Fischer syngeneic rat glioma model in terms of percentage tumor growth or regression and growth rate. In vivo MRI demonstrated considerable variation in tumor volume and frequency between the 2 rat models despite the same stereotactic implantation technique. Faster and more reproducible glioma growth occurred in the immunoresponsive environment of the F98-Fischer model, because the immune response is minimized toward syngeneic cells. The marked inability of the C6-Wistar allogeneic system to generate a reproducible model and the episodes of spontaneous tumor regression with this system may have been due to the increased humoral and cellular immune responses after tumor implantation.

The Evolutionary Relationships between Endosymbiotic Green Algae of Paramecium bursaria Syngens Originating from Different Geographical Locations.

Science.gov (United States)

Zagata, Patrycja; Greczek-Stachura, Magdalena; Tarcz, Sebastian; Rautian, Maria

2016-01-01

Paramecium bursaria (Ehrenberg 1831), a freshwater ciliate, typically harbors hundreds of green algal symbionts inside the cell. The aim of present study was the molecular identification of newly analyzed P. bursaria symbionts. The second aspect of the present survey was testing a hypothesis whether endosymbionts prefer the specified syngen of the host, and the specified geographical distribution. Ten strains of endosymbionts isolated from strains of P. bursaria originating from different geographical locations were studied. We analyzed for the first time, both the fragment of plastid genome containing 3'rpl36-5' infA genes and a fragment of a nuclear gene encoding large subunit ribosomal RNA (LSU rDNA). The analysis of the LSU rDNA sequences showed the existence of 3 haplotypes and the haplotype diversity of 0.733, and 8 haplotypes for the 3'rpl36-5' infA gene fragment and haplotype diversity of 0.956. The endosymbionts isolated from P. bursaria strains were identified as Chlorella vulgaris, Ch. variabilis and Micractinium conductrix. There was no correlation between the syngen of P. bursaria and the species of endosymbiont.

Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice.

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Syed Nuruddin

Full Text Available Research on Alzheimer's disease (AD has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh and its receptor (Gnrhr were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate. The study was performed on mice carrying the Arctic and Swedish amyloid-β precursor protein (AβPP mutations (tgArcSwe. At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental

Radiolabeling of anti-human prostatic specific membrane antigen antibody with 99Tcm and its biodistribution in nude mice bearing human prostate cancer

International Nuclear Information System (INIS)

Tu Shaohua; Shen Jiangfan; Tao Rong; Ji Xiaowen; Wang Yancheng

2012-01-01

Objective: To study the binding affinity of 99 Tc m labeled anti-human prostatic specific membrane antigen (PSMA) monoclonal antibody (McAb) J591 to prostate cancer cells and the biodistribution of 99 Tc m -J591 in nude mice bearing human prostate cancer. Methods: The McAb J591 was labeled with vTcm by improved Schwarz method and the labeled McAb was purified by Sephadex G-50. The binding affinity of J591 with prostate cancer cells was measured by Flow Cytometry. The nude mice bearing PSMA-positive C4-2 prostate carcinoma xenografts were served as experiment groups, mice with PSMA-negative pc3 tumors served as controls. The biodistribution of 99 Tc m -J591 were carried out in both model nude mice. Results: The radiolabeling efficiency of 99 Tc m -J591 was 78.9±6.2%, and radiochemical purity was more than 90% after purification. The 99 Tc m -J591 showed a good combination with PSMA-positive C4-2 cells and no combination with PSMA-negative PC3 cells in vitro. The biodistribution results showed that 99 Tcm-J591 was accumulated in tumor tissue during the 2-24 hours after injection in experiment groups, and no significant uptake in control group. The uptake of 99 Tcm-J591 in tumor tissue reached a maximum 15.91±5.16 % ID/g in experimental group at 12h post-injection. There was a significant difference compared with controls (P 0.05). Conclusion: The monoclonal antibody J591 exhibits an excellent immuno-reactivity and tumor targeting property, and it may be used in diagnosis and target therapy of prostate cancer. (authors)

Lack of immunoglobulin M suppression by immunoglobulin G antibody in thymectomized, irradiated, and bone marrow-reconstituted mice infected with Toxoplasma gondii.

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Aryanpour, J; Hafizi, A; Modabber, F

1980-03-01

Thymectomized, irradiated, bone marrow-reconstituted (T-deprived) mie infected with an avirulent strain of Toxoplasma gondii produced antibody titers comparable to those produced in intact syngeneic mice. Both immunoglobulin M (IgM) and IgG antibodies were produced in T-deprived animals; however, the IgM antibody remained constant in the presence of increasing amounts of IgG. In the intact animals, IgM became undetectable by day 50 postinfection as expected. Feedback inhibition of IgM by IgG seems to be dependent upon T-cells in Toxoplasma-infected mice.

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

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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. © 2015 American Society for Bone

Differences in the immunologic reactivity of mice treated with UVB or methoxsalen plus UVA radiation

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Kripke, M.L.; Morison, W.L.; Parrish, J.A.

1981-01-01

Skin tumors induced in mice by chronic exposure to UVB radiation are often highly antigenic and regress when transplanted into normal syngeneic animals, but grow progressively in immunosuppressed mice. Exposure of mice to subtumorigenic doses of UVB radiation can abolish this immunologic rejection phenomenon. In this study, we have investigated the effects of treatment with 8-methoxypsoralen plus UVA radiation (PUVA) on the rejection of antigenic UVB-induced tumors. PUVA treatment, with either topical or systemic administration of the psoralen, did not alter the normal process of rejection of UVB-induced tumors. Mice treated with both minimally and markedly phototoxic doses of PUVA rejected tumors with a frequency similar to that seen in untreated animals, although these tumors grew progressively in UVB-irradiated mice. These results indicate that the effects of PUVA treatment differ from those of UVB irradiation in that PUVA treatment does not alter the immunologic rejection of UVB-induced tumors

Antioxidant Activities of Total Phenols of Prunella vulgaris L. in Vitro and in Tumor-bearing Mice

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Feng Shi

2010-12-01

Full Text Available Prunella vulgaris L. (PV, Labiatae is known as a self-heal herb. The different extracts of dried spikes were studied for the best antioxidant active compounds. The 60% ethanol extract (P-60 showed strong antioxidant activity based on the results of 2,2’-azino-di(3-ethylbenzthiazoline-6-sulfonic acid (ABTS˙+, 2,2-diphenyl-1-picrylhydrazyl (DPPH and ferric reducing antioxidant power (FRAP assay methods. High performance liquid chromatography (HPLC and LC/MS analysis showed that the main active compounds in P-60 were phenols, such as caffeic acid, rosmarinic acid, rutin and quercetin. Total phenols were highly correlated with the antioxidant activity (R2 = 0.9988 in ABTS˙+; 0.6284 in DPPH and 0.9673 FRAP tests. P-60 could inhibit significantly the tumor growth in C57BL/6 mice. It can also been showed that increased superoxide dismutase (SOD activity and decreased malondialdehyde (MDA content in serum of tumor-bearing mice. These results suggested that P-60 extract had high antioxidant activity in vitro and in vivo and total phenols played an important role in antioxidant activity for inhibition of tumor growth.

Improved antiangiogenic and antitumour activity of the combination of the natural flavonoid fisetin and cyclophosphamide in Lewis lung carcinoma-bearing mice

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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

The catabolism of radioiodinated anti-lung-cancer monoclonal antibodies in tumor-bearing nude mice

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Shi Xubao

1991-01-01

Nude mice bearing humor lung cancer xenografts were injected intravenously or intraperitoneally with a mixture of radioiodinated anti-lung-cancer monoclonal antibodies, 2E3 and 6D1. The blood radioactivity versus time curve was fitted to a two-compartment open model with a 3.4 day blood radioactivity clearance half-life and a 636 ml/kg apparent distribution volume. Radioiodinated 2E3 and 6D1 given intraperitoneally were rapidly absorbed, with a 2.08 absorption half-life and 89% bioavailability. The highest radioactivity levels were found in the tumor, blood, liver and spleen 1-3 days after injection; next came the lung, kidney, stomach and intestine. The relative radioactivity increased in the tumor as levels in blood and normal tissues decreased. The in vivo deiodination of radioiodinated 2E3 and 6D1 was about 18.6% and free radioiodine was excreted in the urine

Characterization of Regulatory Dendritic Cells That Mitigate Acute Graft-versus-Host Disease in Older Mice Following Allogeneic Bone Marrow Transplantation

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Scroggins, Sabrina M.; Olivier, Alicia K.; Meyerholz, David K.; Schlueter, Annette J.

2013-01-01

Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD) is often a fatal complication following hematopoietic stem cell transplant (HSCT). Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg) in young bone marrow transplanted (BMT) mice has been shown to decrease GVHD-associated mortality. To evaluate thi...

In vitro Cytotoxicity, Pharmacokinetics, Tissue Distribution, and Metabolism of Small-Molecule Protein Kinase D Inhibitors, kb-NB142-70 and kb-NB165-09, in Mice bearing Human Cancer Xenografts

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Guo, Jianxia; Clausen, Dana M.; Beumer, Jan H.; Parise, Robert A.; Egorin, Merrill J.; Bravo-Altamirano, Karla; Wipf, Peter; Sharlow, Elizabeth R.; Wang, Qiming Jane; Eiseman, Julie L.

2012-01-01

Purpose Protein kinase D (PKD) mediates diverse biological responses including cell growth and survival. Therefore, PKD inhibitors may have therapeutic potential. We evaluated the in vitro cytotoxicity of two PKD inhibitors, kb-NB142-70 and its methoxy analog, kb-NB165-09, and examined their in vivo efficacy and pharmacokinetics. Methods The in vitro cytotoxicities of kb-NB142-70 and kb-NB165-09 were evaluated by MTT assay against PC-3, androgen independent prostate cancer cells, and CFPAC-1 and PANC-1, pancreatic cancer cells. Efficacy studies were conducted in mice bearing either PC-3 or CPFAC-1 xenografts. Tumor-bearing mice were euthanized between 5 and 1440 min after iv dosing, and plasma and tissue concentrations were measured by HPLC-UV. Metabolites were characterized by LC-MS/MS. Results kb-NB142-70 and kb-NB165-09 inhibited cellular growth in the low-mid μM range. The compounds were inactive when administered to tumor-bearing mice. In mice treated with kb-NB142-70, the plasma Cmax was 36.9 nmol/mL and the PC-3 tumor Cmax was 11.8 nmol/g. In mice dosed with kb-NB165-09, the plasma Cmax was 61.9 nmol/mL while the PANC-1 tumor Cmax was 8.0 nmol/g. The plasma half-lives of kb-NB142-70 and kb-NB165-09 were 6 and 14 min, respectively. Both compounds underwent oxidation and glucuronidation. Conclusions kb-NB142-70 and kb-NB165-09 were rapidly metabolized, and concentrations in tumor were lower than those required for in vitro cytotoxicity. Replacement of the phenolic hydroxyl group with a methoxy group increased the plasma half-life of kb-NB165-09 2.3-fold over that of kb-NB142-70. Rapid metabolism in mice suggests that next-generation compounds will require further structural modifications to increase potency and/or metabolic stability. PMID:23108699

Anti-tumor effects of (1→3)-β-d-glucan from Saccharomyces cerevisiae in S180 tumor-bearing mice.

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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 (CD 4 and CD 8 ), 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 CD 4 to CD 8 . 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

Genetic constraints in the induction of the immune response to Ehrlich ascites tumor in mice

International Nuclear Information System (INIS)

Marusic, M.; Perkins, E.H.

1981-01-01

A single injection of irradiated Ehrlich ascites tumor (EAT) cells induces immunity in normal mice but fails to do so in T-cell-deficient-thymectomized, lethally irradiated, bone marrow-reconstituted (TIR) mice. TIR mice injected with normal syngeneic T cells develop an immune response to EAT when injected with irradiated EAT cells and reject a subsequent tumor cell challenge. In the present studies allogeneic T cells were unable to protect against EAT in TIR recipients even if harvested from donors tolerant to the recipient's transplantation antigens and injected into the TIR mice tolerant to the transplantation antigens of the injected T cells. Tolerance was produced by establishing long-term radiation chimeras of the P → F 1 type. Semiallogeneic T cells also failed to afford protection against EAT in TIR recipients. Whereas tolerance to other parental-strain transplantation antigens did not reverse the inability of parental T cells (cells from P → F 1 chimeric donors) to protect against EAT in F 1 TIR mice, it did enable F 1 T cells to afford protection in P → F 1 TIR mice

Survival of bone marrow-engrafted mice subsequent to protection from lethal radiation by WR 2721

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Kinnamon, K.E.; Ketterling, L.L.; Ledney, G.D.; Lorenz, G.B.; Mioduszewski, R.J.; Stampfli, H.F.

1980-01-01

For the first time data are presented for animals treated with bone marrow cells after lethal radiation exposure while protected with WR 2721 (the single radioprotective chemical compound with the highest known dose reduction factor). The LD 50 30 (lethal dose to 50% in 30 days) for mice exposed to whole-body 60 Co radiation was elevated from 824 +- 8 rad in unprotected and untreated mice to (a) 1181 +- 33 rad in animals which received syngeneic bone marrow cells after exposure; (b) 1342 +- 27 rad in animals which received WR 2721 before radiation exposure; and (c) 1608 +- 33 rad in animals receiving both the radioprotective agent before exposure and bone marrow engraftment after exposure

Sunlight suppressing rejection of 280- to 320-nm UV-radiation-induced skin tumors in mice

International Nuclear Information System (INIS)

Morison, W.L.; Kelley, S.P.

1985-01-01

Repeated exposure of female C3H/HeNCR- mice to sunlight prevented the normal immunologic rejection of a UV-induced tumor. This systemic immunologic alteration was transferred to syngeneic lethally X-irradiated animals with lymphoid cells from mice exposed to sunlight. The lymphoid cells also were able to suppress the capacity of lymphoid cells from normal animals to reject a UV-induced tumor. The 295- to 320-nm wave band appeared to be responsible for this immunosuppressive effect of sunlight because suppression was prevented by filtration of the radiation through Mylar and by application of a sunscreen containing para-aminobenzoic acid. These observations may have importance in understanding the pathogenesis of sunlight-induced skin cancer in humans

A Type II Arabinogalactan from Anoectochilus formosanus for G-CSF Production in Macrophages and Leukopenia Improvement in CT26-Bearing Mice Treated with 5-Fluorouracil.

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Yang, Li-Chan; Lu, Ting-Jang; Lin, Wen-Chuan

2013-01-01

Anoectochilus formosanus is an herb well known in Asian countries. The polysaccharide isolated from A. formosanus consists of type II arabinogalactan (AGAF), with branched 3,6-Gal as the major moiety. In this study, AGAF was examined for the granulocyte colony-stimulating factor (G-CSF) production and related protein expression in RAW 264.7 murine macrophages. The signaling pathway of G-CSF production involves AGAF and mitogen-activated protein kinases (MAPKs) inhibitors and pattern-recognition receptor antibodies. AGAF was evaluated to ease the leukopenia in CT26-colon-cancer-bearing mice treated with 5-fluorouracil (5-FU). The results of this study showed that AGAF was a stimulant for Toll-like receptor 2 and Dectin-1 and that it induced G-CSF production, through p38 and ERK MAPK, and NF- κ B pathways. In vivo examination showed that the oral administration of AGAF mitigated the side effects of leukopenia caused by 5-FU in colon-cancer-bearing mice. In conclusion, the botanic type II AGAF in this study was a potent G-CSF inducer in vivo and in vitro.

A Type II Arabinogalactan from Anoectochilus formosanus for G-CSF Production in Macrophages and Leukopenia Improvement in CT26-Bearing Mice Treated with 5-Fluorouracil

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Li-Chan Yang

2013-01-01

Full Text Available Anoectochilus formosanus is an herb well known in Asian countries. The polysaccharide isolated from A. formosanus consists of type II arabinogalactan (AGAF, with branched 3,6-Gal as the major moiety. In this study, AGAF was examined for the granulocyte colony-stimulating factor (G-CSF production and related protein expression in RAW 264.7 murine macrophages. The signaling pathway of G-CSF production involves AGAF and mitogen-activated protein kinases (MAPKs inhibitors and pattern-recognition receptor antibodies. AGAF was evaluated to ease the leukopenia in CT26-colon-cancer-bearing mice treated with 5-fluorouracil (5-FU. The results of this study showed that AGAF was a stimulant for Toll-like receptor 2 and Dectin-1 and that it induced G-CSF production, through p38 and ERK MAPK, and NF-κB pathways. In vivo examination showed that the oral administration of AGAF mitigated the side effects of leukopenia caused by 5-FU in colon-cancer-bearing mice. In conclusion, the botanic type II AGAF in this study was a potent G-CSF inducer in vivo and in vitro.

Anti-CD45 radioimmunotherapy with 90Y but not 177Lu is effective treatment in a syngeneic murine leukemia model.

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Johnnie J Orozco

Full Text Available Radioimmunotherapy (RIT for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine CD45 Ab conjugates (DOTA-30F11 targeted hematologic tissues, as at 24 hours 48.8 ± 21.2 and 156 ± 14.6% injected dose per gram of tissue (% ID/g of 90Y-DOTA-30F11 and 54.2 ± 9.5 and 199 ± 11.7% ID/g of 177Lu-DOTA-30F11 accumulated in bone marrow (BM and spleen, respectively. However, 90Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit: 60% of mice treated with 300 µCi 90Y-DOTA-30F11 lived over 180 days after therapy, and mice treated with 100 µCi 90Y-DOTA-30F11 had a median survival 66 days. 90Y-anti-CD45 RIT was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, 177Lu- anti-CD45 RIT yielded no long-term survivors. Thus, 90Y was more effective than 177Lu for anti-CD45 RIT of AML in this murine leukemia model.

Angiogenesis for tumor vascular normalization of Endostar on hepatoma 22 tumor-bearing mice is involved in the immune response.

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Xu, Qingyu; Gu, Junfei; Lv, You; Yuan, Jiarui; Yang, Nan; Chen, Juan; Wang, Chunfei; Hou, Xuefeng; Jia, Xiaobin; Feng, Liang; Yin, Guowen

2018-03-01

Tumor vascular normalization involved in immune response is beneficial to the chemotherapy of tumors. Recombinant human endostatin (Endostar), an angiogenesis inhibitor, has been demonstrated to be effective in hepatocellular cancer (HCC). However, its vascular normalization in HCC and the role of the immune response in angiogenesis were unclear. In the present study, effects of Endostar on tumor vascular normalization were evaluated in hepatoma 22 (H22) tumor-bearing mice. Endostar was able to inhibit the proliferation and infiltration of tumor cells and improve α-fetoprotein, tumor necrosis factor-α and cyclic adenosine 5'-phosphate levels in the serum of H22-bearing mice, as well as the protein expression levels of the immune factors interferon-γ and cluster of differentiation (CD)86 in liver tissue. Endostar also exhibited more marked downregulation of the levels of vascular endothelial growth factor, CD31, matrix metalloproteinase (MMP)-2, MMP-9 and interleukin-17 during day 3-9 treatment, resulting in short-term normalization of tumor blood vessels. The period of vascular normalization was 3-9 days. The results of the present study demonstrated that Endostar was able to induce the period of vascular normalization, contributing to a more efficacious means of HCC treatment combined with other chemotherapy, and this effect was associated with the immune response. It may be concluded that Endostar inhibited immunity-associated angiogenesis behaviors of vascular endothelial cells in response to HCC. The results of the present study provided more reasonable possibility for the combination therapy of Endostar for the treatment of HCC.

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

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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-388D 1 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-388D 1 tumor-bearing CDF 1 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-388D 1 cells. Georg Thieme Verlag KG Stuttgart · New York.

Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice.

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Noriyuki Kashiyama

Full Text Available Allogeneic transplantation (Tx of induced pluripotent stem cells (iPSCs is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET imaging targets translocator protein (TSPO, which is highly expressed on mitochondrial membrane, especially in activated macrophage. N,N-diethyl-2-[4-(2-fluoroethoxy phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714 is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs of allogeneic origin may be quantitated using 18F-DPA-714-PET imaging study. iPSC-CM cell-sheets of C57BL/6 mice origin were transplanted on the surface of the left ventricle (LV of C57BL/6 mice as a syngeneic cell-transplant model (syngeneic Tx group, or Balb/c mice as an allogeneic model (allogeneic Tx group. 18F-DPA-714-PET was used to determine the uptake ratio, calculated as the maximum standardized uptake value in the anterior and septal wall of the LV. The uptake ratio was significantly higher in the allogeneic Tx group than in the syngeneic group or the sham group at days 7 and day 10 after the cell transplantation. In addition, the immunochemistry showed significant presence of CD68 and CD3-positive cells at day 7 and 10 in the transplanted graft of the allogeneic Tx group. The expression of TSPO, CD68, IL-1 beta, and MCP-1 was significantly higher in the allogeneic Tx group than in the syngeneic Tx and the sham groups at day 7. The 18F-DPA-714-PET imaging study enabled quantitative visualization of the macrophages-mediated immune

Intracranial AAV-IFN-β gene therapy eliminates invasive xenograft glioblastoma and improves survival in orthotopic syngeneic murine model.

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GuhaSarkar, Dwijit; Neiswender, James; Su, Qin; Gao, Guangping; Sena-Esteves, Miguel

2017-02-01

The highly invasive property of glioblastoma (GBM) cells and genetic heterogeneity are largely responsible for tumor recurrence after the current standard-of-care treatment and thus a direct cause of death. Previously, we have shown that intracranial interferon-beta (IFN-β) gene therapy by locally administered adeno-associated viral vectors (AAV) successfully treats noninvasive orthotopic glioblastoma models. Here, we extend these findings by testing this approach in invasive human GBM xenograft and syngeneic mouse models. First, we show that a single intracranial injection of AAV encoding human IFN-β eliminates invasive human GBM8 tumors and promotes long-term survival. Next, we screened five AAV-IFN-β vectors with different promoters to drive safe expression of mouse IFN-β in the brain in the context of syngeneic GL261 tumors. Two AAV-IFN-β vectors were excluded due to safety concerns, but therapeutic studies with the other three vectors showed extensive tumor cell death, activation of microglia surrounding the tumors, and a 56% increase in median survival of the animals treated with AAV/P2-Int-mIFN-β vector. We also assessed the therapeutic effect of combining AAV-IFN-β therapy with temozolomide (TMZ). As TMZ affects DNA replication, an event that is crucial for second-strand DNA synthesis of single-stranded AAV vectors before active transcription, we tested two TMZ treatment regimens. Treatment with TMZ prior to AAV-IFN-β abrogated any benefit from the latter, while the reverse order of treatment doubled the median survival compared to controls. These studies demonstrate the therapeutic potential of intracranial AAV-IFN-β therapy in a highly migratory GBM model as well as in a syngeneic mouse model and that combination with TMZ is likely to enhance its antitumor potency. © 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Size and spatial orientation of uterine tissue transplants on the peritoneum crucially determine the growth and cyst formation of endometriosis-like lesions in mice.

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Körbel, Christina; Menger, Michael D; Laschke, Matthias W

2010-10-01

In many studies in rodents, intraperitoneal endometriosis-like lesions are surgically induced by syngeneic or autologous transplantation of uterine tissue samples, which are sutured to the abdominal wall. However, until now the surgical techniques have not been standardized, and we address this issue here. Uterine tissue samples were transplanted to the peritoneum of C57BL/6 mice (four study groups, n = 7 each). Using non-invasive high-resolution ultrasound imaging over a period of 4 weeks, we analyzed growth characteristics and cyst formation of the endometriosis-like lesions which developed, in relation to mode of transplantation (syngeneic versus autologous), type of tissue fixed adjacent to the peritoneum (endometrium versus perimetrium), and size of tissue transplanted (2 versus 3 mm). Immunohistochemical analysis was also performed. When the perimetrium, with underlying myometrium, was sutured next to the host peritoneum the endometriosis-like lesions which developed exhibited a higher growth rate (Pendometriosis-like lesions. Our study demonstrates that size and spatial orientation of peritoneally fixed uterine tissue samples crucially determine growth and cyst formation of endometriotic lesions in mice. These findings should improve the standardization and reliability of future studies, performed in the frequently used mouse model of surgically induced endometriosis.

Reutilization of amino acid carbons in relation to albumin turnover in nongrowing mice with sarcoma

International Nuclear Information System (INIS)

Karlberg, I.; Ekman, L.; Edstroem, S.; Schersten, T.; Lundholm, K.

1982-01-01

Reutilization of amino acid carbons was evaluated in relation to increased turnover of albumin in tumor-bearing mice. A methylcholanthrene-induced sarcoma (MCG 101) was used in nongrowing mice (C57BL/6J). Sarcoma-bearing mice developed hypoalbuminemia, but pair-fed controls did not. The hypoalbuminemia was caused by increased albumin degradation rate, measured by injection of Na 214 CO 3 , and by exponentially increased deposition of albumin into the tumor compartment. The fractional synthesis rate of albumin was doubled in tumor-bearing mice compared with controls. The translational capacity of albumin synthesis evaluated in vitro was maintained in tumor host livers. The recycling of [ 14 C]leucine carbons was almost extinguished in plasma albumin of sarcoma-bearing mice, while that of control mice contributed to 30 to 40% of the total leucine carbon flux in turned over albumin. The recycling of arginine carbons was also different when measured after simultaneous injection of [guanido- 14 C]arginine and [2,3- 3 H]arginine. The hepatic pool of free leucine was increased by 22% in tumor-bearing mice. It is concluded that increased albumin degradation in cancer may be a disordered event and is earlier and of initially greater quantitative importance than is altered synthesis of albumin for the development of hypoalbuminemia in experimental cancer

Pharmacokinetics of chimeric L6 conjugated to indium-111- and yttrium-90-DOTA-peptide in tumor-bearing mice

International Nuclear Information System (INIS)

DeNardo, S.J.; Zhong, G.R.; Salako, Q.

1995-01-01

A bifunctional chelating agent, DOTA-Gly 3 -L-(p-isothiocyanato)-phenylalanine amide (DOTA-peptide-NCS), was studied in nude mice bearing human breast cancer xenografts (HBT 3477) to determine its potential for radioimmunoconjugate therapy. Indium-111 and yttrium-90 were attached to an anti-adenocarcinoma chimeric L6 (ChL6) monoclonal antibody (MAb) after pre-chelation to the DOTA-peptide-NCS and the desired neutral radiochelates were obtained by purification. The unique characteristic of the DOTA-peptide-NCS to form neutral complexes with trivalent metals was utilized to separate the resulting 111 In and 90 Y radiochelates from excess chelating agent and other anionic by-products resulting from metal impurities. The purified radiochelates were then conjugated to ChL6. The paramacokinetics of 111 In- and 90 Y-DOTA-peptide-ChL6 were obtained for 5 days after injection in nude mice bearing HBT 3477 xenographs. The results were compared with the pharmacokinetics of 125 I-ChL6 obtained in the same mouse model. The whole-body clearance of 125 I-ChL6, 90 Y-and 111 In-DOTA-peptide-ChL6 was monoexponential with biologic half-times of 92, 104 and 160 hr, respectively. Blood clearances of the three radiopharmaceuticals were biphasic. The radiometal immunoconjugates had greater tumor uptake and slower clearances. Indium-111- and 90 Y-DOTA-peptide-ChL6 can be produced at high specific activity with fewer than one chelate per MAb by using a pre-labeling method that permits radiochelate purification by charge selection. Studies in mouse xenografts indicate that tumor uptake in enhanced and a favorable therapeutic index is achieved using these agents. 29 refs., 7 figs., 2 tabs

The Effect of Docetaxel-Loaded Micro-Bubbles Combined with Low-Frequency Ultrasound in H22 Hepatocellular Carcinoma-Bearing Mice.

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Ren, Shu-Ting; Shen, Shu; He, Xin-Ying; Liao, Yi-Ran; Sun, Peng-Fei; Wang, Bing; Zhao, Wen-Bao; Han, Shui-Ping; Wang, Yi-Li; Tian, Tian

2016-02-01

A novel lipid micro-bubble (MB) loaded with docetaxel (DOC-MB) was investigated in a previous study. However, its anti-tumor effects and mechanism of action in combination with low-frequency ultrasound (LFUS) in vivo are still unclear. DOC-MBs containing 5.0 mg of DOC were prepared by lyophilization with modification via ultrasonic emulsification. Then, the effects of DOC-MBs combined with LFUS on tumor growth, proliferating cell nuclear antigen (PCNA) expression and cell apoptosis, as well as local DOC delivery, were investigated in H22 hepatocellular carcinoma (HCC)-bearing mice. Compared with the previously prepared DOC-MBs (1.6 mg of DOC loaded), the encapsulation efficiency (81.2% ± 3.89%) and concentration ([7.94 ± 0.04] × 10(9) bubbles/mL) of the DOC-MBs containing 5.0 mg of DOC were higher, but the bubble size (1.368 ± 0.004 μm) was smaller. After treatment with the DOC-MBs and LFUS, the H22 HCC growth inhibition rate was significantly increased, PCNA expression in tumor tissue was significantly inhibited and local release of DOC was induced. In conclusion, new DOC-MBs containing 5.0 mg of DOC were successfully prepared with a high encapsulation efficiency and superior bubble size and concentration, and their combination with LFUS significantly enhanced the anti-tumor effect of DOC in H22 HCC-bearing mice by inhibiting tumor cell proliferation and increasing local drug delivery. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Anti-tumor effect of total body irradiation of low doses on WHT/Ht mice

International Nuclear Information System (INIS)

Miyamoto, Miyako; Sakamoto, Kiyohiko

1987-01-01

The effect of low dose (0.05 - 1.0 Gy) of total body irradiation (TBI) on non-tumor bearing and tumor bearing mice were investigated. Mice received TBI of 0.1 Gy during 6 - 12 hours before tumor cell inoculation demonstrated to need larger number of tumor cells (approximately 2.5 times) for 50 per cent tumor incidence, compared to recipient mice not to receive TBI. On the other hand, in tumor bearing mice given 0.1 Gy of TBI only tumor cell killing effect was not detected, however enhancement of tumor cell killing effect and prolonged growth delay were observed when tumor bearing mice were treated with 0.1 Gy of TBI in combined with local irradiation on tumors, especially cell killing effect was remarkable in dose range over 6 Gy of local exposure. The mechanism of the effect of 0.1 Gy TBI is considered to be host mediated reactions from the other our experimental results. (author)

Inhibition of experimental lung metastasis by systemic lentiviral delivery of kallistatin

International Nuclear Information System (INIS)

Shiau, Ai-Li; Wu, Chao-Liang; Lee, Che-Hsin; Teo, Min-Li; Chen, Shin-Yao; Wang, Chrong-Reen; Hsieh, Jeng-Long; Chang, Meng-Ya; Chang, Chih-Jui; Chao, Julie; Chao, Lee

2010-01-01

Angiogenesis plays an important role in the development and progression of tumors. Kallistatin exerts anti-angiogenic and anti-inflammatory activities that may be effective in inhibiting tumor metastasis. We investigated the antitumor effect of lentivirus-mediated kallistatin gene transfer in a syngeneic murine tumor model. Lentiviral vector encoding kallistatin (LV-Kallistatin) was constructed. The expression of kallistatin was verified by enzyme-linked immunosorbent assay (ELISA), and the bioactivity of kallistatin was determined by using cell proliferation, migration, and invasion assays. In addition, antitumor effects of LV-Kallistatin were evaluated by the intravenous injection of virus into tumor-bearing mice. The conditioned medium from LV-Kallistatin-treated cells inhibited the migration and proliferation of endothelial cells. Meanwhile, it also reduced the migration and invasion of tumor cells. In the experimental lung metastatic model, tumor-bearing mice receiving LV-Kallistatin had lower tumor nodules and longer survival than those receiving control virus or saline. Moreover, the microvessel densities, the levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, and nuclear factor κB (NF-κB) transcriptional activity were reduced in the LV-Kallistatin-treated mice. Results of this study showed that systemic administration of lentiviral vectors encoding kallistatin inhibited the growth of metastatic tumor and prolonged the survival of tumor-bearing mice. These results suggest that gene therapy using lentiviruses carrying the kallistatin gene, which exerts anti-angiogenic and anti-inflammatory activities, represents a promising strategy for the treatment of lung cancer

Pharmacokinetic study of radiolabeled anti-colorectal carcinoma monoclonal antibodies in tumor-bearing nude mice

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Douillard, J.Y.; Chatal, J.F.; Curtet, C.; Kremer, M.; Saccavini, J.C.; Peuvrel, P.; Koprowski, H.

1985-09-01

Monoclonal antibodies (MoAbs) 17-1A and 19-9, which specifically bind human colorectal carcinoma (CRC) cells, were tested for their usefulness in localizing colorectal tumors in nude mice. One of the /sup 131/I-labeled MoAbs and an irrelevant /sup 125/I-labeled immunoglobulin of the same isotype were injected into nude mice simultaneously bearing a human CRC and a human melanoma. The percentage of the injected dose of antibody per gram of tissue, the CRC/tissue ratios of antibody distribution, and the localization indicees were calculated at various time intervals (2 h to 10 days). For both MoAbs, labeling to a specific activity of 10 ..mu..Ci/..mu..g by the iodogen method gave optimum immunoreactivity. The accumulation of MoAb 17-1A in CRC reached its maximum at 5 days and remained at this level for up to 9 days postinjection. For MoAb 19-9, which detects a circulating antigen shed by the tumor into the serum, the accumulation in the CRC was maximum at 24 h, and decreased thereafter. The CRC/organ ratios and localization indices for-both MoAbs increased with time in the CRC tissue, but remained low and unchanged in the melanoma and normal tissue. Using F(ab')/sub 2/ antibody fragments, faster kinetics with earlier maximum accumulation, higher tumor/organ ratios, and better localization indices were achieved than with intact MoAbs. The data obtained was useful in defining parameters which must be considered before radiolabeled MoAbs are used in cancer patients for diagnostic purposes.

Transfer of intestine-derived diamines into tumour cells during treatment of Ehrlich-ascites--carcinoma-bearing mice with polyamine anti-metabolites.

Science.gov (United States)

Kallio, A; Nikula, P; Jänne, J

1984-01-01

Treatment of Ehrlich-ascites-carcinoma-bearing mice with methylglyoxal bis(guanylhydrazone) alone or in combination with 2-difluoromethylornithine greatly enhanced the transfer of intragastrically administered radioactive putrescine and cadaverine into the carcinoma cells. Difluoromethylornithine alone did not have any effect on the accumulation of intestine-derived diamines in the tumour cells. The frequently reported restoration of difluoromethylornithine-induced polyamine depletion on administration of methylglyoxal bis(guanylhydrazone) is in all likelihood attributable to a profound inhibition of intestinal diamine oxidase (EC 1.4.3.6), resulting in an enhanced entry of intestinal (bacterial) diamines into general circulation and finally into tumour cells. PMID:6424664

Hypolocomotion, asymmetrically directed behaviors (licking, lifting, flinching, and shaking and dynamic weight bearing (gait changes are not measures of neuropathic pain in mice

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Schorscher-Petcu Ara

2010-06-01

Full Text Available Abstract Background Spontaneous (non-evoked pain is a major clinical symptom of neuropathic syndromes, one that is understudied in basic pain research for practical reasons and because of a lack of consensus over precisely which behaviors reflect spontaneous pain in laboratory animals. It is commonly asserted that rodents experiencing pain in a hind limb exhibit hypolocomotion and decreased rearing, engage in both reflexive and organized limb directed behaviors, and avoid supporting their body weight on the affected side. Furthermore, it is assumed that the extent of these positive or negative behaviors can be used as a dependent measure of spontaneous chronic pain severity in such animals. In the present study, we tested these assumptions via blinded, systematic observation of digital video of mice with nerve injuries (chronic constriction or spared nerve injury, and automated assessment of locomotor behavior using photocell detection and dynamic weight bearing (i.e., gait using the CatWalk® system. Results We found no deficits in locomotor activity or rearing associated with neuropathic injury. The frequency of asymmetric (ipsilaterally directed behaviors were too rare to be seriously considered as representing spontaneous pain, and in any case did not statistically exceed what was blindly observed on the contralateral hind paw and in control (sham operated and unoperated mice. Changes in dynamic weight bearing, on the other hand, were robust and ipsilateral after spared nerve injury (but not chronic constriction injury. However, we observed timing, pharmacological, and genetic dissociation of mechanical allodynia and gait alterations. Conclusions We conclude that spontaneous neuropathic pain in mice cannot be assessed using any of these measures, and thus caution is warranted in making such assertions.

FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model.

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Szymiczek, Agata; Pastorino, Sandra; Larson, David; Tanji, Mika; Pellegrini, Laura; Xue, Jiaming; Li, Shuangjing; Giorgi, Carlotta; Pinton, Paolo; Takinishi, Yasutaka; Pass, Harvey I; Furuya, Hideki; Gaudino, Giovanni; Napolitano, Andrea; Carbone, Michele; Yang, Haining

2017-03-15

Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet. Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)-a major target of FTY720. The binding of the endogenous inhibitor SET to PP2A in presence of FTY720 was evaluated by immunoblotting and immunoprecipitation. Signaling and activation of programmed cell death were evaluated by immunoblotting and flow cytometry. A syngeneic mouse model was used to evaluate anti-tumor efficacy and toxicity profile of FTY720 in vivo. We show that FTY720 significantly suppressed MM cell viability and anchorage-independent growth without affecting normal HM cells. FTY720 inhibited the phosphatase activity of PP2A by displacement of SET protein, which appeared overexpressed in MM, as compared to HM cells. FTY720 promoted AKT dephosphorylation and Bcl-2 degradation, leading to induction of programmed cell death, as demonstrated by caspase-3 and PARP activation, as well as by cytochrome c and AIF intracellular translocation. Moreover, FTY720 administration in vivo effectively reduced tumor burden in mice without apparent toxicity. Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment.

Relationship between strains of tumor-bearing animals and the tumor affinity of /sup 169/Yb and /sup 67/Ga

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Ando, A; Hiraki, T [Kanazawa Univ. (Japan). School of Paramedicine; Hisada, K; Ando, I; Ugiie, T

1975-02-01

It is well a well-known fact that ytterbium-169 is a strong bone seeking element. We have already reported that this element was concentrated in nonosseous tumor tissues and that its tumor affinity was stronger than that of gallium-67 in our previous experiment using Yoshida sarcoma-bearing rats. Ytterbium-169 citrate and gallium-67 citrate were compared in four strains of tumor-bearing rats and mice. The uptake rate of ytterbium-169 in tumor tissues was much larger than that of gallium-67 in Ehrlich cancer-bearing mice, but these values of ytterbium-169 were slightly smaller than those of gallium-67 in Yoshida sarcoma-bearing rats, Walker carcinosarcoma 256-bearing rats and sarcoma 180-bearing mice. Tumor to organ ratios of ytterbium-169, which were most important for tumor scanning agents, were much larger than those of gallium-67 in all four strains except for the tumor to bone ratio of ytterbium-169. From the above-described facts, it was shown that ytterbium-169 citrate had a stronger tumor affinity than did gallium-67 citrate and that the tumor affinity of ytterbium-169 citrate was similar in each of these four strains of tumor-bearing animals.

Effects of low dose radiation on tumor growth and changes of erythrocyte immune function and activity of SOD in tumor-bearing mice

International Nuclear Information System (INIS)

Yu Hongsheng; Lu Yanda

2001-01-01

Objective: To study the effect of low dose radiation on tumor growth and changes of erythrocyte immune function and activity of SOD in the tumor-bearing mice. Methods: Kunming strain male mice were implanted with S 180 sarcoma cells in the right inguen subcutaneously as an experimental in situ animal model. Six hours before implantation the mice were given 75 mG whole-body X-ray irradiation and tumor-formation rate was counted 5 days late. From then, every two days the tumor volume was measured to draw a tumor growth curve. Fifteen days later, all mice were killed to measure the tumor weight, observe the necrosis area and the tumor-infiltration lymphoreticular cells (TIL) in the tumor pathologically. At the same time, erythrocyte immune function and activity of SOD were tested. Results: (1) The mice pre-exposed to low dose radiation had a lower tumor formation rate than those without a pre-exposed (P < 0.05). (2) The tumor growth slowed down significantly in mice receiving a low does irradiation; The average tumor weight in mice receiving a low dose irradiation was lighter too (P < 0.05). (3) The tumor necrosis areas were larger and TILs were more in the irradiation group than those of the control group. (4) The erythrocyte immune function and activity of SOD in the irradiation group were all higher significantly than those of the control group ( P < 0.05). Conclusion: Low dose radiation could markedly increase anti-tumor ability of the organism and improve the erythrocyte immune function and activity of SOD in red cells, suggesting it could be useful in clinical cancer treatment

Effects of low dose radiation combined with cyclophosphamide on tumor cell apoptosis, cell cycle and proliferation of bone marrow in tumor-bearing mice

International Nuclear Information System (INIS)

Yu Hongsheng; Fei Conghe; Shen Fangzhen; Liang Jun

2004-01-01

Objective: To study the effect of low dose radiation (LDR) combined with cyclophosphamide on tumor cell apoptosis, cell cycle, and proliferation of bone marrow in mice tumor-bearing mice. Methods: Kunming strain male mice were implanted with S180 sarcoma cells in the left hind leg subcutaneously as an experimental animal model. Five and 8 days after implantation, the mice were given 75 mGy whole-body γ-ray radiation and CTX(300 mg/kg) by intraperitoneal injection 36 hour after LDR. All mice were sacrificed to measure the tumor volume, tumor cell apoptosis, and cell cycle; the proliferation of bone marrow was analyzed by flow cytometry. Results: Tumor growth was significantly slowed down in the treated groups. The apoptosis of tumor cells increased significantly after LDR. The tumor cells were arrested in G 1 phase in CTX and CTX+LDR groups, more significantly in the latter group than in the former group. Concentration of bone marrow cells and proliferation index in CTX + LDR group were higher than those in CTX group, although concentration of bone marrow cells in CTX and CTX+LDR groups were much lower than that in normal mice. Conclusion: Low dose radiation combined with cyclophosphamide causes more significant G 1 -phase arrest than cyclophosphamide alone and enhances anti-tumor effect markedly. At the same time LDR significantly protects hematopoietic function of bone marrow, which is of practical significance as an adjuvant chemotherapy

Animal experimental model of a graft-versus-host (GVH) reaction after allogenic transplantation of bone marrow in lethally irradiated mice

International Nuclear Information System (INIS)

Schwenke, H.; Muench, S.; Haubold, S.; Weber, B.

1977-01-01

The graft-versus-host (GVH) disease represents a serious still unsolved problem in the human allogenic transplantation of bone marrow. An experimental model of GVH reaction after an allogenic transplantation of bone marrow in the adult mouse has been worked out as a prerequisite for further studies on the therapeutic influence of this syndrome. 3 groups have been formed out of 82 lethally X-irradiated C57 Bl mice. The non-transplanted control group died to a hundred per cent within 12 days. While out of the 2nd group treated with syngenic bone marrow 55 per cent survived from the 22nd day, 30 per cent of the third animal group, allogenicly transplanted with histoincompatible AKR donor marrow developed a chronic GVH syndrome. The following symptoms were observed: retardation, alterations of the skin, diarrhea, edemas of the legs, failing increase of leukocytes in blood and proliferation of lymphocytes in bone marrow of about 60 per cent (18 per cent in syngenically transplanted animals), in lacking proliferation of hematopoiesis. The increase of liver and especially spleen index is not characteristic in comparison with the syngenically transplanted group, since in the latter there is also an increase of the values on account of a strong hematopoetic proliferation. The model is suitable and sufficiently well characterized for the performance of further experimental studies. (author)

Cell surface antigens of radiation leukemia virus-induced BALB/c leukemias defined by syngeneic cytotoxic T lymphocytes

International Nuclear Information System (INIS)

Kaneko, Yukio; Oettgen, H.F.; Obata, Yuichi; Nakayama, Eiichi.

1989-01-01

Two cell surface antigens of mouse leukemias were defined by BALB/c cytotoxic T lymphocytes (CTL) generated against syngeneic radiation leukemia virus (RadLV)-induced leukemia, BALBRV1 or BALBRVD. Hyperimmunization of BALB/c mice with irradiated leukemias followed by in vitro sensitization of primed spleen cells resulted in the generation of CTL with high killing activity. The specificity of CTL was examined by direct cytotoxicity assays and competitive inhibition assays. A shared cell surface antigen, designated as BALBRV1 antigen, was detected by BALB/c anti-BALBRV1 CTL. BALBRV1 antigen was expressed not only on RadLV-induced BALB/c leukemias except for BALBRVD, but also on spontaneous or X-ray-induced BALB/c leukemias, chemically-induced leukemias with the H-2 d haplotype and some chemically-induced BALB/c sarcomas. In contrast, a unique cell surface antigen, designated as BALBRVD antigen, was detected by BALB/c anti-BALBRVD CTL. BALBRVD antigen was expressed only on BALBRVD, but not on thirty-nine normal lymphoid or tumor cells. These two antigens could be distinguished from those previously defined on Friend, Moloney, Rauscher or Gross murine leukemia virus (MuLV) leukemias, or MuLV-related antigens. Both cytotoxic responses were blocked by antisera against H-2K d , but not H-2D d . The relationship of BALBRV1 antigen and BALBRVD antigen to endogenous MuLV is discussed with regard to the antigenic distribution on tumor cell lines. (author)

Induction of the immune response suppression in mice inoculated with Candida albicans.

Science.gov (United States)

Valdez, J C; Mesón, D E; Sirena, A; de Petrino, S F; Eugenia, M; de Jorrat, B B; de Valdex, M G

1986-03-01

There is a controversy in respect to the immunological response (humoral or cellular) concerning the defense against Candida albicans. Candidosis would induce sub-populations of suppressor cells in the host cell-immune response. This report tries to show the effect of different doses of C. albicans (alive or heat-killed) on the expression of cell-mediated and humoral immunity. The effect upon cell immunity was determined by inoculating different lots of singeneic mice, doses of varied concentration of C. albicans and checking for delayed-type hipersensitivity (D.T.H.). D.T.H. was also controlled in syngeneic normal mice which had previously been injected with inoculated mice spleen cells. Humoral immunity was assayed by measuring the induced blastogenesis by Pokeweed Mitogen on spleen mononuclear cells with different doses of C. albicans. Results obtained show that the different doses gave origin to: Suppression of humoral and cell response (10(8) alive); Suppression of only humoral response (10(6) alive); Suppression of cell response and increase of humoral response (10(9) dead); Increase of both responses (10(8) dead).

Factors related to resistance to hematopoietic death in mice

International Nuclear Information System (INIS)

Mori, Nobuko; Okumoto, Masaaki; Yonezawa, Morio; Nishikawa, Ryosuke; Takamori, Yasuhiko; Esaki, Kozaburo.

1994-01-01

Mouse strain difference in the radiosensitivity to hematopoietic death is thought to be determined by several factors besides radiosensitivity and the initial number of hematopoietic stem cells. Factors related to the survival of mice exposed to X-irradiation were analyzed using BALB/cHeA and STS/A strains whose LD 50/30 values differ markedly (BALB/cHeA, 5.55 Gy; STS/A, 8.45 Gy). STS/A mice exposed to 4 Gy of X-irradiation showed a small reduction but rapid recovery of blood cells (leukocytes, erythrocytes, and thrombocytes) when compared with BALB/cHeA mice. The survival of endogenous and exogenous CFU-S was much higher, by a magnitude of one log or more, in STS/A mice than those in BALB/cHeA mice; whereas the initial numbers of femoral CFU-S were similar for the two strains. The recovery of exogenous CFU-S was much more rapid in STS/A mice than it was in BALB/cHeA mice after 4 Gy of X-irradiation. Furthermore, spleen colonies produced by the transfusion of STS/A marrow cells into syngeneic recipients were significantly larger than those produced by BALB/cHeA marrow cells, regardless of whether the mice used for sources of marrow cells had been irradiated. But, there was no such difference when unirradiated marrow cells from the two strains were transfused into (BALB/cHeA X STS/A) F 1 recipients. These results indicate the possible contribution of a host factor (s) that stimulates the growth of spleen colonies after radiation to the radioresistance of STS/A mice, in addition to the primary effect of higher number of survivals of endogenous and exogenous CFU-S in STS/A mice. (author)

Focal glomerulosclerosis in proviral and c-fms transgenic mice links Vpr expression to HIV-associated nephropathy

International Nuclear Information System (INIS)

Dickie, Peter; Roberts, Amanda; Uwiera, Richard; Witmer, Jennifer; Sharma, Kirti; Kopp, Jeffrey B.

2004-01-01

Clinical and morphologic features of human immunodeficiency virus (HIV)-associated nephropathy (HIVAN), such as proteinuria, sclerosing glomerulopathy, tubular degeneration, and interstitial disease, have been modeled in mice bearing an HIV proviral transgene rendered noninfectious through a deletion in gag/pol. Exploring the genetic basis of HIVAN, HIV transgenic mice bearing mutations in either or both of the accessory genes nef and vpr were created. Proteinuria and focal glomerulosclerosis (FGS) only developed in mice with an intact vpr gene. Transgenic mice bearing a simplified proviral DNA (encoding only Tat and Vpr) developed renal disease characterized by FGS in which Vpr protein was localized to glomerular and tubular epithelia by immunohistochemistry. The dual transgenic progeny of HIV[Tat/Vpr] mice bred to HIV[ΔVpr] proviral transgenic mice displayed a more severe nephropathy with no apparent increase in Vpr expression, implying that multiple viral genes contribute to HIVAN. However, the unique contribution of macrophage-specific Vpr expression in the development of glomerular disease was underscored by the induction of FGS in multiple murine lines bearing a c-fms/vpr transgene

Adenovirus-mediated interleukin-12 gene transfer combined with cytosine deaminase followed by 5-fluorocytosine treatment exerts potent antitumor activity in Renca tumor-bearing mice

International Nuclear Information System (INIS)

Hwang, Kyung-Sun; Cho, Won-Kyung; Yoo, Jinsang; Yun, Hwan-Jung; Kim, Samyong; Im, Dong-Soo

2005-01-01

Therapeutic gene transfer affords a clinically feasible and safe approach to cancer treatment but a more effective modality is needed to improve clinical outcomes. Combined transfer of therapeutic genes with different modes of actions may be a means to this end. Interleukin-12 (IL-12), a heterodimeric immunoregulatory cytokine composed of covalently linked p35 and p40 subunits, has antitumor activity in animal models. The enzyme/prodrug strategy using cytosine deaminase (CD) and 5-fluorocytosine (5-FC) has been used for cancer gene therapy. We have evaluated the antitumor effect of combining IL-12 with CD gene transfer in mice bearing renal cell carcinoma (Renca) tumors. Adenoviral vectors were constructed encoding one or both subunits of murine IL-12 (Ad.p35, Ad.p40 and Ad.IL-12) or cytosine deaminase (Ad.CD). The functionality of the IL-12 or CD gene products expressed from these vectors was validated by splenic interferon (IFN)-γ production or viability assays in cultured cells. Ad.p35 plus Ad.p40, or Ad.IL-12, with or without Ad.CD, were administered (single-dose) intratumorally to Renca tumor-bearing mice. The animals injected with Ad.CD also received 5-FC intraperitoneally. The antitumor effects were then evaluated by measuring tumor regression, mean animal survival time, splenic natural killer (NK) cell activity and IFN-γ production. The inhibition of tumor growth in mice treated with Ad.p35 plus Ad.p40 and Ad.CD, followed by injection of 5-FC, was significantly greater than that in mice treated with Ad.CD/5-FC, a mixture of Ad.p35 plus Ad.p40, or Ad.GFP (control). The combined gene transfer increased splenic NK cell activity and IFN-γ production by splenocytes. Ad.CD/5-FC treatment significantly increased the antitumor effect of Ad.IL-12 in terms of tumor growth inhibition and mean animal survival time. The results suggest that adenovirus-mediated IL-12 gene transfer combined with Ad.CD followed by 5-FC treatment may be useful for treating cancers

Chemotherapy synergizes with radioimmunotherapy targeting La autoantigen in tumors.

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Fares Al-Ejeh

Full Text Available To date, inefficient delivery of therapeutic doses of radionuclides to solid tumors limits the clinical utility of radioimmunotherapy. We aim to test the therapeutic utility of Yttrium-90 ((90Y-radio-conjugates of a monoclonal antibody, which we showed previously to bind specifically to the abundant intracellular La ribonucleoprotein revealed in dead tumor cells after DNA-damaging treatment.Immunoconjugates of the DAB4 clone of the La-specific monoclonal antibody, APOMAB, were prepared using the metal chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA, and then radiolabeled with (90Y. Mice bearing established subcutaneous tumors were treated with (90Y-DOTA-DAB4 alone or after chemotherapy. Non-radiosensitizing cyclophosphamide/etoposide chemotherapy was used for the syngeneic EL4 lymphoma model. Radiosensitizing cisplatin/gemcitabine chemotherapy was used for the syngeneic Lewis Lung carcinoma (LL2 model, and for the xenograft models of LNCaP prostatic carcinoma and Panc-1 pancreatic carcinoma. We demonstrate the safety, specificity, and efficacy of (90Y-DOTA-DAB4-radioimmunotherapy alone or combined with chemotherapy. EL4 lymphoma-bearing mice either were cured at higher doses of radioimmunotherapy alone or lower doses of radioimmunotherapy in synergy with chemotherapy. Radioimmunotherapy alone was less effective in chemo- and radio-resistant carcinoma models. However, radioimmunotherapy synergized with radiosensitizing chemotherapy to retard significantly tumor regrowth and so prolong the survival of mice bearing LL2, LNCaP, or Panc-1 subcutaneous tumor implants.We report proof-of-concept data supporting a unique form of radioimmunotherapy, which delivers bystander killing to viable cancer cells after targeting the universal cancer antigen, La, created by DNA-damaging treatment in neighboring dead cancer cells. Subsequently we propose that DAB4-targeted ionizing radiation induces additional cycles of tumor cell death

PGE from Octopus aegina Induces Apoptosis in Ehrlich's Ascites Carcinoma of Mice.

Science.gov (United States)

Karthigayan, S; Balasubashini, M Sri; Balasubramanian, T; Somasundaram, S T

2007-01-01

ABSTRACT The present study was carried out to assess the antitumor effect of venomous peptide from the cephalopod Octopus aegina on Ehrlich's ascites carcinoma (EAC). Male albino Swiss mice were used in the present study. Four groups of animals were treated with three doses of the sublethal dose of venom, 15, 75, and 150 mug/kg body weight (intraperitoneal injection), along with the standard drug 5-fluorouracil (20 mg/kg b.w.). After 10 days of treatment, six animals from each group were sacrificed for the biochemical analysis and the rest were left to calculate the mean survival time. In EAC-bearing mice, mean lifespan, tumor volume, hemoglobin, red blood cells, and lymphocytes were significantly decreased when compared to the normal animals. While body weight, neutrophils, and viable tumor cell count were increased in the EAC-bearing mice, these changes were brought back to near normal levels in different treatment groups. The macromolecule concentration of peritoneal cells, such as DNA, RNA, and protein, were altered in the EAC-bearing mice and observed to be near normal in the treatment groups. The caspase-3 activity was significantly increased in the peritoneal cells of the treatment groups when compared to the EAC-bearing mice. The role of apoptotic cascade in EAC cell death was confirmed by the DNA fragmentation on agarose gel. Apart from the antitumor effect, octopus venom reduced the tumor burden on the liver and altered the changes in the activities of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP). Therefore, the venom from O. aegina has a potential antitumor effect on the EAC-bearing mice.

In vitro gamma irradiation Medical Center of leukemic cells in mice, rats, and guinea pigs

International Nuclear Information System (INIS)

Gross, L.; Dreyfuss, Y.; Ehrenreich, T.; Feldman, D.; Limbert, L.M.

1980-01-01

In vitro gamma irradiation of virus-induced (Gross) mouse leukemia cells at doses of 350 to 1600 rads (1 rad = 0.01 gray) had no effect on their ability to induce leukemia, usually within 2 weeks, after transplantation into syngeneic mice. However, when cells irradiated at doses of 2000-20,000 rads were transplanted, they induced leukemia after a latency period exceeding 2.5 months, similar to the results observed in mice inoculated with filtered mouse leukemia extracts. Similar results were also obtained after irradiation of leukemic cells derived from rats in which leukemia had been induced by rat-adapted mouse leukemia virus. Apparently, gamma irradiation at a dose of, or exceeding, 2000 rads, inhibits the ability of mouse and rat leukemic cells to induce leukemia after transplantation into syngeneic hosts; however, it does not inactivate the virus carried by such cells nor prevent it from inducing leukemia. [In previous experiments, doses of more than 4,500,000 rads were needed to inactivate the passage A (Gross) leukemia virus carried in either mouse or rat leukemic cells.] In vitro gamma irradiation of L2C guinea pig leukemic cells at doses of 750 to 2500 rads had no apparent effect on their ability to induce leukemia after transplantation into strain 2 guinea pigs. However, irradiation at doses of 3250 to 20,000 rads inactivated their ability to do so. The morphology of mouse, rat, and guinea pig leukemic cells and the virus particles present in such cells was not affected by irradiation at doses of 20,000 rads

Evaluation of 18F-labeled targeted perfluorocarbon-filled albumin microbubbles as a probe for microUS and microPET in tumor-bearing mice.

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Liao, Ai-Ho; Wu, Shih-Yen; Wang, Hsin-Ell; Weng, Chien-Hsiu; Wu, Ming-Fang; Li, Pai-Chi

2013-02-01

In this study, albumin-shelled, targeted MBs (tMBs) were first demonstrated with the expectation of visualization of biodistribution of albumin-shelled tMBs. The actual biodistribution of albumin-shelled tMBs is of vital importance either for molecular imaging or for drug delivery. Recently, albumin microbubbles (MBs) have been studied for drug and gene delivery in vitro and in vivo through cavitation. Targeted lipid-shelled MBs have been applied for ultrasound molecular imaging and conjugated with radiolabeled antibodies for whole-body biodistribution evaluations. The novelty of the work is that, in addition to the lipid tMBs, the albumin tMBs was also applied in biodistribution detection. Multimodality albumin-shelled, (18)F-SFB-labeled VEGFR2 tMBs were synthesized, and their characteristics in mice bearing MDA-MB-231 human breast cancer were investigated with micro-positron-emission tomography (microPET) and high-frequency ultrasound (microUS). Albumin-shelled MBs can be labeled with (18)F-SFB directly and conjugated with antibodies for dual molecular imaging. The albumin-shelled tMBs show a lifetime in 30min in the blood pool and a highly specific adherence to tumor vessels in mice bearing human breast cancer. From the evaluations of whole-body biodistribution, the potential of the dual molecular imaging probe for drug or gene delivery in animal experiments with albumin shelled MBs has been investigated. Copyright © 2012 Elsevier B.V. All rights reserved.

Study of trace element metabolism in normal and cancerous mice using multitracer technique

International Nuclear Information System (INIS)

Wang Xiao; Kong Fuquan; Zhao Kui; Zhang Xiang; Qin Zhi

2008-01-01

A radioactive multitracer solution of the 24 elements, e.g. Be, Na, K, Rb, Mg, Ca, Sr, Ga, As, Sc, V, Cr, Mn, Co, Fe, Zn, Y, Zr, Mo, Nb, To, Ru, Ag and In, was obtained from the nuclear reaction of 25 MeV/u 40 Ar + Se with a series of chemical process. The multitracer solution was orally administered to normal and muscular turnout-bearing mice of male Balb/c mice. Urine and faeces samples of mice were collected. The two group mice were saerificed after 96 h. The uptake of 17 elements, Na, Rb, Ga, As, Sc, V, Cr, Mn, Co, Fe, Zn, Y, Zr, Tc, Ru, Ag and In, were simultaneously detected in normal mice while 15 elements, Na, Rb, Ga, Sc, V, Cr, Mn, Co, Fe, Y, Zr, Tc, Ru, Ag and In, were simultaneously detected in tumour-bearing mice. Our results indicate that the majority of the detected elements were distributed in liver, kidney, pelt, turnout while a small fraction of the biotrace elements were distributed in heart and spleen. (tumour-bearing mice) in the two groups of mice. The higher concentrations of Fe, Na, Mn were detected in heart or kidney of normal mice. Na, Mn, Fe and Co showed better absorption in most tissues in the normal mice, except for Na and Mn in heart. (authors)

Inhibition of experimental lung metastasis by systemic lentiviral delivery of kallistatin

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Chao Julie

2010-05-01

Full Text Available Abstract Background Angiogenesis plays an important role in the development and progression of tumors. Kallistatin exerts anti-angiogenic and anti-inflammatory activities that may be effective in inhibiting tumor metastasis. We investigated the antitumor effect of lentivirus-mediated kallistatin gene transfer in a syngeneic murine tumor model. Methods Lentiviral vector encoding kallistatin (LV-Kallistatin was constructed. The expression of kallistatin was verified by enzyme-linked immunosorbent assay (ELISA, and the bioactivity of kallistatin was determined by using cell proliferation, migration, and invasion assays. In addition, antitumor effects of LV-Kallistatin were evaluated by the intravenous injection of virus into tumor-bearing mice. Results The conditioned medium from LV-Kallistatin-treated cells inhibited the migration and proliferation of endothelial cells. Meanwhile, it also reduced the migration and invasion of tumor cells. In the experimental lung metastatic model, tumor-bearing mice receiving LV-Kallistatin had lower tumor nodules and longer survival than those receiving control virus or saline. Moreover, the microvessel densities, the levels of vascular endothelial growth factor (VEGF, tumor necrosis factor (TNF-α, and nuclear factor κB (NF-κB transcriptional activity were reduced in the LV-Kallistatin-treated mice. Conclusion Results of this study showed that systemic administration of lentiviral vectors encoding kallistatin inhibited the growth of metastatic tumor and prolonged the survival of tumor-bearing mice. These results suggest that gene therapy using lentiviruses carrying the kallistatin gene, which exerts anti-angiogenic and anti-inflammatory activities, represents a promising strategy for the treatment of lung cancer.

[Changes and significance of peripheral blood platelet count in tumor shrinkage induced by a low dose of CTX in T739 mice].

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Li, Mo-lin; Jia, Yu-jie; Jiang, Miao-na; Shu, Xiao-hong; Li, Chuan-gang

2008-06-01

To establish a mouse model for BTT739 tumor-bearing mice cured by a low dose of cyclophosphamide (CTX). And then to observe the dynamic changes and significance of peripheral blood counts especially blood platelet count during tumor shrinkage induced by a low dose of CTX in T739 mice. Mouse bladder carcinoma tissues were inoculated subcutaneously into T739 mice. Seven days later, different doses of CTX or the same volume of NS were administered intraperitoneally to treat these tumor-bearing T739 mice. Tumor sizes were observed and recorded subsequently to find out the minimal dose of CTX that could cure most of these tumor-bearing mice. Then another 12 tumor-bearing mice were randomly divided into 15 mg/kg CTX treatment group and control group. Blood samples were obtained from orbital venous sinus on different times after CTX treatment. Complete blood counts were performed and the relationship between peripheral blood platelet counts and tumor shrinkage was analyzed. Within 2 weeks after CTX treatment, the speed of tumor shrinkage had a positive relationship with the dose of CTX used; but the survival rate of the tumor-bearing mice had a negative relationship with the dose of CTX used in 2 months after CTX treatment. 15 mg/kg CTX could cure most of the tumor bearing mice, while it had no remarkably inhibitive effects on peripheral blood cells. The perpherial platelet count increased to (1483.4+/-184.4)x10(9)/L in mice 6 h after CTX treatment. There was significant difference compared with that in mice of control group (1086.6+/-81.0)x10(9)/L (P0.05). CTX 15 mg/kg could cure most of bladder tumor-bearing T739 mice. The transient increase of the peripheral platelet count in 6 h after CTX treatment may relate to the antitumor effects of CTX.

Growth of SJL/J-derived transplantable reticulum cell sarcoma as related to its ability to induce T-cell proliferation in the host- III. Studies on thymectomized and congenitally athymic SJL mice

International Nuclear Information System (INIS)

Katz, I.R.; Chapman-Alexander, J.; Jacobson, E.B.; Lerman, S.P.; Thorbecke, G.J.

1981-01-01

When SJL mice are irradiated and reconstituted with syngeneic bone marrow (XBM) they support growth of transplantable reticulum cell sarcoma to approximately 60% of that in normal mice. The ability to support RCS growth gradually improves with time after irradiation and reaches 90% of normal by 8-12 weeks. However, if the mice are thymectomized 4 weeks prior to treatment (Tx-XBM) they initially show 50% which increases to only 65% of growth in normal mice after 12 weeks. The ability of lymphoid cells from these mice to proliferate in vitro in response to irradiated RCS cells is normal 4 weeks after treatment in XBM, but remains <10% of normal in Tx-XBM mice. Nude mice of SJL background also show greatly diminished RCS growth. It is concluded that T cells promote RCS growth in vivo possibly via their tendency to proliferate upon exposure to RCS

Lack of immunoglobulin M suppression by immunoglobulin G antibody in thymectomized, irradiated, and bone marrow-reconstituted mice infected with Toxoplasma gondii.

OpenAIRE

Aryanpour, J; Hafizi, A; Modabber, F

1980-01-01

Thymectomized, irradiated, bone marrow-reconstituted (T-deprived) mie infected with an avirulent strain of Toxoplasma gondii produced antibody titers comparable to those produced in intact syngeneic mice. Both immunoglobulin M (IgM) and IgG antibodies were produced in T-deprived animals; however, the IgM antibody remained constant in the presence of increasing amounts of IgG. In the intact animals, IgM became undetectable by day 50 postinfection as expected. Feedback inhibition of IgM by IgG ...

Improvement of macrophage dysfunction by administration of anti-transforming growth factor-beta antibody in EL4-bearing hosts.

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Maeda, H; Tsuru, S; Shiraishi, A

1994-11-01

An experimental therapy for improvement of macrophage dysfunction caused by transforming growth factor-beta (TGF-beta) was tried in EL4 tumor-bearing mice. TGF-beta was detected in cell-free ascitic fluid from EL4-bearers, but not in that from normal mice, by western blot analysis. The ascites also showed growth-suppressive activity against Mv1Lu cells, and the suppressive activity was potentiated by transient acidification. To investigate whether the functions of peritoneal macrophages were suppressed in EL4-bearers, the abilities to produce nitric oxide and tumor necrosis factor-alpha (TNF-alpha) upon lipopolysaccharide (LPS) stimulation were measured. Both abilities of macrophages in EL4-bearing mice were suppressed remarkably on day 9, and decreased further by day 14, compared with non-tumor-bearing controls. TGF-beta activity was abrogated by administration of anti-TGF-beta antibody to EL4-bearing mice. While a large amount of TGF-beta was detected in ascitic fluid from control EL4-bearers, little TGF-beta was detectable in ascites from EL4-bearers given anti-TGF-beta antibody. Furthermore, while control macrophages exhibited little or no production of nitric oxide and TNF-alpha on LPS stimulation in vitro, macrophages from EL4-bearers administered with anti-TGF-beta antibody showed the same ability as normal macrophages. These results clearly indicate that TGF-beta contributes to macrophage dysfunction and that the administration of specific antibody for TGF-beta reverses macrophage dysfunction in EL4-bearing hosts.

Effect of cotransplantation of hematopoietic stem cells and embryonic AGM stromal cells on hematopoietic reconstitution in mice after bone marrow transplantation

International Nuclear Information System (INIS)

Tao Si; Sun Hanying; Liu Wenli

2007-01-01

Objective: To explore the effects of cotransplantation of hematopoietic stem cells and stromal cells derived from aorta-gonad-mesonephros (AGM) region on hematopoietic reconstitution in mice after bone marrow transplantation (BMT). Methods: The typical mice model of syngeneic BMT was established and the mice were randomly divided into 4 groups: the control group, the BMT group, the group of cotransplantation of HSC with AGM stromal cells (the cotransplantation group) and the ligustrazine group (the LT group). On days 3, 7, 10, 14, 21 and 28 after BMT, the peripheral blood cells and bone marrow mononuclear cells (BMMNC) were counted, and histology changes of bone marrow were detected. Results: The levels of peripheral WBC, RBC, platelet, and BMMNC in the contransplantation group were significantly higher than those in the single BMT group and the LT group (P<0.05). Conclusions: Cotransplantation with AGM stromal cells could significantly promote hematopoietic reconstruction in mice after BMT. (authors)

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

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Damon Deming

2006-12-01

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.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.

PET Imaging on Dynamic Metabolic Changes after Combination Therapy of Paclitaxel and the Traditional Chinese Medicine in Breast Cancer-Bearing Mice.

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Chen, Yao; Wang, Ling; Liu, Hao; Song, Fahuan; Xu, Caiyun; Zhang, Kai; Chen, Qing; Wu, Shuang; Zhu, Yunqi; Dong, Ying; Zhou, Min; Zhang, Hong; Tian, Mei

2018-04-01

The aim of the study was to non-invasively evaluate the anticancer activity of a traditional Chinese medicine-Huaier, combined with paclitaxel (PTX) in breast cancer bearing mice by detecting dynamic metabolic changes with positron emission tomography (PET). Balb/c nude mice were randomly divided into one of the four groups: Huaier, PTX, PTX + Huaier, or the control. PET imaging with 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) was performed to monitor the metabolic changes in BT474 (luminal B) and MDA-MB-231 (triple-negative) breast cancer xenografts. Immunohistochemistry (IHC) study was performed immediately after the final PET scan to assess the expressions of phosphatidylinositol 3-kinase (PI3K), phospho-AKT (p-AKT), caspase-3, and vascular endothelial growth factor (VEGF). Compared to the control group, [ 18 F]FDG accumulation demonstrated a significant decrease in PTX + Huaier (p PET imaging could be a potential non-invasive approach to assess the metabolic changes after chemotherapy combined with traditional Chinese medicine in the breast cancer.

Discrepancies between measured changes of radiobiological hypoxic fraction and oxygen tension monitoring using two assay systems

International Nuclear Information System (INIS)

Sasai, K.; Brown, J.M.

1994-01-01

This study was conducted to assess the ability of computerized pO 2 histography to measure changes in tumor oxygenation produced by low oxygen breathing. Female syngeneic C3H/Km mice bearing SCC VII/St carcinomas were used in these experiments. Changes in tumor oxygenation produced by the mice breathing 10% oxygen were assessed with computerized pO2 histography, 3 H-misonidazole binding, and the paired survival curve assay of radiosensitivity. The hypoxic cell fraction of the tumors in mice breathing 10% oxygen was 3.1 times higher than that of tumors in mice breathing normal air determined by an in vivo-in vitro clonogenic assay. Binding of radiolabeled misonidazole to the tumors in mice breathing 10% oxygen was also significantly higher than that to tumors in mice breathing normal air (p 2 value for the tumor. The number of pO 2 readings lower than 5 mmHg in the tumor was not affected by the 10% oxygen breathing. These findings indicate that increases in radiobiological hypoxic fraction produced by lower blood oxygen levels may not correlate well with the results of polarographic measurements of tumor pO 2 levels. 29 refs., 4 figs., 1 tab

Effect of oral administration of lactobacillus acidophilus on the immune responses and survival of BALB/c mice bearing human breast cancer

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Soltan Dallal MM

2010-02-01

Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: In according to immunomodulatory effect of probiotics and effect of these bacteria on the effectiveness of immune responses, at the present work we proposed the evaluation of oral administration of L.acidophilus on the immune statues in BALB/c mice bearing breast cancer."n"nMethods: A total of 30 In-bred BALB/c mices aged from six to eight weeks weighting 25-30g were randomly enrolled in our study, in two groups each consist of 15 mices. The L.acidophilus ATCC4356 strain used in this study was inoculated in MRS broth and cultivated for a day at 37°C under anaerobic conditions, collected by centrifugation and resuspend in Phosphate Buffer Saline (PBS. After preparation of proper amount of these suspensions it was orally administered to the mice with a gastric feeding, Control mices received an equal volume of PBS in duration of study."n"nResults: Results showed the increase in production of IFnγ (p<0.005, and decrease in production of Th2 cytokines such as IL4 (p=0.347 in the L.acidophilus administered mice in comparison to control group of mice. In addition the proliferation of immune cells in probiotic group was significantly higher than controls, and most importantly probiotic administered mice showed

Study of DNA synthesis and mitotic activity of hepatocytes and its relation to angiogenesis in hepatectomised tumour bearing mice.

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Andrini, Laura B; García, Marcela N; Inda, Ana María; Errecalde, Ana Lía

2013-11-01

Partial hepatectomy (PH) alters serum concentrations of substances involved in cellular proliferation, leading to the compensatory liver hyperplasia. Furthermore, angiogenesis is mainly stimulated by vascular endothelial growth factor (VEGF) and is a fundamental requirement either in liver regeneration or in tumours growth. This study looks at the expression of VEGF, DNA synthesis (DNAs) and mitotic activity (MA) in hepatectomised (H) and hepatectomised-tumour bearing (HTB) mice throughout a 24 h period. Adult male mice were sacrificed every 4 h from 26 to 50 h post-hepatectomy. H mice show a circadian rhythm in VEGF expression with a maximum value of 2.6 ± 0.1 at 08/46 h of day/hours posthepatectomy (HD/HPH); in DNAs, the maximum value was 3.4 ± 0.3 at 16/30 (HD/HPH) and in MA it was 2.3 ± 0.01 at 12/50 (HD/HPH). In HTB animals the peak of VEGF expression appears at 16/30 (HD/HPH) with a maximum value of 3.7 ± 0.1, the peak of DNAs was at 00/38 (HD/HPH) with a value of 4.6 ± 0.3 and the maximum value of MA of 08/46 (HD/HPH) with a value of 3.01 ± 0.3. We can conclude that the presence of the tumour induces modifications in the intensity and the temporal distribution of the circadian curves of VEGF expression, DNAs and MA of hepatectomised animals. © 2013 International Federation for Cell Biology.

Biological Effect of Ganoderma lucidum in Mice Suffering from Ehrlich Carcinoma and Gamma Radiation

International Nuclear Information System (INIS)

Fahim, Th.M.; Sherif, N.H.; Abd El-Azime, A.Sh.

2013-01-01

The popular edible mushroom Ganoderma lucidum (G. lucidum) has been widely used for the general promotion of health and longevity in oriental countries. The present study was performed to investigate the antitumor effect of G. lucidum on Ehrlich carcinoma (EC) cells and/or gamma radiation-induced oxidative stress, kidney dysfunction and histopathological changes in the albino mouse. G. lucidum was orally administered via gavages to mice for a period of 3 weeks at a dose of 100 mg/kg body weight begins on the 10th day of tumor inoculation. Animals were exposed to 4 Gy whole body γ radiation after 2 weeks of tumor inoculation. The antitumor effect of G. lucidum was evident in terms of a reduction in tumor viable cells count, inhibited both weight loss and tumor growth rate of EC-tumor bearing mice alone and in combination with gamma-radiation. Inoculation of mice with EC cells resulted in biochemical and histopathological changes leading to kidney damage. Oral administration of G. lucidum improved kidney functions through a recovery of the elevated levels of serum urea, creatinine, uric acid and increased albumin level and decreased the levels of tumor markers. Also, treatment of mice with G. lucidum induced a reduction of lipid peroxidation (MDA) level, improvement in glutathione content (GSH) and superoxide dismutase (SOD) activity in the kidney compared with those EC and /or irradiated damaged mice. On the other hand, treatment EC bearing mice with gamma radiation or G. lucidum combined showed increase in MDA level and decrease in GSH content and SOD activity, as compared to EC bearing mice. Histopathological studies showed that suffering from EC caused fatty degeneration, presence of necrosis and enlargement of kidney cells nuclei. Furthermore, an elevation of tail DNA % was recorded in the tumor tissue of mice treated with G. lucidum and/or γ radiation compared to EC control group. Treatment of EC bearing mice with G. lucidum and/or γ radiation exhibited

The biodistribution and pretargeting radioimmunoimaging of the fusion protein of anti-CEA single-chain antibody and core-streptavidin in human rectocolonic tumor bearing nude mice

International Nuclear Information System (INIS)

Yang Weidong; Li Biao; Zhu Chengmo; Jiang Xufeng; Feng Guowei; Wu Xiangpu

2002-01-01

Objective: To investigate the biodistribution and two-step pretargeting radioimmunoimaging of the fusion protein of anti-carcinoembryonic antigen (CEA) single-chain antibody (ScFv) and core-streptavidin in human rectocolonic tumor bearing nude mice. Methods: Before the injection of 153 Sm-biotin, the fusion protein of ScFv-core-streptavidin was pretargeted for 24 h (200 μg every nude mouse), 24 h later 153 Sm-biotin was injected. The uptake of radioactivity in tumor and normal tissues in 20 nude mice was measured at 1, 4, 8 and 24 h and the other 3 nude mice was scanned at 8 and 24 h after peritoneal injection of 153 Sm-biotin. Results: The tumor to blood ratio (tumor/blood) reached 0.49 , 1.21, 1.56 and 3.09 at 1, 4, 8 and 24 h respectively. Radioactivity concentration peaked at 8 h in tumor site and demonstrated a 'hot' area, with significant decreasing its background at 24 h. Conclusion: The fusion protein can elevate the tumor/blood ratio, shorten pretargeting and imaging process and also improve image quality

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.

Science.gov (United States)

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.

Role of diamine oxidase during the treatment of tumour-bearing mice with combinations of polyamine anti-metabolites.

Science.gov (United States)

Kallio, A; Jänne, J

1983-01-01

Treatment of mice bearing L1210 leukaemia with 2-difluoromethylornithine, a specific inhibitor of ornithine decarboxylase (EC 4.1.1.17), produced a profound depletion of putrescine and spermidine in the tumour cells. Sequential combination of methylglyoxal bis(guanylhydrazone), an inhibitor of adenosylmethionine decarboxylase (EC 4.1.1.50), with difluoromethylornithine largely reversed the polyamine depletion and led to a marked accumulation of cadaverine in the tumour cells. Experiments carried out with the combination of difluoromethylornithine and aminoguanidine, a potent inhibitor of diamine oxidase (EC 1.4.3.6), indicated that the methylglyoxal bis(guanylhydrazone)-induced reversal of polyamine depletion was mediated by the known inhibition of diamine oxidase by the diguanidine. In spite of the normalization of the tumour cell polyamine pattern upon administration of methylglyoxal bis(guanylhydrazone) to difluoromethylornithine-treated animals, the combination of these two drugs produced a growth-inhibitory effect not achievable with either of the compounds alone. PMID:6411077

Paclitaxel-Fe3O4 nanoparticles inhibit growth of CD138–  CD34– tumor stem-like cells in multiple myeloma-bearing mice

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Yang C

2013-04-01

Full Text Available Cuiping Yang,1,3,* Jing Wang,2,* Dengyu Chen,1,* Junsong Chen,1 Fei Xiong,4 Hongyi Zhang,1 Yunxia Zhang,2 Ning Gu,4 Jun Dou11Department of Pathogenic Biology and Immunology, Medical School, 2Department of Gynecology and Obstetrics, Zhongda Hospital, Southeast University, Nanjing, 3Department of Pathogenic Biology and Immunology, School of Basic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 4School of Biological Science and Medical Engineering, Southeast University, Nanjing, People’s Republic of China*These authors contributed equally to this workBackground: There is growing evidence that CD138– CD34– cells may actually be tumor stem cells responsible for initiation and relapse of multiple myeloma. However, effective drugs targeted at CD138– CD34– tumor stem cells are yet to be developed. The purpose of this study was to investigate the inhibitory effect of paclitaxel-loaded Fe3O4 nanoparticles (PTX-NPs on CD138– CD34– tumor stem cells in multiple myeloma-bearing mice.Methods: CD138– CD34– cells were isolated from a human U266 multiple myeloma cell line using an immune magnetic bead sorting method and then subcutaneously injected into mice with nonobese diabetic/severe combined immunodeficiency to develop a multiple myeloma-bearing mouse model. The mice were treated with Fe3O4 nanoparticles 2 mg/kg, paclitaxel 4.8 mg/kg, and PTX-NPs 0.64 mg/kg for 2 weeks. Tumor growth, pathological changes, serum and urinary interleukin-6 levels, and molecular expression of caspase-3, caspase-8, and caspase-9 were evaluated.Results: CD138– CD34– cells were found to have tumor stem cell characteristics. All the mice developed tumors in 40 days after injection of 1 × 106 CD138– CD34– tumor stem cells. Tumor growth in mice treated with PTX-NPs was significantly inhibited compared with the controls (P <  0.005, and the groups that received nanoparticles alone (P < 0.005 or paclitaxel alone (P < 0.05. In addition

Differences in the effects of host suppression on the adoptive immunotherapy of subcutaneous and visceral tumors

International Nuclear Information System (INIS)

Chang, A.E.; Shu, S.Y.; Chou, T.; Lafreniere, R.; Rosenberg, S.A.

1986-01-01

A syngeneic transplantable sarcoma induced in C57BL/6 mice, MCA 105, was used in studies to examine host suppression on the adoptive immunotherapy of established intradermal and experimentally induced pulmonary and hepatic metastases. Fresh immune splenocytes were generated from mice immunized to the MCA 105 tumor by a mixture of viable tumor cells and Corynebacterium parvum. The adoptive immunotherapy of intradermal MCA 105 tumor with immune cells required prior immunosuppression of the recipient by sublethal irradiation with 500 R or T-cell depletion. The effect of whole-body sublethal irradiation appeared to eliminate a systemic host suppression mechanism, since partialbody irradiation involving the tumor-bearing area did not permit successful immunotherapy. Host irradiation was not required to achieve successful immunotherapy of experimentally induced pulmonary or hepatic metastases. In nonirradiated recipients bearing both intradermal and pulmonary tumors, host suppression did not affect the function of transferred immune cells to induce regression of pulmonary metastases. Thus, suppression of adoptive immunotherapy appears to be relevant to tumors confined to the skin and subcutaneous tissue but not to tumor in visceral sites, such as the lung and liver

Impact of N-acetylcysteine on antitumor activity of doxorubicin and landomycin A in NK/Ly lymphoma-bearing mice

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Yu. S. Kozak

2018-04-01

Full Text Available N-acetylcysteine (NAC is a dietary supplement demonstrating antioxidant and liver protecting effects that is widely used in clinics. NAC is considered to possess potential therapeutic activity for health disorders characterized by generation of free oxygen radicals, as well as potential for decreasing negative side effects of various drugs. However, the mechanisms of such tissue-protective actions of NAC remain poorly understood. The main aim of this work was to study therapeutic effects of NAC applied together with the “gold standard” of chemotherapy doxorubicin (Dx or the novel experimental drug landomycin A (LA to mice bearing NK/Ly lymphoma. It was revealed that NAC significantly decreased the nephrotoxicity of Dx (measured as creatinine level, possessed moderate immunomodulating activity (as revealed by an increase in number of cytotoxic T-lymphocytes, and partially increased survival of NK/Ly lymphoma-bearing animals treated with Dx. On the contrary, there was little tissue-protective effect of NAC towards LA due to the weak side effects of this anticancer drug, however, the combined use of NAC and LA significantly increased survival (60+ days of LA-treated animals with NK/Ly lymphoma. Summarizing, NAC possesses a moderate tissue-protective activity towards Dx action but lacks a major therapeutic effect. However, in the case of LA action, NAC significantly increases its anticancer activity with no impact on its negative side effects. Further studies of the molecular mechanisms underlying that activity of NAC towards the action of LA are in progress.

A poliomyelitis model through mucosal infection in transgenic mice bearing human poliovirus receptor, TgPVR21

International Nuclear Information System (INIS)

Nagata, Noriyo; Iwasaki, Takuya; Ami, Yasushi; Sato, Yuko; Hatano, Ikuyoshi; Harashima, Ayako; Suzaki, Yuriko; Yoshii, Takao; Hashikawa, Tsutomu; Sata, Tetsutaro; Horiuchi, Yoshinobu; Koike, Satoshi; Kurata, Takeshi; Nomoto, Akio

2004-01-01

Transgenic mice bearing the human poliovirus receptor (TgPVR) are less susceptible to oral inoculation, although they are susceptible to parenteral inoculation. We investigated the susceptibility of TgPVR 21 line [Arch. Virol. 130 (1994) 351] to poliovirus through various mucosal routes. Intranasal inoculation of a neurovirulent Mahoney strain (OM1) caused flaccid paralysis with viral replication in the central nervous system at a dose of 10 6 cell culture infectious dose (CCID 50 ), in contrast, no paralysis following oral or intragastric inoculation of the same dose. Intranasal inoculation of a vaccine strain, Sabin 1, at 10 6 CCID 50 , resulted in no paralysis. Initial replication of poliovirus in the nasal cavity was confirmed by virus isolation and detection of negative-stranded replicative intermediates by RT-PCR and viral antigens using a high-sensitive immunohistochemistry and genome/transcripts by in situ hybridization. Poliovirus-specific IgG antibodies were elevated in the sera of surviving TgPVR21. This model can be used as a mucosal infection model and for differentiation of neurovirulent and attenuated poliovirus strains

Biodistribution and SPECT imaging of 125/131I-crotoxin on mice bearing Ehrlich solid tumour

International Nuclear Information System (INIS)

Soares, Marcella Araugio; Santos, Raquel Gouvea dos; Silveira, Marina B.; Simal, Carlos

2009-01-01

The search of specific radiopharmaceuticals to be used in breast tumour diagnosis is relevant to complement the techniques applied in conventional medicine. Crotalus durissus terrificus venom (CV) and its main polypeptide, Crotoxin (Crtx), are natural source of several bioactive substances with therapeutical potential. The aim of this work was to evaluate the binding of Crtx with tumour targets in vivo, as well as, evaluate its applicability for breast tumours diagnosis. Crtx was labelled with 125/131 I using lactoperoxidase method and radiochemical analysis was performed by chromatography. 125 I-Crtx was used for biodistribution and pharmacokinetics studies on swiss mice bearing Ehrlich solid tumour, while 131 I-Crtx was used for single photon emission computed tomography (SPECT) imaging. Crtx presented specific binding sites on Ehrlich tumour cells and had a rapid blood clearance (T 1/2 = 201.1 min.). Intratumoral administration increased significantly the activity delivered into the tumour site (128-fold higher) and reduced the kidney burden (7.2-fold lower). 131 I-Crxt demonstrated to interact with tumour cells for until 72 hours allowing good quality images of tumour. Our results indicate the biotechnological potential of Crtx as template for radiopharmaceutical design for cancer diagnosis. (author)

Comparative activation states of tumor-associated and peritoneal macrophages from mice bearing an induced fibrosarcoma.

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Valdez, J C; de Alderete, N; Meson, O E; Sirena, A; Perdigon, G

1990-11-01

Balb/c mice bearing a methylcholanthrene-induced fibrosarcoma were used to compare the activation levels of tumor-associated and peritoneal macrophages. Two stages of tumor growth were examined, namely "small" and "large" tumors, with average diameters of 10 and 30 mm, respectively. The activation state, determined by measurement of both phagocytic index and beta-glucuronidase content, was found to be markedly higher in tumor-associated macrophages than in their peritoneal counterparts and it was, in addition, independent of tumor progression. The percentage of tumor-associated macrophages, which were detected on the basis of Fc receptor expression, remained constant in the growing neoplasm, at approximately 23% of total cell population. None of these parameters were affected by inoculation with an immunopotentiating dose of heat-killed Candida albicans which, on the other hand, seemed not to alter the course of the tumor. These data suggest that within the tumor microenvironment macrophages would somehow be maintained at a constant proportion and at a highly activated state, while outside the tumor they would be at a lower activation level. Our results also suggest that TAM would not possess antitumor activity in vivo, although we have found this activity in vitro.

Natural killer cell activity, lymphocyte proliferation, and cytokine profile in tumor-bearing mice treated with MAPA, a magnesium aggregated polymer from Aspergillus oryzae.

Science.gov (United States)

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.

Noninvasive Evaluation of Metabolic Tumor Volume in Lewis Lung Carcinoma Tumor-Bearing C57BL/6 Mice with Micro-PET and the Radiotracers 18F-Alfatide and 18F-FDG: A Comparative Analysis.

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Yu-Chun Wei

Full Text Available To explore the value of a new simple lyophilized kit for labeling PRGD2 peptide (18F-ALF-NOTA-PRGD2, denoted as 18F-alfatide in the determination of metabolic tumor volume (MTV with micro-PET in lewis lung carcinoma (LLC tumor-bearing C57BL/6 mice verified by pathologic examination and compared with those using 18F-fluorodeoxyglucose (FDG PET.All LLC tumor-bearing C57BL/6 mice underwent two attenuation-corrected whole-body micro-PET scans with the radiotracers 18F-alfatide and 18F-FDG within two days. 18F-alfatide metabolic tumor volume (VRGD and 18F-FDG metabolic tumor volume (VFDG were manually delineated slice by slice on PET images. Pathologic tumor volume (VPath was measured in vitro after the xenografts were removed.A total of 37 mice with NSCLC xenografts were enrolled and 33 of them underwent 18F-alfatide PET, and 35 of them underwent 18F-FDG PET and all underwent pathological examination. The mean ± standard deviation of VPath, VRGD, and VFDG were 0.59±0.32 cm3 (range,0.13~1.64 cm3, 0.61±0.37 cm3 (range,0.15~1.86 cm3, and 1.24±0.53 cm3 (range,0.17~2.20 cm3, respectively. VPath vs. VRGD, VPath vs. VFDG, and VRGD vs. VFDG comparisons were t = -0.145, P = 0.885, t = -6.239, P<0.001, and t = -5.661, P<0.001, respectively. No significant difference was found between VPath and VRGD. VFDG was much larger than VRGD and VPath. VRGD seemed more approximate to the pathologic gross tumor volume. Furthermore, VPath was more strongly correlated with VRGD (R = 0.964,P<0.001 than with VFDG (R = 0.584,P<0.001.18F-alfatide PET provided a better estimation of gross tumor volume than 18F-FDG PET in LLC tumor-bearing C57BL/6 mice.

In vivo enhancement of anticancer therapy using bare or chemotherapeutic drug-bearing nanodiamond particles

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Li Y

2014-02-01

Full Text Available Yingqi Li,1,2 Yaoli Tong,1 Ruixia Cao,1 Zhimei Tian,2 Binsheng Yang,2 Pin Yang2 1Department of Chemistry, College of Chemistry and Chemical Engineering, 2Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Molecular Science, Shanxi University, Taiyuan, People's Republic of China Background: This study investigated the use of nanodiamond particles (NDs as a promising material for drug delivery in vivo and in vitro. Methods: HepG2 cells (a human hepatic carcinoma cell line were used to determine the characteristics of a nanodiamond-doxorubicin complex (ND-DOX when taken up by cells in vitro using laser scanning confocal microscopy and dialysis experiments. We also compared the survival rate and histopathology of tumor-bearing mice after treatment with NDs or ND-DOX in vivo. Results: In vitro investigation showed that ND-DOX has slow and sustained drug release characteristics compared with free doxorubicin. In vivo, the survival rate of tumor-bearing mice treated with ND-DOX was four times greater than that of mice treated with free doxorubicin. Interestingly, the survival rate in mice treated with NDs alone was close to that of mice treated with free doxorubicin. This indicates that treatment with ND-DOX can prolong the lifespan of tumor-bearing mice significantly compared with conventional doxorubicin and that NDs can have this effect as well. Histopathological analysis showed that neither the NDs nor ND-DOX were toxic to the kidney, liver, or spleen in contrast with the well-known toxic effects of free doxorubicin on the kidney and liver. Further, both the bare NDs and ND-DOX could suppress tumor growth effectively. Conclusion: NDs can potentially prolong survival, and ND-DOX may act as a nanodrug with promising chemotherapeutic efficacy and safety.  Keywords: nanodiamond, drug delivery, sustained release, survival rate, cancer, treatment

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

Science.gov (United States)

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.

Erythrokinetics in mice bearing tumours in either preirradiated or unirradiated tissue

International Nuclear Information System (INIS)

Jirtle, R.L.; Clifton, K.H.

1978-01-01

Experiments were designed to clarify the causes of anaemia in hosts bearing tumours in either unirradiated or preirradiated tissue. Isotopic methods are described which enable the estimation of erythrocyte destruction and production rates, and the potential red cell life spans in tumour-bearing animals. In this experimental system, anaemia (a) is in large part due to accelerated random erythrocyte loss, (b) is exacerbated as tumours grow by a progressive reduction in the potential erythrocyte life span due to intrinsic erythrocyte defects. (c) is accompanied by an increase in erythrocyte production of six- to ten-fold and (d) is postponed in onset and decreased in magnitude by preirradiation of the tumour transplant site. (author)

Erythrokinetics in mice bearing tumours in either preirradiated or unirradiated tissue

Energy Technology Data Exchange (ETDEWEB)

Jirtle, R L; Clifton, K H [Wisconsin Univ., Madison (USA). Div. of Clinical Oncology

1978-11-01

Experiments were designed to clarify the causes of anaemia in hosts bearing tumours in either unirradiated or preirradiated tissue. Isotopic methods are described which enable the estimation of erythrocyte destruction and production rates, and the potential red cell life spans in tumour-bearing animals. In this experimental system, anaemia (a) is in large part due to accelerated random erythrocyte loss, (b) is exacerbated as tumours grow by a progressive reduction in the potential erythrocyte life span due to intrinsic erythrocyte defects. (c) is accompanied by an increase in erythrocyte production of six- to ten-fold and (d) is postponed in onset and decreased in magnitude by preirradiation of the tumour transplant site.

Phospholipid makeup of the breast adipose tissue is impacted by obesity and mammary cancer in the mouse: Results of a pilot study.

Science.gov (United States)

Margolis, Michael; Perez, Osvaldo; Martinez, Mitchell; Santander, Ana M; Mendez, Armando J; Nadji, Mehrdad; Nayer, Ali; Bhattacharya, Sanjoy; Torroella-Kouri, Marta

2015-01-01

Obesity, an established risk factor for breast cancer (BC), is associated with systemic inflammation. The breast contains adipose tissue (bAT), yet whether it plays a role in BC progression in obese females is being intensively studied. There is scarce knowledge on the lipid composition of bAT in health and disease. The purpose of this pilot study was: 1) to determine whether obesity and BC are associated with inflammatory changes in bAT 2) to analyze for the first time the lipid profile of bAT in obese and lean mammary tumor-bearing and normal mice. Syngeneic E0771 mammary tumor cells were implanted into the mammary fat pad of lean and diet-induced obese C57BL/6 mice. BATs were analyzed four weeks after tumor cell inoculation by immunohistochemistry and mass spectrometry. Phospholipids were identified and subjected to ratiometric quantification using a TSQ Quantum Access Max triple quadrupole mass spectrometer utilizing precursor ion scan or neutral ion loss scan employing appropriate class specific lipid standards in a two step quantification process. Four main classes of phospholipids were analyzed: phosphatidylcholines phosphatidylserines, phosphatidylethanolamines and phosphatidylinositols. Our results showed that bAT in obese (normal and tumor-bearing) mice contained hypertrophic adipocytes compared with their corresponding samples in lean mice; higher numbers of macrophages and crown-like structures were observed in obese tumor bearers compared to obese normal mice. BAT from normal obese mice revealed higher concentrations of phosphatidylethanolamines. Furthermore, bAT from tumor-bearing mice expressed higher phosphatidylcholines than that from non-tumor bearing mice, suggesting the presence of the tumor is associated with phosphatidylcholines. Conversion of phosphatidylethanolamines to phosphatidylcholines will be investigated in E0771 cells. Additional studies are projected to investigate macrophage activation by these specific classes of phospholipids

Intrathymic selection of NK1.1+α/β T cell antigen receptor (TCR)+ cells in transgenic mice bearing TCR specific for chicken ovalbumin and restricted to I-Ad

Science.gov (United States)

Iwabuchi, Chikako; Iwabuchi, Kazuya; Nakagawa, Ken-ichi; Takayanagi, Toshiaki; Nishihori, Hiroki; Tone, Saori; Ogasawara, Kazumasa; Good, Robert A.; Onoé, Kazunori

1998-01-01

Generation and negative selection of NK1.1+α/β T cell receptor (TCR)+ thymocytes were analyzed using TCR-transgenic (B10.D2 × DO10)F1 and (C57BL/6 × DO10)F1 mice and Rag-1−/−/DO10 mice, which had been established by breeding and backcrossing between Rag-1−/− and DO10 mice. Almost all T cells from these mice were shown to bear Vα13/Vβ8.2 that is specific for chicken ovalbumin (cOVA) and restricted to I-Ad. A normal proportion of the NK1.1+ Vα13/Vβ8.2+ thymocytes was generated in these mice. However, the actual cell number of both NK1.1+ and NK1.1− thymocytes in I-Ad/d mice (positive selecting background) was larger than that in I-Ab/d mice (negative selecting background). Markedly low but significant proportions of NK1.1+ Vα13/Vβ8.2+ cells were detected in the spleens from I-Ad/d and I-Ab/d mice. It was shown that the splenic NK1.1+ T cells of the I-Ab/d mice were anergized against stimulation through TCR. When (B10.D2 × DO10)F1 and (C57BL/6 × DO10)F1 mice were given cOVA, extensive or intermediate elimination of NK1.1+α/βTCR+ thymocytes was induced in I-Ad/d or I-Ab/d mice, respectively. However, the clonal elimination was not as complete as that seen in the major NK1.1− thymocyte population. The present findings indicate that normal generation of NK1.1+α/βTCR+ thymocytes occurs in the absence of Vα14-Jα281 and that substantial negative selection operates on the NK1.1+α/βTCR+ cells. PMID:9653164

Some mechanisms of disturbances and recovery of T-lymphocyte migratory properties in irradiated mice

International Nuclear Information System (INIS)

Anokhin, G.N.; Yarilin, A.A.

1984-01-01

Migration of 51 Cr-labelled T cells from irradiated mice into lymph nodes of syngeneic unirradiated recipients decreased in a dose-dependent fashion. Influx of labelled T cells between 4 and 24 hr after injection (secondary migration) is more radiosensitive than lymph-node migration of T cells in the first 4 hr (primary migration). Treatment of T cells from irradiated mice in vitro with Con A or with trypsin does not enhance radiation-induced alteration of their migratory properties, but irradiation enhances the effects of Con A and trypsin on T-cell migration. Recovery of primary migration of irradiated T cells is completed 3 months after irradiation; it is probably caused by T-cell renewal. The defect of T-cell secondary migration is more stable: it remains 6 months after irradiation in a dose of 4 gy. Post-irradiation defects of the T-cell differentiation process as a cause of long-lasting alteration of T-cell secondary migration are discussed. (author)

Abrogation of bone marrow allograft resistance in mice by increased total body irradiation correlates with eradication of host clonable T cells and alloreactive cytotoxic precursors

International Nuclear Information System (INIS)

Schwartz, E.; Lapidot, T.; Gozes, D.; Singer, T.S.; Reisner, Y.

1987-01-01

Host-vs-graft activity presents a major obstacle for transplantation of T cell-depleted bone marrow in HLA-mismatched patients. In a primate model, conditioned exactly like leukemia patients, it was shown that residual host clonable T cells, as well as alloreactive cytotoxic precursors, were present in peripheral blood and spleen after completion of cytoreduction. We have now extended this study in a mouse model for allogeneic bone marrow transplantation. C 3 H/HeJ mice were treated by 9 Gy total body irradiation (TBI), and 24 hr later their spleen cells were cultured in the presence of T cell growth factor and phytohemagglutinin according to the limit dilution procedure. After 7 days of culture the average frequency of clonable cells was 2.5 X 10(-3) compared with 37 X 10(-3) in the spleens of normal mice. The T cell derivation of the growing cells was ascertained by complement-mediated cytotoxicity with anti-Thy-1 as well as with anti-Lyt-2 and anti-Ly-3T4. In parallel, we found that the initial engraftment rate of bone marrow allograft in mice given 9 Gy TBI was lower than that found in recipients of syngeneic marrow. The initial engraftment rate was measured by the number of colony-forming units in the spleen and by splenic uptake of 125 IUdR. A slight increase in TBI from 9 Gy to 11 Gy markedly reduced the difference in the number of spleen colony-forming units or the IUdR uptake between recipients of allogeneic and syngeneic bone marrow. This increase in TBI also coincided with eradication of detectable clonable T cells. Moreover, in mice transplanted with T cell-depleted bone marrow after 9 Gy TBI, we also demonstrate that cytotoxicity against donor-type target cells is present in the spleen 10 to 14 days posttransplantation, whereas in mice treated by 11 Gy TBI such alloreactivity could not be detected

Pharmacokinetic Analysis of 64Cu-ATSM Dynamic PET in Human Xenograft Tumors in Mice

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Li, Fan; Jørgensen, Jesper Tranekjær; Madsen, Jacob

2015-01-01

The aim of this study was to evaluate the feasibility to perform voxel-wise kinetic modeling on datasets obtained from tumor-bearing mice that underwent dynamic PET scans with 64Cu-ATSM and extract useful physiological parameters.METHODS: Tumor-bearing mice underwent 90-min dynamic PET scans...... relevant parameters from voxel-wise pharmacokinetic analysis to be used for preclinical validation of 64Cu-ATSM as a hypoxia-specific PET tracer....

Enhanced efficacy of radiation-induced gene therapy in mice bearing lung adenocarcinoma xenografts using hypoxia responsive elements

International Nuclear Information System (INIS)

Wang Wei-dong; Chen Zheng-tang; Li De-zhi; Duan Yu-zhong; Cao Zheng-huai; Li Rong

2005-01-01

The aim of the present study was to investigate whether the hypoxia responsive element (HRE) could be used to enhance suicide gene (HSV-tk) expression and tumoricidal activity in radiation-controlled gene therapy of human lung adenocarcinoma xenografts. A chimeric promoter, HRE-Egr, was generated by directly linking a 0.3-kb fragment of HRE to a 0.6-kb human Egr-1 promoter. Retroviral vectors containing luciferase or the HSV-tk gene driven by Egr-1 or HRE-Egr were constructed. A human adenocarcinoma cell line (A549) was stably transfected with the above vectors using the lipofectamine method. The sensitivity of transfected cells to prodrug ganciclovir (GCV) and cell survival rates were analyzed after exposure to a dose of 2 Gy radiation and hypoxia (1%). In vivo, tumor xenografts in BALB/c mice were transfected with the constructed retroviruses and irradiated to a total dose of 6 Gy, followed by GCV treatment (20 mg/kg for 14 days). When the HSV-tk gene controlled by the HRE-Egr promoter was introduced into A549 cells by a retroviral vector, the exposure to 1% O 2 and 2 Gy radiation induced significant enhancement of GCV cytotoxicity to the cells. Moreover, in nude mice bearing solid tumor xenografts, only the tumors infected with the hybrid promoter-containing virus gradually disappeared after GCV administration and radiation. These results indicate that HRE can enhance transgene expression and tumoricidal activity in HSV-tk gene therapy controlled by ionizing radiation in hypoxic human lung adenocarcinoma. (author)

Anti-tumor effect of low dose radiation in mice

International Nuclear Information System (INIS)

Fan Zhengping; Lu Jiaben; Zhu Bingchai

1997-01-01

The author reports the effects of the total body irradiation of low dose radiation (LDR) and/or the local irradiation of large dose on average tumor weights and tumor inhibitory rates in 170 mice inoculated S 180 sarcoma cell, and the influence of LDR on average longevity in 40 tumor-bearing animals. Results show (1) LDR in the range of 75∼250 mGy can inhibit tumor growth to some extent; (2) fractionated irradiation of 75 mGy and local irradiation of 10 Gy may produce a synergism in tumor growth inhibition; and (3)LDR may enhance average longevity in ascitic tumor-bearing mice

Structural variations in the H-2 genes of AKR lymphomas.

NARCIS (Netherlands)

K. Hui; L. Minamide; N. Prandoni; H. Festenstein; F.G. Grosveld (Frank)

1986-01-01

textabstractK36.16 is an AKR H-2k thymoma which expresses an aberrant H-2Dd-like allospecificity, does not have a detectable amount of the H-2Kk syngeneic antigen and grows very easily in syngeneic mice. By DNA-mediated gene transfer experiments, we were able to obtain transformed clones which do

Some genetic profiles in liver of Ehrlich ascites tumor-bearing mice under the stress of irradiation

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Amal I. Hassan

2014-04-01

Full Text Available Radiation therapy aims to kill cancer cells with a minimum of normal tissue exposure. In an attempt to define the molecular and biochemical changes associated with exposure to radiotherapy, the objective of the present study is to explore the effect of gamma (γ irradiation on nuclear factor, erythroid 2 (NFE2, P53, stromelysin-1 (matrix metalloproteinase-3 (MMP3, BCL-2 and BAX genes expression in Ehrlich ascites carcinoma (EAC bearing mice. Various biochemical parameters such as liver function, H2O2, B% and T% lymphocytes, total antioxidants and MDA were investigated to evaluate their usefulness as possible during cancer treatment with radiotherapy. Rats were irradiated with a single whole body Cobalt 60-gamma radiation dose of 0.5 Gy. Sixty-four female mice, weighing 20–25 g were used in this study and divided into three main groups. The first group served as control group, while the second were injected intraperitoneally with EAC then was subdivided into two groups, II A and II B. The latter one (group II B, the animals were exposed to a single dose of 0.5 Gy whole body γ irradiation. The third main group, were irradiated with a single dose of 0.5 Gy whole body γ irradiation. Blood and liver tissue samples were collected at 4, 24 and 96 h post-irradiation. The gene expression levels in the livers of animals from each exposure group were compared individually with that of pooled sham-irradiated animals. MMP3 and NFE2 were overexpressed in liver samples of EAC group post 4, 24 and 96 h of γ irradiation (IIB. On the other hand, P53 and BCL-2 genes were downregulated by using RT-PCR analysis post 4, 24 and 96 h of γ irradiation (IIB. As well as, liver function and MDA were increased significantly in the γ - irradiation group (3rd group when compared to control mice (1st group. Gamma irradiation 3rd group revealed increase in the level of T% and B% lymphocytes. According to the obtained results, both γ rays and time period alter

Augmentation of transfer of experimental autoimmune thyroiditis (EAT) in mice by irradiation of recipients

International Nuclear Information System (INIS)

Williams, W.V.; Kyriakos, M.; Sharp, G.C.; Braley-Mullen, H.

1987-01-01

Experimental autoimmune thyroiditis (EAT) can be adoptively transferred to normal syngeneic recipients using spleen cells from susceptible strains of mice primed in vivo with mouse thyroglobulin (MTg) and lipopolysaccharide (LPS) following in vitro activation of spleen cells by culture with MTg. Irradiation of recipient animals markedly augments the severity of thyroiditis induced in this system. Irradiation of recipients does not alter the time course of the development of thyroiditis, nor does it alter the requirement for both in vivo priming and in vitro activation of spleen cells for the development of EAT. Spleen cells from EAT-resistant strains of mice (e.g., Balb/c) do not induce EAT in irradiated recipients. Irradiated recipients develop significant levels of anti-MTg antibodies while unirradiated recipients have little detectable antibody response. The augmenting effect of irradiation can be substantially reversed by transferring naive spleen cells to recipients prior to the transfer of MTg/LPS-primed in vitro-activated spleen cells. In addition athymic CBA/Tufts nude mice develop more severe EAT than CBA/Tufts nude/+ littermates following transfer of activated CBA/J spleen cells. These data suggest that natural suppressor cells may regulate the development of EAT at the effector cell level

Study on biodistribution and imaging of radioiodinated antisense oligonucleotides in nude mice bearing human lymphoma

International Nuclear Information System (INIS)

Wang, R.F.; Shen, J.; Zhang, C.L.; Liu, M.; Guo, F.Q.

2005-01-01

The incidence of sporadic lymphoma has risen due to an increase in immunosuppressed patients, particularly those with human immunodeficiency virus (HIV) infection. Sometimes suspect lymphoma has an undetectable location and we can not get the pathological specimen. Management of lymphoma is also difficult because the persistence of a significant number of residual tumor cells after intensive treatment. These relative failures can be attributed to make us choose this study for opening a new diagnostic and therapeutic field of lymphoma from molecular level. Immunoglobulin (Ig) heavy chain framework region (FR) of V1 family have been verified to be a major determinant of malignant phenotype of V1 family B-cell lymphoma. Most of targets for tumor antisense therapy study are protooncogenes, such as c-myc, bc1-2, which are broad -spectrum tumor imaging agents. The aim of this study was to investigate the possibility of using radioiodine labeled 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 labeled with 125 I or 131 I using the chloramine T method. Normal CD-1 mice were injected via a tail vein with 148 kBq of 125 I-FR-ASON (2∼3 μ g). Animals were sacrificed at 1, 2, 4 and 24 h and tissue samples were studied. Liposome-mediated 3.33 MBq of 131 I-FR-ASON (7 ∼ 9μ g) was injected intratumorally into tumor-bearing BALB/c mice (6 weeks after inoculation of 10 7 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. The percentage of the injected dose per gram (%ID/g) 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

Histology and cell kinetics of rectal mucosa of A/HeJ mice administered syngeneic rectal antigen and its effects on radiation induced rectal cancer, 1

International Nuclear Information System (INIS)

Terada, Yoritaka

1980-01-01

1. Four-week-old A/HeJ mice were immunized by rectal antigen and at the age of 6 weeks the pelvic region was exposed to 2,000 rad of X-ray for two times. They were observed for a maximum period of 84 weeks. The first rectal cancer detected 36 days after irradiation was histologically found to be mucous-secreting-adenocarinoma. Within 32 weeks after irradiation, rectal cancer was observed in 21 (61.76%) of the 34 autopsied mice. During the entire period of observation, rectal cancer was observed in 25 (55.56%) of the 45 mice. 2. On the other hand, among the mice whose pelvic region was exposed to 2,000 rad for two times, the first cancer was observed 56 days after irradiation. Within 32 weeks after irradiation, rectal cancer was observed in 4 (18.18%) of the 22 autopsied mice. During the entire period of observation, rectal cancer was observed in 12 (33.33%) of the 36 mice. 3. In the group of 51 non-irradiated mice, no rectal cancer was observed. 4. The stainability of HID-AB stain of the histologically normal mucosa near irradiated site was compared between cancer induced cases and normal cases. In 22 (84.62%) mice among 26 with induced cancer and in 9 (45%) among 20 mice without cancer, rectal crypt with AB positive goblet cells could be observed. (author)

The Effects of Angelica Sinensis Polysaccharide on Tumor Growth and Iron Metabolism by Regulating Hepcidin in Tumor-Bearing Mice

Directory of Open Access Journals (Sweden)

Feng Ren

2018-05-01

Full Text Available Background/Aims: Iron plays a fundamental role in cell biology and its concentration must be precisely regulated. It is well documented that excess iron burden contributes to the occurrence and progression of cancer. Hepcidin secreted by liver plays an essential role in orchestrating iron metabolism. In the present study, we aimed to investigate the ability of angelica sinensis polysaccharide (ASP to decrease iron burden in tumor-bearing mice and the mechanism of ASP regulation hepcidin expression. Methods: Western blot, RT-PCR, immunohistochemistry (IHC, and enzyme-linked immunosorbent assay (ELISA were used to detect the regulation of hepcidin and related cytokines by ASP. The role of ASP in tumor proliferation was investigated using in vivo assays. Iron depositions and iron concentrations in organs were determined by hematoxylin-eosin (H&E staining and atomic absorption spectrophotometer. Results: We found that ASP could inhibit tumor growth in mice xenografted with 4T1 and H22 cancer cells. In vivo experiments also showed that ASP could potently regulate hepcidin expression in liver and serum and decrease iron burden in liver, spleen and grafted tumors in mouse model. Treatment with ASP in hepatic cell lines reproduced comparable results in decreasing hepcidin as in mouse liver. Furthermore, we found that ASP markedly suppressed the expression of interleukin-6 (IL-6, JAK2, p-STAT3, and p-SMAD1/5/8 in liver, suggesting that JAK/STAT and BMP-SMAD pathways were involved in the regulation of hepcidin expression by ASP. We also found down-regulation of iron-related cytokines in ASP treated mice. Conclusion: The present study provides new evidence that ASP decreases hepcidin expression, which can reduce iron burden and inhibit tumor proliferation. These findings might aid ASP developed as a potential candidate for cancer treatment in patients with iron overload.

[Compound K suppresses myeloid-derived suppressor cells in a mouse model bearing CT26 colorectal cancer xenograft].

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Wang, Rong; Li, Yalin; Wang, Wuzhou; Zhou, Meijuan; Cao, Zhaohui

2015-05-01

To investigate the effect of ginseng-derived compound K (C-K) on apoptosis, immunosuppressive activity, and pro-inflammatory cytokine production of myeloid-derived suppressor cells (MDSCs) from mice bearing colorectal cancer xenograft. Flow-sorted bone marrow MDSCs from Balb/c mice bearing CT26 tumor xenograft were treated with either C-K or PBS for 96 h and examined for apoptosis with Annexin V/7-AAD, Cox-2 and Arg-1 expressions using qRT-PCR, and supernatant IL-1β, IL-6, and IL-17 levels with ELISA. C-K- or PBS-treated MDSCs were subcutaneously implanted along with CT26 tumor cells in WT Balb/c mice, and the tumor size and morphology were evaluated 21 days later. C-K treatment significantly increased the percentages of early and late apoptotic MDSCs in vitro (Pimmunosuppresive effect of MDSCs to inhibit tumor cell proliferation in mice, which suggests a new strategy of tumor therapy by targeting MDSCs.

Antibody responses to allergen Lol pIV are suppressed following adoptive transfer of B lymphocytes from the internal image anti-idiotypic antibody-treated mice.

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Zhou, E M; Kisil, F T

1995-10-01

An internal image anti-idiotypic antibody, designated B1/1, was generated against an idiotope (Id91) of the monoclonal antibody (mAb91) specific for Lol pIV. The administration of B1/1 in PBS, at doses ranging from 100 ng to 100 micrograms/mouse, to syngeneic Balb/c mice resulted in the suppression of the formation of anti-Lol pIV antibodies that possessed the Id91. Spleen cells obtained from the mice 2 weeks after the treatment with B1/1 (25 micrograms/mouse) were adoptively transferred intravenously into the syngeneic recipients which were challenged intraperitoneally with Lol pIV in alum 2 hr after the transfer. The recipients were boosted with Lol pIV 14 days later. It was demonstrated that the transfer of splenic B cells (but not of T cells) from B1/1-treated donors induced a significant suppression of not only the level of IgE and IgG antibodies to Lol pIV, but also the level of antibodies possessing the Id91. Treatment of the B cells with mAb91 plus complement abrogated their ability to transfer the suppression. This study indicates that the treatment with the anti-Id B1/1 generated B cells that were characterized, serologically, as possessing the anti-Id-like antibodies on their surface and were responsible for transferring the suppression of the formation of antibodies to allergen Lol pIV and the expression of Id91.

Treatment with anti-IL-6 receptor antibody prevented increase in serum hepcidin levels and improved anemia in mice inoculated with IL-6–producing lung carcinoma cells

International Nuclear Information System (INIS)

Noguchi-Sasaki, Mariko; Sasaki, Yusuke; Shimonaka, Yasushi; Mori, Kazushige; Fujimoto-Ouchi, Kaori

2016-01-01

Hepcidin, a key regulator of iron metabolism, is produced mainly by interleukin-6 (IL-6) during inflammation. A mechanism linking cancer-related anemia and IL-6 through hepcidin production is suggested. To clarify the hypothesis that overproduction of IL-6 elevates hepcidin levels and contributes to the development of cancer-related anemia, we evaluated anti-IL-6 receptor antibody treatment of cancer-related anemia in an IL-6–producing human lung cancer xenograft model. Nude mice were subcutaneously inoculated with cells of the IL-6–producing human lung cancer cell line LC-06-JCK and assessed as a model of cancer-related anemia. Mice bearing LC-06-JCK were administered rat anti-mouse IL-6 receptor antibody MR16-1 and their serum hepcidin levels and hematological parameters were determined. LC-06-JCK–bearing mice developed anemia according to the production of human IL-6 from xenografts, with decreased values of hemoglobin, hematocrit, and mean corpuscular volume (MCV) compared to non–tumor-bearing (NTB) mice. LC-06-JCK–bearing mice showed decreased body weight and serum albumin with increased serum amyloid A. MR16-1 treatment showed significant inhibition of decreased body weight and serum albumin levels, and suppressed serum amyloid A level. There was no difference in tumor volume between MR16-1-treated mice and immunoglobulin G (IgG)-treated control mice. Decreased hemoglobin, hematocrit, and MCV in LC-06-JCK–bearing mice was significantly relieved by MR16-1 treatment. LC-06-JCK–bearing mice showed high red blood cell counts and erythropoietin levels as compared to NTB mice, whereas MR16-1 treatment did not affect their levels. Serum hepcidin and ferritin levels were statistically elevated in mice bearing LC-06-JCK. LC-06-JCK–bearing mice showed lower values of MCV, mean corpuscular hemoglobin (MCH), and serum iron as compared to NTB mice. Administration of MR16-1 to mice bearing LC-06-JCK significantly suppressed levels of both serum hepcidin and

Tolerance and immunity in mice infected with herpes simplex virus: studies on the mechanism of tolerance to delayed-type hypersensitivity.

Science.gov (United States)

Nash, A A; Phelan, J; Gell, P G; Wildy, P

1981-06-01

Tolerance to delayed-type hypersensitivity is produced in mice following an intravenous injection of herpes simplex virus. This form of tolerance is produced early on, following simultaneous injections of virus subcutaneously and intravenously, and is long lasting (greater than 100 days). The early tolerance mechanism is resistant to high doses of cyclophosphamide and is not transferable by serum or spleen cells taken after 7 days. However, spleen cells taken at 14 days onwards inhibit the induction of delayed hypersensitivity when transferred to normal syngeneic recipients. These cells are T lymphocytes and are specific for the herpes type used in the induction.

Defining the Role of BTLA in Breast Cancer Immunosurveillance and Selective Targeting of the BTLA-HVEM-LIGHT Constimulatory System

Science.gov (United States)

2011-05-01

noted below. Briefly, allogeneic P815 (H-2Kd) or syngeneic EL4 (H-2Kb) target cells were labeled with 1 M CFSE. Target cells were suspended in...not observed toward syngeneic (H-2Kb) EL4 cell targets (data not shown). The mean SEM of three mice per group is shown. Table I. Global gene...noted below. Briefly, allogeneic P815 (H-2Kd) or syngeneic EL4 (H-2Kb) target cells were labeled with 1 M CFSE. Target cells were suspended in medium at

Properties of murine leukemia viruses produced by leukemic cells established from NIH Swiss mice with radiation-induced leukemia

Energy Technology Data Exchange (ETDEWEB)

Okumoto, Masaaki; Nishikawa, Ryosuke; Takamori, Yasuhiko; Iwai, Yoshiaki; Iwai, Mineko [Radiation Center of Osaka Prefecture, Sakai (Japan); Imai, Shunsuke; Morimoto, Junji; Tsubura, Yoshihiko

1984-06-01

Three leukemic cell lines, designated NIH-RL1, NIH-RL2 and NFS-RL1, were established from spleen and thymuses of NIH Swiss and NFS mice with radiation-induced leukemia. The culture fluids of these cell lines contained RNA-dependent DNA polymerase (RDDP) activities associated with particles of buoyant density of 1.15-1.17 (g/cm/sup 3/). The divalent cation reqirement of these enzymes was characteristic for that of murine leukemia viruses. In competition radioimmunoassay, a major core protein, p30, was detected in culture fluid of each leukemic cell line. Competition curves of viral p30 produced by these cell lines revealed that these viruses were very similar to those of xenotropic viruses of NZB mice. These viruses were undetectable both by XC plaque assay using SC-1 cells as an indicator cell, and by mink S/sup +/L/sup -/ focus induction assay. These viruses also lacked productive infectivity to mink lung cells (CCL-64), and were nononcogenic in syngeneic mice when the viruses were intrathymically inoculated.

Low-dose radiation enhances therapeutic HPV DNA vaccination in tumor-bearing hosts.

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Tseng, Chih-Wen; Trimble, Cornelia; Zeng, Qi; Monie, Archana; Alvarez, Ronald D; Huh, Warner K; Hoory, Talia; Wang, Mei-Cheng; Hung, Chien-Fu; Wu, T-C

2009-05-01

Current therapeutic approaches to treatment of patients with bulky cervical cancer are based on conventional in situ ablative modalities including cisplatin-based chemotherapy and radiation therapy. The 5-year survival of patients with nonresectable disease is dismal. Because over 99% of squamous cervical cancer is caused by persistent infection with an oncogenic strain of human papillomavirus (HPV), particularly type 16 and viral oncoproteins E6 and E7 are functionally required for disease initiation and persistence, HPV-targeted immune strategies present a compelling opportunity in which to demonstrate proof of principle. Sublethal doses of radiation and chemotherapeutic agents have been shown to have synergistic effect in combination with either vaccination against cancer-specific antigens, or with passive transfer of tumor-specific cytotoxic T lymphocytes (CTLs). Here, we explored the combination of low-dose radiation therapy with DNA vaccination with calreticulin (CRT) linked to the mutated form of HPV-16 E7 antigen (E7(detox)), CRT/E7(detox) in the treatment of E7-expressing TC-1 tumors. We observed that TC-1 tumor-bearing mice treated with radiotherapy combined with CRT/E7(detox) DNA vaccination generated significant therapeutic antitumor effects and the highest frequency of E7-specific CD8(+) T cells in the tumors and spleens of treated mice. Furthermore, treatment with radiotherapy was shown to render the TC-1 tumor cells more susceptible to lysis by E7-specific CTLs. In addition, we observed that treatment with radiotherapy during the second DNA vaccination generated the highest frequency of E7-specific CD8(+) T cells in the tumors and spleens of TC-1 tumor-bearing mice. Finally, TC-1 tumor-bearing mice treated with the chemotherapy in combination with radiation and CRT/E7(detox) DNA vaccination generate significantly enhanced therapeutic antitumor effects. The clinical implications of the study are discussed.

Mechanisms of cardiac transplantation tolerance in syngeneic rat radiation chimeras

International Nuclear Information System (INIS)

Moran, T.M.

1981-01-01

Seventy-five percent of adult LEW rats, lethally irradiated (860 R), transplanted with an RT-1 incompatible Wistar Furth (WF) heart or kidney and repopulated on day 2 with a 4:1 mixture of syngeneic thymus and bone marrow cells accept these grafts. In order to look at the ability of animals tolerating WF organ grafts to respond against WF spleen cells in vitro we developed a rat mixed lymphocyte culture. Tolerant animals were tested for the ability to respond to donor antigens and approximately half of the 50 animals tested, were responsive. We attempted to demonstrate suppressor cells which might be responsible for maintaining tolerance in the nonresponders. Neither mixtures at the sensitization or the effector level suggested that tolerance was being maintained by a suppressor cell. An in vivo assay which tested the ability of various cell populations to affect the survival of allogeneic hearts transplanted into sublethally irradiated recipients was then employed. Tolerance is induced using this protocol in a manner similar or identical to tolerance produced by neonatal injection of antigen. This tolerance might be maintained in part by suppressor cells which prevents the generation of clones of cells reactive against the heart donor. The mechanism of tolerance in rats with demonstrable clones of reactive cells remains to be determined

Core temperature rhythms in normal and tumor-bearing mice.

Science.gov (United States)

Griffith, D J; Busot, J C; Lee, W E; Djeu, D J

1993-01-01

The core temperature temporal behavior of DBA/2 mice (11 normal and 13 with an ascites tumor) was studied using surgically implanted radio telemetry transmitters. Normal mice continuously displayed a stable 24 hour temperature rhythm. Tumor-bearers displayed a progressive deterioration of the temperature rhythm following inoculation with tumor cells. While such disruptions have been noted by others, details on the dynamics of the changes have been mostly qualitative, often due to time-averaging or steady-state analysis of the data. The present study attempts to quantify the dynamics of the disruption of temperature rhythm (when present) by continuously monitoring temperatures over periods up to a month. Analysis indicated that temperature regulation in tumor-bearers was adversely affected during the active period only. Furthermore, it appears that the malignancy may be influencing temperature regulation via pathways not directly attributable to the energy needs of the growing tumor.

Serum hepatic biochemistry and electrophoretic protein profile of healthy and Ehrlich tumor-bearing mice treated with extracts of Agaricus blazei Murill

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Durval Verçosa Junior

2016-04-01

Full Text Available Compounds isolated from Agaricus blazei Murill represent a group of promising natural immunomodulators for use in the treatment of neoplasms. We have evaluated the serum biochemical profile of healthy and Ehrlich tumor-bearing mice treated with different extracts of A. blazei. Total, supernatant, and polysaccharide extracts of A. blazei were obtained from suspensions (at acidic or neutral pH kept in a water bath at 60 °C or in an ultrasonic bath at 37 °C. After oral administering the extracts to mice for 21 days, blood samples were collected for determination of aspartate aminotransferase (AST, alanine aminotransferase (ALT, creatine kinase (CK, urea, total protein, albumin, globulins, and alpha-, beta- and gamma-globulin fractions. The presence of the tumor led to a significant increase in serum CK and AST activities and in the concentrations of total globulin and the gamma-globulin fraction, and to a decrease in the albumin and alpha2-globulin levels. The polysaccharide extracts of A. blazei reduced the serum AST and ALT activities, probably due to a hepatoprotective effect. In addition, polysaccharide and supernatant extracts inhibited the tumor-induced increase in gamma-globulin levels. Thus, the supernatant and polysaccharide fractions of the extract of A. blazei have potential for use in complementary antineoplastic treatments.

Studies on the transfer of protective immunity with lymphoid cells from mice immune to malaria sporozoites

International Nuclear Information System (INIS)

Verhave, J.P.; Strickland, G.T.; Jaffe, H.A.; Ahmed, A.

1978-01-01

In an effort to understand the mechanisms involved in the protective immunity to malarial sporozoites, an A/J mouse/Plasmodium berghei model was studied. Protective immunity could consistently be adoptively transferred only by using sublethal irradiation of recipients (500 R); a spleen equivalent (100 x 10 6 ) of donor cells from immune syngeneic mice; and a small booster immunization (1 x 10 4 ) of recipients with irradiation-attenuated sporozoites. Recipient animals treated in this manner were protected from lethal challenge with 1 x 10 4 nonattenuated sporozoites. Immune and nonimmune serum and spleen cells from nonimmune animals did not protect recipient mice. Fewer immune spleen cells (50 x 10 6 ) protected some recipients. In vitro treatment of immune spleen cells with anti-theta sera and complement abolished their ability to transfer protection. This preliminary study suggests that protective sporozoite immunity can be transferred with cells, and that it is T cell dependent

Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice.

Science.gov (United States)

Samuels, S E; Knowles, A L; Tilignac, T; Debiton, E; Madelmont, J C; Attaix, D

2001-07-01

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C(6)H(12)CIN(3)O(4)S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower (P synthesis (-38%; P synthesis (~-54 to -69%; P synthesis (+46 to +73%; P synthesis and degradation.

Increased apoptotic potential and dose-enhancing effect of gold nanoparticles in combination with single-dose clinical electron beams on tumor-bearing mice

International Nuclear Information System (INIS)

Chang Mengya; Chen Yuhung; Chang Chihjui; Chen Helen H-W; Wu Chaoliang; Shiau Aili

2008-01-01

High atomic number material, such as gold, may be used in conjunction with radiation to provide dose enhancement in tumors. In the current study, we investigated the dose-enhancing effect and apoptotic potential of gold nanoparticles in combination with single-dose clinical electron beams on B16F10 melanoma tumor-bearing mice. We revealed that the accumulation of gold nanoparticles was detected inside B16F10 culture cells after 18 h of incubation, and moreover, the gold nanoparticles were shown to be colocalized with endoplasmic reticulum and Golgi apparatus in cells. Furthermore, gold nanoparticles radiosensitized melanoma cells in the colony formation assay (P=0.02). Using a B16F10 tumor-bearing mouse model, we further demonstrated that gold nanoparticles in conjunction with ionizing radiation significantly retarded tumor growth and prolonged survival compared to the radiation alone controls (P<0.05). Importantly, an increase of apoptotic signals was detected inside tumors in the combined treatment group (P<0.05). Knowing that radiation-induced apoptosis has been considered a determinant of tumor responses to radiation therapy, and the length of tumor regrowth delay correlated with the extent of apoptosis after single-dose radiotherapy, these results may suggest the clinical potential of gold nanoparticles in improving the outcome of melanoma radiotherapy. (author)

Increase of survival of x-irradiated mice by postirradiation injections of a splenic extract prepared from vaccine or endotoxin-treated syngeneic animals

Energy Technology Data Exchange (ETDEWEB)

Tsuneoka, K; Takagi, Y; Shikita, M [National Inst. of Radiological Sciences, Chiba (Japan)

1977-05-01

Spleens of mice which had been treated with E. coli endotoxin or typhoid-paratyphoid vaccine were extracted with isotonic saline. The extract was filtered through an asbestos filter and chromatographed on a Sephadex G-200 column. The fraction which was excluded at around 2.5-void volume (molecular weight, about 20,000) was significantly effective in increasing survival of animals when it was repeatedly injected in mice after x irradiation (600 R). The injection caused an increase of the weight of spleen of the animals with an increased number of endogenous spleen colonies. The result suggests that the life-saving effect of the spleen extract is based on its effect of stimulating repopulation of autochthonous hematopoietic cells in the x-irradiated animals. A similar splenic extract prepared from normal mice had an ambiguous effect on the survival of x-irradiated animals.

Ehrlich ascites tumor-bearing mice treated with aqueous ethanol ...

African Journals Online (AJOL)

Conclusion: Euphorbia tirucalli extract inhibits Ehrlich ascites tumor in mice, but the therapeutic ... traditional treatment of cancer. ... can be used with therapeutic purposes, this .... investigation suggested an antitumor action of E. .... Prasad SB, Giri A. Antitumor effect of cisplatin against ... Identification of the molecular basis of.

A transplantable TH-MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma.

Science.gov (United States)

Kroesen, Michiel; Nierkens, Stefan; Ansems, Marleen; Wassink, Melissa; Orentas, Rimas J; Boon, Louis; den Brok, Martijn H; Hoogerbrugge, Peter M; Adema, Gosse J

2014-03-15

Current multimodal treatments for patients with neuroblastoma (NBL), including anti-disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well-explored autologous mouse model for NBL is the TH-MYCN model. However, the immunobiology of the TH-MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH-MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Similar to human NBL cells, syngeneic TH-MYCN-derived 9464D cells endogenously express the tumor antigen GD2 and low levels of MHC Class I. The presence of the adaptive immune system had little or no influence on tumor growth, showing the low immunogenicity of the NBL cells. In contrast, depletion of NK1.1+ cells resulted in enhanced tumor outgrowth in both wild-type and Rag1(-/-) mice, showing an important role for NK cells in the natural anti-NBL immune response. Analysis of the tumor infiltrating leukocytes ex vivo revealed the presence of both tumor associated myeloid cells and T regulatory cells, thus mimicking human NBL tumors. Finally, anti-GD2 mAb mediated NBL therapy resulted in ADCC in vitro and delayed tumor outgrowth in vivo. We conclude that the transplantable TH-MYCN model represents a relevant model for the development of novel immunocombinatorial approaches for NBL patients. © 2013 UICC.

Graft-versus-host reaction and immune function. III. Functional pre-T cells in the bone marrow of graft-versus-host-reactive mice displaying T cell immunodeficiency

International Nuclear Information System (INIS)

Seddik, M.; Seemayer, T.A.; Lapp, W.S.

1986-01-01

Studies were performed to determine whether pre-T cells develop normally in the bone marrow of mice displaying thymic dysplasia and T cell immunodeficiency as a consequence of a graft-versus-host (GVH) reaction. GVH reactions were induced in CBAxAF1 mice by the injection of A strain lymphoid cells. To test for the presence of pre-T cells in GVH-reactive mice, bone marrow from GVH-reactive mice (GVHBM) was injected into irradiated syngeneic F1 mice and 30-40 days later thymic morphology and function were studied. Morphology studies showed nearly normal thymic architectural restoration; moreover, such glands contained normal numbers of Thy-1-positive cells. Functional pre-T cells were evaluated by transferring thymocytes from the irradiated GVHBM-reconstituted mice into T-cell-deprived mice. These thymocytes reconstituted allograft reactivity, T helper cell function and Con A and PHA mitogen responses of T-cell-deprived mice. These results suggest that the pre-T cell population in the bone marrow is not affected by the GVH reaction. Therefore, the T cell immunodeficiency associated with the GVH reaction is not due to a deficiency of pre-T cells in the bone marrow but is more likely associated with GVH-induced thymic dysplasia

Dynamic of distribution of human bone marrow-derived mesenchymal stem cells after transplantation into adult unconditioned mice.

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Allers, Carolina; Sierralta, Walter D; Neubauer, Sonia; Rivera, Francisco; Minguell, José J; Conget, Paulette A

2004-08-27

The use of mesenchymal stem cells (MSC) for cell therapy relies on their capacity to engraft and survive long-term in the appropriate target tissue(s). Animal models have demonstrated that the syngeneic or xenogeneic transplantation of MSC results in donor engraftment into the bone marrow and other tissues of conditioned recipients. However, there are no reliable data showing the fate of human MSC infused into conditioned or unconditioned adult recipients. In the present study, the authors investigated, by using imaging, polymerase chain reaction (PCR), and in situ hybridization, the biodistribution of human bone marrow-derived MSC after intravenous infusion into unconditioned adult nude mice. As assessed by imaging (gamma camera), PCR, and in situ hybridization analysis, the authors' results demonstrate the presence of human MSC in bone marrow, spleen, and mesenchymal tissues of recipient mice. These results suggest that human MSC transplantation into unconditioned recipients represents an option for providing cellular therapy and avoids the complications associated with drugs or radiation conditioning.

In vivo immunologic selection of class I major histocompatibility complex gene deletion variants from the B16-BL6 melanoma.

Science.gov (United States)

Talmadge, J E; Talmadge, C B; Zbar, B; McEwen, R; Meeker, A K; Tribble, H

1987-06-01

The mechanism by which tumor allografts escape host immunologic attack was investigated. B16-BL6 cells (the bladder 6 subline of the B16 melanoma) (H-2b) were transfected with a gene (Dd) encoding an allogeneic class I major histocompatibility complex antigen. Clones that expressed Dd antigen were injected into the footpads of nonimmune syngeneic mice, syngeneic immune mice, and nude mice. Under conditions of immunologic selection a clone that contained multiple copies of the transfected gene formed variants that lacked the transfected gene. Primary tumors and pulmonary metastases of immunized mice and pulmonary metastases of nonimmunized mice had lost the Dd gene and, in most cases, all of the associated plasmid. In contrast, in immunodeficient nude mice, primary tumors and pulmonary metastases retained the Dd gene and the associated plasmid. Deletion of genes encoding cell surface antigens may be one of the mechanisms by which allogeneic tumors escape immunologic attack.

Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer.

Science.gov (United States)

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

The Gut Microbiota Modulates Energy Metabolism in the Hibernating Brown Bear Ursus arctos.

Science.gov (United States)

Sommer, Felix; Ståhlman, Marcus; Ilkayeva, Olga; Arnemo, Jon M; Kindberg, Jonas; Josefsson, Johan; Newgard, Christopher B; Fröbert, Ole; Bäckhed, Fredrik

2016-02-23

Hibernation is an adaptation that helps many animals to conserve energy during food shortage in winter. Brown bears double their fat depots during summer and use these stored lipids during hibernation. Although bears seasonally become obese, they remain metabolically healthy. We analyzed the microbiota of free-ranging brown bears during their active phase and hibernation. Compared to the active phase, hibernation microbiota had reduced diversity, reduced levels of Firmicutes and Actinobacteria, and increased levels of Bacteroidetes. Several metabolites involved in lipid metabolism, including triglycerides, cholesterol, and bile acids, were also affected by hibernation. Transplantation of the bear microbiota from summer and winter to germ-free mice transferred some of the seasonal metabolic features and demonstrated that the summer microbiota promoted adiposity without impairing glucose tolerance, suggesting that seasonal variation in the microbiota may contribute to host energy metabolism in the hibernating brown bear. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Specific anti-EL4-lymphoma immunity in mice cured 2 years earlier with doxorubicin and interleukin-2.

Science.gov (United States)

Ehrke, M J; Verstovsek, S; Zaleskis, G; Ho, R L; Ujházy, P; Maccubbin, D L; Mihich, E

1996-05-01

This laboratory has reported the conditions for an effective, non-toxic, chemoimmunotherapy utilizing doxorubicin in combination with prolonged administration of interleukin-2 and the identification of the critical role of activated CD8+ T cells in the therapeutic effect. Mice (C57BL/6) cured in those studies have been followed for the remainder of their life spans. These mice, approximately 2 months of age when initially inoculated with syngeneic EL4 lymphoma, survived for more than 2 years, the normal life span of C57BL/6 mice. Mice 4 months old reinoculated with the EL4 cells all survived. At about 1 year of age mice were sacrificed and the ability of their thymocytes and splenocytes to develop specific CD8+ anti-EL4 activity was as high as it had been at the time of tumor rejection. At about 2 years of age EL4 was reimplanted into mice; all of them survived. These surviving mice, at 2 years 2 months of age, as well as a group of 2-year-old mice not rechallenged, were killed and functional antitumor activity and phenotype characteristics of various lymphocyte populations were determined in comparison to those of young and age-matched control mice. The phenotyping of the lymphocytes from the cured mice indicated very notable differences in subset distribution and increased CD44 expression. Functionally they developed high levels of anti-EL4 activity, which was ablated by combined treatment with monoclonal antibodies against CD8 and CD44, indicating the role of memory cells. Consistent with cells from aged mice, these same cell populations had a very reduced allogeneic responsiveness. It appears that cured mice have developed an immune memory specific for EL4.

Harnessing the Foreign Body Reaction in Marginal Mass Device-less Subcutaneous Islet Transplantation in Mice.

Science.gov (United States)

Pepper, Andrew R; Pawlick, Rena; Bruni, Antonio; Gala-Lopez, Boris; Wink, John; Rafiei, Yasmin; Bral, Mariusz; Abualhassan, Nasser; Shapiro, A M James

2016-07-01

Islet transplantation is a successful β-cell replacement therapy for selected patients with type 1 diabetes mellitus. However, despite early insulin independence, long-term graft attrition gradually reverts recipients to exogenous insulin dependency. Undoubtedly, as insulin producing stem cell therapies progress, a transplant site that is retrievable is desirable. This prerequisite is currently incompatible with intrahepatic islet transplantation. Herein, we evaluate the functional capacity of a prevascularized subcutaneous site to accommodate marginal islet mass transplantation in mice. Syngeneic mouse islets (150) were transplanted either under the kidney capsule (KC), into a prevascularized subcutaneous device-less (DL) site, or into the unmodified subcutaneous (SC) tissue. The DL site was created 4 weeks before diabetes induction and islet transplantation through the transient placement of a 5-Fr vascular catheter. Recipient mice were monitored for glycemic control and intraperitoneal glucose tolerance. A marginal islet mass transplanted into the DL site routinely reversed diabetes (n = 13 of 18) whereas all SC islet recipients failed to restore glycemic control (n = 0 of 10, P islet-KC mice (n = 15 of 16) became euglycemic posttransplant. The DL recipients' glucose profiles were comparable to KC islet grafts, postintrapertioneal glucose tolerance testing, whereas SC recipients remained hyperglycemic postglucose challenge. All normoglycemic mice maintained graft function for 100 days until graft retrieval. DL and KC islet grafts stained positively for insulin, microvessels, and a collagen scaffold. The device-less prevascularized approach supports marginal mass islet engraftment in mice.

Antitumor activity of baicalein on the mice bearing U14 cervical cancer

African Journals Online (AJOL)

Baicalein is one of the major constituents of Scutellaria baicalensis, and some cancer cells could be inhibited by it according to some studies in recent years. Mice tumor models of U14 cervical cancer was established in our study, baicalein of high and low dose (40 and 20 mg/kg, respectively) were given orally to mice.

Biodistribution and SPECT imaging of {sup 125/131}I-crotoxin on mice bearing Ehrlich solid tumour

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Soares, Marcella Araugio; Santos, Raquel Gouvea dos [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil)], e-mail: marcellaaraugio@yahoo.com.br, e-mail: santosr@cdtn.br; Silveira, Marina B.; Simal, Carlos [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Faculdade de Medicina; Dias, Consuelo L. Fortes [Fundacao Ezequiel Dias (FUNED), Belo Horizonte, MG (Brazil)

2009-07-01

The search of specific radiopharmaceuticals to be used in breast tumour diagnosis is relevant to complement the techniques applied in conventional medicine. Crotalus durissus terrificus venom (CV) and its main polypeptide, Crotoxin (Crtx), are natural source of several bioactive substances with therapeutical potential. The aim of this work was to evaluate the binding of Crtx with tumour targets in vivo, as well as, evaluate its applicability for breast tumours diagnosis. Crtx was labelled with {sup 125/131}I using lactoperoxidase method and radiochemical analysis was performed by chromatography. {sup 125}I-Crtx was used for biodistribution and pharmacokinetics studies on swiss mice bearing Ehrlich solid tumour, while {sup 131}I-Crtx was used for single photon emission computed tomography (SPECT) imaging. Crtx presented specific binding sites on Ehrlich tumour cells and had a rapid blood clearance (T{sub 1/2}= 201.1 min.). Intratumoral administration increased significantly the activity delivered into the tumour site (128-fold higher) and reduced the kidney burden (7.2-fold lower). {sup 131}I-Crxt demonstrated to interact with tumour cells for until 72 hours allowing good quality images of tumour. Our results indicate the biotechnological potential of Crtx as template for radiopharmaceutical design for cancer diagnosis. (author)

Regeneration of CFUs in the marrow of mice exposed to 300 rads after having recovered from 950 rads

International Nuclear Information System (INIS)

Kedo, A.; Barone, J.; Fried, W.

1976-01-01

Exposure to 950 rads 60 Co radiation has been reported to cause long-lasting damage to the hematopoietic stroma (HS), although the size of the CFUs population recovers to pre-irradiation levels. In these studies HS damage was detected only after subcutaneously implanting the femurs of the irradiated mice into syngeneic hosts. To exclude the possibility that what was considered to be HS damage was merely caused by artifacts due to the process of implantation in a new host, the rate of regeneration of CFUs in mice which had recovered from 950 rads prior to receiving 300 rads 60 Co radiation (950 + 300 rads group) was compared with that of mice which received only 300 rads (0 + 300 rads group). The CFUs population in the 950 + 300 rads group grew exponentially for 2 weeks at a rate which did not differ significantly from that of CFUs in the 0 + 300 rads group. However, the rate of CFUs growth reached a plateau before full recovery was achieved in contrast to that in the 0 + 300 rads mice. It was therefore concluded that the incomplete regeneration of CFUs in the marrows of 950 + 300 rads mice was most likely caused by X-irradiation-induced damage to the HS rather than damage to the inherent repopulation potential of the CFUs per se. (author)

Delayed-type hypersensitivity to Babesia microti-infected erythrocytes in mice

International Nuclear Information System (INIS)

Ruebush, M.J.; Troutman, E.H.; Kennedy, D.A.

1986-01-01

Strong delayed-type hypersensitivity (DTH) to Babesia microti was elicited when intraerythrocytic parasites (IEP) were inoculated subcutaneously into the flank of normal mice 6 to 14 days before challenge in the ipsilateral footpad with 10(8) IEP. Intraperitoneal or intravenous administration of antigen did not sensitize mice for DTH. When challenge was given 21 days after immunization, the response was approximately half of the maximum and then rose again slowly over the next 3 weeks to levels that were not significantly different from those maximal values. The response was classified as a true DTH reaction on the basis of kinetics, histology, and the transfer of responsiveness with immune T lymphocytes of the Ly 1+ phenotype, but not with serum. The reaction was specific for IEP since control groups given two injections of red blood cells from uninfected syngeneic mice (NRBC) or one injection of NRBC or sheep red blood cells (SRBC) and one of IEP never developed significant footpad swelling. Freed parasites obtained by osmotic rupture, density gradient sedimentation, and lethally irradiated IEP were also effective for elicitation of DTH. Anti-IEP DTH was expressed in a dose-dependent fashion with 10(6), 10(7), or 10(8) parasites sufficing for immunizing inoculum as long as 10(8) parasites were used as the challenge dose. Mice immunized and challenged with 10(8) lethally irradiated IEP (60 krad, 60Co), were protected against subsequent intraperitoneal challenge with 10(8) viable IEP. If mice were infected intraperitoneally with 10(8) IEP at any time between 21 days before immunization to 2 hr after challenge, their ability to respond to immunization and challenge was profoundly depressed. Development of a strong anti-parasite DTH response can occur in parallel with resistance to infection, but is not a rapid sequela of bloodborne infection

Bearing system

Science.gov (United States)

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.

Improved survival of mice bearing liver metastases of colon cancer cells treated with a combination of radioimmunotherapy and antiangiogenic therapy

International Nuclear Information System (INIS)

Kinuya, Seigo; Yokoyama, Kunihiko; Bai, Jingming; Michigishi, Takatoshi; Tonami, Norihisa; Koshida, Kiyoshi; Mori, Hirofumi; Shiba, Kazuhiro; Watanabe, Naoto; Shuke, Noriyuki

2004-01-01

We attempted to determine whether the combined regimen of radioimmunotherapy (RIT) and antiangiogenic therapy would favorably affect the survival of animals bearing liver metastases of colon cancer cells. Daily antiangiogenic therapy with 2-methoxyestradiol (2-ME), 75 mg/kg, was initiated at 3 days following intrasplenic cell inoculation of LS180 colon cancer cells. RIT with 7 MBq of 131 I-A7, an IgG1 anti-colorectal monoclonal antibody, or 131 I-HPMS-1, an irrelevant IgG1, was conducted at 7 days. Production of vascular endothelial growth factor (VEGF) by LS180 cells was assessed in vitro. All nontreated mice died by 31 days following cell inoculation (n=5). Monotherapy comprising 2-ME treatment resulted in slightly better survival of mice (n=8) (P 131 I-A7 RIT displayed a marked therapeutic effect (n=8) (P 131 I-A7 RIT and antiangiogenic therapy demonstrated a superior therapeutic effect in comparison to monotherapy consisting of either RIT or antiangiogenic therapy (n=10) (P 131 I-HPMS-1 RIT failed to provide an appreciable benefit (n=5). Treatment with 2-ME decreased VEGF production by LS180 cells in a dose-dependent fashion. In conclusion, a combination regimen comprising RIT and antiangiogenic therapy initiated at the early stage of metastasis would be of great benefit in terms of improvement of the therapeutic efficacy with respect to liver metastases. (orig.)

Anti-tumor angiogenesis effect of aminopeptidase inhibitor bestatin against B16-BL6 melanoma cells orthotopically implanted into syngeneic mice.

Science.gov (United States)

Aozuka, Yasushi; Koizumi, Keiichi; Saitoh, Yurika; Ueda, Yasuji; Sakurai, Hiroaki; Saiki, Ikuo

2004-12-08

We investigated the effect of bestatin, an inhibitor of aminopeptidase N (APN)/CD13 and aminopeptidase B, on the angiogenesis induced by B16-BL6 melanoma cells. Oral administration of bestatin (100-200 mg/kg/day) was found to significantly inhibit the melanoma cell-induced angiogenesis in a mouse dorsal air sac assay. Additionally, anti-APN/CD13 mAb (WM15), which neutralizes the aminopeptidase activity in tumor cells, as well as bestatin inhibited the tube-like formation of human umbilical vein endothelial cells (HUVECs) in vitro. Furthermore, the intraperitoneal administration of bestatin (50-100 mg/kg/day) after the orthotopic implantation of B16-BL6 melanoma cells into mice reduced the number of vessels oriented towards the established primary tumor mass on the dorsal side of mice. These findings suggest that bestatin is an active anti-angiogenic agent that may inhibit tumor angiogenesis in vivo and tube-like formation of endothelial cells in vitro through its inhibition of APN/CD13 activity.

Enhancement of syngeneic murine tumour transplantability by whole body irradiation

International Nuclear Information System (INIS)

Peters, L.J.

1975-01-01

Experiments were undertaken to test the general validity of the assumption that potentiation of tumour transplantability by sublethal whole body irradiation (WBI) implies some degree of immunological resistance in the intact host. A transplantable carcinoma of spontaneous origin in CBA mice which exhibits a large WBI effect was assayed quantitatively in mice which had been immunologically crippled in terms of allograft acceptance by depletion of thymus derived lymphocytes. The mean number of tumour cells required for 50% successful takes (TD 50 ) in these mice was found to be not significantly different from that in normal controls but highly significantly greater than in WBI mice. On the other hand, in mice which underwent laparotomy immediately before assay, the TD 50 was reduced significantly though not to the same extent as in WBI mice. It was concluded that WBI effect was not due to impaired host immunity but possibly to physiological changes resulting from acute stress. The hypothesis that hyperfibrinogenaemia which occurs after both WBI and laparotomy might increase tumour transplantability was rejected because of the lack of correlation between TD 50 and fibrinogen levels at different times after each procedure. From this and other work it is apparent that TD 50 data, in themselves, give no reliable indication of host immunity. (author)

Protective specific immunity induced by cyclophosphamide plus tumor necrosis factor alpha combination treatment of EL4-lymphoma-bearing C57BL/6 mice.

Science.gov (United States)

Krawczyk, C M; Verstovsek, S; Ujházy, P; Maccubbin, D; Ehrke, M J

1995-06-01

A combination treatment protocol initiated 12 days after tumor injection, when the tumor was large, by administering cyclophosphamide (CY, 150 or 250 mg/kg) intraperitoneally followed by intravenous tumor necrosis factor alpha (TNF alpha, 1000 units injection) on days 13, 16, 18, 21, and 23, resulted in about 60% long-term survival (i.e., survival for at least 60 days) in the syngeneic C57BL/6 mouse/EL4 lymphoma model system. The establishment of a specific antitumor immune memory and its possible therapeutic relevance was verified by reinjecting 60-day survivors with EL4 cells; all 60-day survivors that had received the combination treatments rejected the implants and survived for a further 60 days. Thymic cellularity was reduced during treatment and its recovery appeared to correlate with long-term survival and immunity. Thymocytes from mice treated with the combination were found to express significant levels of specific anti-EL4 cytolytic activity following a 4-day stimulation culture with X-irradiated EL4 cells and low concentrations of interleukin-2. This response could not be generated with thymocytes from naive animals. In each case the effect seen with the combination of a moderate CY dose (150 mg/kg) with TNF alpha was better than that seen with either dose of CY alone and equal to or better than that seen with the higher dose of CY combined with TNF alpha. These results indicate that treatment with a single moderate dose of CY in combination with TNF alpha is effective against a large, established tumor in this murine model. Furthermore, all the long-term survivors induced by this treatment developed protective immunity against reimplanted tumor and demonstrated a long-term specific immune memory in the thymus.

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

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Nikhil, Kumar; Sharan, Shruti; Chakraborty, Ajanta [Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand (India); Bodipati, Naganjaneyulu; Krishna Peddinti, Rama [Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand (India); Roy, Partha, E-mail: paroyfbs@iitr.ernet.in [Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand (India)

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.

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

International Nuclear Information System (INIS)

Nikhil, Kumar; Sharan, Shruti; Chakraborty, Ajanta; Bodipati, Naganjaneyulu; Krishna Peddinti, Rama; Roy, Partha

2014-01-01

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 50 =25±0.38) when compared to reference compound PTER (IC 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

Repopulation of the Stem-Cell Compartment in Haemopoietic and Lymphatic Tissues of Mice after X-Irradiation

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Vos, O. [Medical Biological Laboratory of the National Defense Organization TNO, Rijswijk Z.H. (Netherlands)

1968-08-15

Repopulation in haemopoietic tissues of mice was studied at various times after irradiation with a sub-lethal X-ray dose of 460 R and after exposure to a lethal X-ray dose of 800 R followed by transplantation of 4 x 10{sup 6} syngeneic bone-marrow cells. The number of stem cells was determined with the exogenous and endogenous spleen colony technique in the bone-marrow of the femur and in the spleen. Repopulation in lymphatic tissues was investigated at various times after sub-lethal irradiation with 460 R, sub-lethal irradiation with 460 R followed by allogeneic skin transplantation, lethal irradiation with 800 R followed by transplantation of 2 x 10{sup 6} syngeneic bone-marrow cells, and irradiation with 800 R followed by transplantation of 2 x 10{sup 6} and 5 x 10{sup 6} syngeneic bone-marrow and lymph node cells, respectively. The number of stem cells was estimated in the spleen and in lymph nodes with a technique based on a graft-versus- host reaction. The results showed that a rapid repopulation occurred in haemopoietic tissues under all circumstances. In the spleen an overshoot was found during a period beginning shortly after the 7th day and lasting for some weeks. In lymphatic tissues repopulation by stem cells was slow. During the first one or two weeks some decrease was even observed. This was followed by a slow repopulation that around 100 days after irradiation reached a level slightly below that found in control animals. Small differences of repopulation in the various organs and under different circumstances are discussed. It was postulated that immuno-competent lymphatic stem cells (antigen-sensitive cells or PC{sub 1} cells) do not proliferate or do so only to a limited extent. This compartment must be replenished by repopulation of differentiating stem cells from the bone marrow. It seems probable that stem-cell depletion or antigeneic stimulation has only a marginal effect upon repopulation. (author)

Lentinan: hematopoietic, immunological, and efficacy studies in a syngeneic model of acute myeloid leukemia.

Science.gov (United States)

McCormack, Emmet; Skavland, Jørn; Mujic, Maja; Bruserud, Øystein; Gjertsen, Bjørn Tore

2010-01-01

Lentinan, a beta-glucan nutritional supplement isolated from the shitake mushroom (Lentula edodes), is a biological response modifier with immunostimulatory properties. Concomitantly, the role of beta-glucans as chemoimmunotherapeutic in a number of solid cancers has been widely documented. We investigated the effects of nutritional grade lentinan upon BN rats and in a preclinical syngeneic model of acute myeloid leukemia. BN rats supplemented daily with lentinan exhibited weight gains, increased white blood cells, monocytes, and circulating cytotoxic T-cells; and had a reduction in anti-inflammatory cytokines IL-4, IL-10, and additionally IL-6. Lentinan treatment of BN rats with BNML leukemia resulted in improved cage-side health and reduced cachexia in the terminal stage of this aggressive disease. Combination of lentinan with standards of care in acute myeloid leukemia, idarubicin, and cytarabine increased average survival compared with monotherapy and reduced cachexia. These results indicate that nutritional supplementation of cancer patients with lentinan should be further investigated.

Parental resistance of irradiated mice to (CBAXM523)F/sub 1/ lymphocytes: the destiny of transplanted cells, duration of resistance and its specificity

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Kondrat' eva, T K; Fontalin, L N; Nagurskaya, E V; Novikova, T K; Blandova, Z K; Chernousov, A D [Akademiya Meditsinskikh Nauk SSSR, Moscow. Inst. Ehpidemiologii i Mikrobiologii

1979-05-01

The immunologic reactivity of mouse (CBAxM523)F/sub 1/ lymphocytes to alien antigens (ram erythrocytes) in the organisms of lethally irradiated CBA mice was studied. If the irradiation, cell transfer and antigen test-injection were performed on the same day, the activity of the transplant was suppressed as compared to the syngenic system. If the intervals between these procedures increased to three days the activity of donor cells was recovered. The retransplantation of recipient spleen cells to the irradiated CBA and F/sub 1/ mice demonstrated the viability of the transplanted cells and the absence of their transadaptation to nonsyngenic microenvironment. The resistance of the recipients could be overcome specifically by preliminary injection of F/sub 1/ mouse cells in combination with cyclophosphamide or without it. The results obtained suggest to conclude, that the genetic parental resistance of CBA mice to F/sub 1/ mouse cells is caused by the immunologically competent recipient cells that are inactivated after three days following irradiation. They do not produce a cytotoxic effect on donor cells, but limit temporarily the activity of the latter.

Journal bearing

Science.gov (United States)

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.

Camshaft bearing arrangement

Energy Technology Data Exchange (ETDEWEB)

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.

Anti-tumor effects of a novel chimeric peptide on S180 and H22 xenografts bearing nude mice.

Science.gov (United States)

Wu, Dongdong; Gao, Yanfeng; Chen, Lixiang; Qi, Yuanming; Kang, Qiaozhen; Wang, Haili; Zhu, Linyu; Ye, Yong; Zhai, Mingxia

2010-05-01

In recent years, many endogenous peptides have been identified by screening combinatory phage display peptide library, which play important roles in the process of angiogenesis. A heptapeptide, ATWLPPR, binds specifically to NRP-1 and selectively inhibits VEGF165 binding to VEGFR-2. Another heptapeptide, NLLMAAS, blocks both Ang-1 and Ang-2 binding to Tie-2 in a dose-dependent manner. In the present study, we aimed to connect ATWLPPR (V1) with NLLMAAS (V2) via a flexible linker, Ala-Ala, to reconstruct a novel peptide ATWLPPRAANLLMAAS (V3). We firstly investigated the anti-tumor and anti-angiogenic effects of peptide V3 on sarcoma S180 and hepatoma H22 bearing BALB/c nude mice. Mice were continuously subcutaneously administrated with normal saline, V1 (320microg/kg/d), V2 (320microg/kg/d), V1+V2 (320microg/kg/d), and V3 (160, 320 and 480microg/kg/d), for 7 days. Treatment with peptide V3 could significantly reduce the tumor weight and volume. Pathological examination showed that the tumors treated with peptide V3 had a larger region of necrosis than that of peptide V1, V2, and V1+V2 at the same dose. A significant decrease of microvessel density (MVD) in a dose-dependent manner was observed in each group of peptide V3. The results of pathological examination on normal tissue, lung, heart, liver, spleen, kidney and white blood cells showed that peptide V3 might have no significant toxicity. In conclusion, our results demonstrated that peptide V3 could be more effective on inhibiting tumor growth and angiogenesis than that of V1, V2, and V1+V2. Peptide V3 could be considered as a novel chimeric peptide with potent anti-tumor activity. Copyright (c) 2010 Elsevier Inc. All rights reserved.

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

Science.gov (United States)

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.

Function and expression of cystic fibrosis transmembrane conductance regulator after small intestinal transplantation in mice.

Directory of Open Access Journals (Sweden)

Penghong Song

Full Text Available The secretion function of intestinal graft is one of the most important factors for successful intestinal transplantation. Cystic fibrosis transmembrane conductance regulator (CFTR mediates HCO3(- and Cl(- secretions in intestinal epithelial cells. In this study, we made investigation on the expression and function of CFTR in an experimental model of murine small intestinal transplantation. Heterotopic intestinal transplantations were performed in syngeneic mice. The mRNA and protein expressions of CFTR were analyzed by real time PCR and western blot. Murine intestinal mucosal HCO3(- and Cl(- secretions were examined in vitro in Ussing chambers by the pH stat and short circuit current (I(sc techniques. The results showed that forskolin, an activator of CFTR, stimulated jejunal mucosal epithelial HCO3(- and Cl(- secretions in mice, but forskolin-stimulated HCO3(- and Cl(- secretions in donor and recipient jejunal mucosae of mice after heterotopic jejunal transplantation were markedly decreased, compared with controls (P<0.001. The mRNA and protein expression levels of CFTR in donor and recipient jejunal mucosae of mice were also markedly lower than those in controls (P<0.001, and the mRNA and protein expression levels of tumor necrosis factor α (TNFα were markedly increased in donor jejunal mucosae of mice (P<0.001, compared with controls. Further experiments showed that TNFα down-regulated the expression of CFTR mRNA in murine jejunal mucosa. In conclusion, after intestinal transplantation, the function of CFTR was impaired, and its mRNA and protein expressions were down-regulated, which may be induced by TNFα.

Combined SEP and anti-PD-L1 antibody produces a synergistic antitumor effect in B16-F10 melanoma-bearing mice.

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Hu, Zhengping; Ye, Liang; Xing, Yingying; Hu, Jinhang; Xi, Tao

2018-01-09

The increased PD-L1 induces poorer prognosis in melanoma. The treatment with PD-1/PD-L1 antibodies have a low response rate. The combination immunotherapies are the encouraging drug development strategy to receive maximal therapeutic benefit. In this study, we investigated the enhanced antitumor and immunomodulatory activity of combined SEP and αPD-L1 in B16-F10 melanoma-bearing mice. The results shown that combined SEP and αPD-L1 presented significant synergistic antitumor effects, increased the frequency of CD8 + and CD4 + T cells in spleen and tumor, cytotoxic activity of CTL in spleen, and IL-2 and IFN-γ levels in splenocytes and tumor. The combination treatment also produced synergistic increase in P-ERK1/2 level in spleen. Immunohistochemistry shown that SEP induced the PD-L1 expression in melanoma tissue possibly by promoting IFN-γ excretion, which led to the synergistic anti-tumor effects of aPD-L1 and SEP. Furthermore, in the purified T lymphocyte from the naive mice, the combination of SEP and αPD-L1 had more potent than SEP or αPD-L1 in promoting T lymphocyte proliferation and cytokines secretion including IL-2 and IFN-γ, at least partially by activating MEK/ERK pathway. Our study provides the scientific basis for a clinical trial that would involve combination of anti-PD-L1 mAb and SEP for sustained melanoma control.

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

Directory of Open Access Journals (Sweden)

Heba Bassiony

Full Text Available 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.

Interleukin 21 controls tumour growth and tumour immunosurveillance in colitis-associated tumorigenesis in mice.

Science.gov (United States)

Jauch, Dominik; Martin, Maria; Schiechl, Gabriela; Kesselring, Rebecca; Schlitt, Hans Jürgen; Geissler, Edward K; Fichtner-Feigl, Stefan

2011-12-01

Colitis-associated tumorigenesis is a balance between proliferation of tumour cells and tumour immunosurveillance. The role of T-helper-cell-derived cytokines in tumour growth is not fully understood. In this study the authors investigated the influence of interleukin (IL) 21 on intestinal tumorigenesis. Chronic colitis was induced in IL-21(-/-) and littermate control wild-type mice with three cycles of 1.5% dextran sulphate sodium (DSS) over 7 days followed by 7 days of drinking water. Mice received an azoxymethane injection on day 0 of DSS-colitis to induce tumorigenesis. Immunohistochemistry was performed on inflamed and tumour-bearing areas of colons. Cytokine expression of isolated colonic CD4 T cells was determined by ELISA. Cytotoxic capacity of isolated colonic CD8 T cells targeting tumour cells was evaluated by flow cytometry and quantitative cytotoxicity assay. Apoptosis of tumour cells was determined by TUNEL assay of colonic sections. Increasing expression of IL-21 was observed in chronic colitis, which showed functional importance, since IL-21 deficiency prevented chronic DSS-colitis development. Further, in the absence of IL-21, significantly fewer tumour nodules were detected, despite a similar extent of intestinal inflammation. In wild-type mice, 8.6±1.9 tumour nodules were found compared with 1.0±1.2 in IL-21-deficient mice. In tumour-bearing IL-21-deficient mice, intestinal inflammation was restored and partly dependent on interferon (IFN)-γ, whereas the inflammation in wild-type mice showed high IL-17A concentrations. In these rare tumours in IL-21-deficient mice, tumour cell proliferation (Ki-67) was decreased, while cell apoptosis was increased, compared with wild-type mice. Increased IFNγ expression in tumour-bearing IL-21-deficient mice led to increased tumour immunosurveillance mediated by cytotoxic CD8CD103 T cells targeting E-cadherin(+) colonic tumour cells and therefore limited tumour growth. These results indicate that IL-21

Synthesis and characteristics in tumor-bearing mice of N-[11C]methyl-1-deoxynojirimycin and N-[11C]methyl-1-deoxymannojirimycin

International Nuclear Information System (INIS)

Ishiwata, Kiichi; Sasaki, Toru; Ishii, Shin-ichi; Senda, Michio; Seki, Hiroyuki; Kitasato Univ.; Nozaki, Tadashi

1993-01-01

N-[ 11 C]Methyl-1-deoxynojirimycin ([ 11 C]MDNM) and N-[ 11 C]methyl-1-deoxymannojirimycin ([ 11 C]MDMM) were prepared by 11 C-methylation of 1-deoxynojirimycin (DNM) and 1-deoxymannojirimycin (DMM), which are specific inhibitors of glucosidase and mannosidase, respectively. In mice bearing Ehrich ascitic tumor, the highest uptake of the [ 11 C]MDNM was observed in the kidney, followed by the liver and small intestine, while the tumour uptake was moderate. By MDNM loading, saturable uptake was observed in these tissues. In homogenates of the kidney and tumor tissues, a considerable amount of radioactivity was detected in a high-molecular weight fraction. These results demonstrate that the [ 11 C]MDNM has a potential for imaging the glucosidase activity by positron emission tomography. On the other hand, [ 11 C]MDMM showed lower uptake than [ 11 C]MDNM in the kidney, liver and small intestine and no effect of carrier DMM, suggesting that the [ 11 C]MDMM would not reflect mannosidase activity. (Author)

Biodistribution, pharmacokinetic, and imaging studies with 186Re-labeled NR-LU-10 whole antibody in LS174T colonic tumor-bearing mice

International Nuclear Information System (INIS)

Goldrosen, M.H.; Biddle, W.C.; Pancook, J.; Bakshi, S.; Vanderheyden, J.L.; Fritzberg, A.R.; Morgan, A.C. Jr.; Foon, K.A.

1990-01-01

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

Induction of B-cell lymphoma by UVB Radiation in p53 Haploinsufficient Mice

International Nuclear Information System (INIS)

Puebla-Osorio, Nahum; Miyahara, Yasuko; Coimbatore, Sreevidya; Limón-Flores, Alberto Y; Kazimi, Nasser; Ullrich, Stephen E; Zhu, Chengming

2011-01-01

The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation. UVB-irradiated p53 +/- mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling. UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV-irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19 + , CD5 + , B220 + , IgM + and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19) translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression. UV-irradiated p53 +/- mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal tumors after chronic exposure to UV light. The

Induction of B-cell lymphoma by UVB Radiation in p53 Haploinsufficient Mice

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Ullrich Stephen E

2011-01-01

Full Text Available Abstract Background The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation. Methods UVB-irradiated p53+/- mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling. Results UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV-irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19+, CD5+, B220+, IgM+ and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19 translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression. Conclusion UV-irradiated p53+/- mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal

Reversal of multidrug resistance with KR-30035: evaluated with biodistribution of Tc-99m MIBI in nude mice bearing human tumor xenografts

International Nuclear Information System (INIS)

Kim, Jung Kyun; Lee, Jae Tae; Lee, Byung Ho

2001-01-01

KR-30035 (KR), a new MDR reversing agent, has been found to produce a similar degree of increased Tc-99m MIBI uptake in cultured tumor cells over-expressing mdr1 mRNA compared to verapamil (VP), with less cardiovascular effects. We assessed the MDR-reversing ability of KR in vivo, and effects of various doses of KR on MIBI uptake in nude mice bearing P-glycoprotein (P-gp) positive (+) and P-gp negative (-) human tumor xenografts. P-gp (+) HCT15/CLO2 colorectal and P-gp (-) A549 non-small cell cancer cells were inoculated in each flank of 120 nude mice (20 mice x 6 groups). Group 1 (Gr1) mice received 10mg/kg Kr i.p. 3 times (x3); Gr2, 10mg/kg VP i.p. x3; Gr3, 10mg/kg KR i.p. x2 + 25mg/kg KR i.p. x1; Gr4, 10mg/kg KR i.p. x 2 + 50mg/kg i.p. x1; Gr5, 10mg/kg Kr i.p. x2 + 25mg/kg KR i.v. x1, GrC, controls. The mice were then injected with Tc-99m MIBI and sacrificed after 10 min, 30 min, 90 min and 240 min. Tumor uptake of MIBI (TU) in each group was compared. Tu in P-gp (+) and (-)tumors were both higher in Gr1 than Gr2. Washout rate between the 10 min and 4 hours was lower in Gr5 of P-gp (+) cell (0.93) than the control. Percentage increases in Tu were higher in P-gp (+) than P-gp (-) tumors with all KR doses. Pgp (+) TU were highest at 10 min (173% of GrC) and persisted up to 240 min (144%) in Gr3. Larger doses of KR resulted in a lesser degree of increase in P-gp (+) TU at 10 min (130% in Gr4 and 117% in Gr5) and 30 min (178%, 129%), but TU increased by time up to 240 min (177%, 196%). Heart and lung uptakes were markedly increased in Gr4 and Gr5 at 10 and 3C min, likely due to cardiovascular effects. No mice died. These data further suggest that KR that has significantly lower cardiovascular toxicity than verapamil can be used as an active inhibitor of MDR. Even a relatively low dose of KR significantly increased Tc-99m MIBI uptake in P-gp (+) tumors in vivo

Antitumor effect of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles on mice bearing breast cancer: a systemic toxicity assay.

Science.gov (United States)

Peixoto, Raphael Cândido Apolinário; Miranda-Vilela, Ana Luisa; de Souza Filho, José; Carneiro, Marcella Lemos' Brettas; Oliveira, Ricardo G S; da Silva, Matheus Oliveira; de Souza, Aparecido R; Báo, Sônia Nair

2015-05-01

Breast cancer is one of the most prevalent cancer types among women. The use of magnetic fluids for specific delivery of drugs represents an attractive platform for chemotherapy. In our previous studies, it was demonstrated that maghemite nanoparticles coated with rhodium (II) citrate (Magh-Rh2Cit) induced in vitro cytotoxicity and in vivo antitumor activity, followed by intratumoral administration in breast carcinoma cells. In this study, our aim was to follow intravenous treatment to evaluate the systemic antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Female Balb/c mice were evaluated with regard to toxicity of intravenous treatments through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine and liver, kidney, and lung histology. The antitumor activity of rhodium (II) citrate (Rh2Cit), Magh-Rh2Cit, and maghemite nanoparticles coated with citrate (Magh-Cit), used as control, was evaluated by tumor volume reduction, histology, and morphometric analysis. Magh-Rh2Cit and Magh-Cit promoted a significant decrease in tumor area, and no experimental groups presented hematotoxic effects or increased levels of serum ALT and creatinine. This observation was corroborated by the histopathological examination of the liver and kidney of mice. Furthermore, the presence of nanoparticles was verified in lung tissue with no morphological changes, supporting the idea that our nanoformulations did not induce toxicity effects. No studies about the systemic action of rhodium (II) citrate-loaded maghemite nanoparticles have been carried out, making this report a suitable starting point for exploring the therapeutic potential of these compounds in treating breast cancer.

Homogeneous immunoglobulins in the serum of irradiated and bone marrow reconstituted mice: the role of thymus and spleen

International Nuclear Information System (INIS)

Mink, J.G.; Radl, J.; Berg, P. van den; Muiswinkel, W.B. van; Oosterom, R. van.

1979-01-01

The influence of thymectomy and splenectomy on the frequency and class distribution of homogeneous immunoglobulins (H-Ig) in serum was studied in lethally irradiated (DBA/2 x C57B1/Rij)F 1 mice reconstituted with syngeneic bone marrow. During four follow-up periods in the first 9 months after transplantation, the sham-operated controls and splenectomized animals developed transient H-Ig in an average frequency of 14.2 and 15.7% respectively. There were no marked differences in the incidence of H-Ig within these two groups. In contrast, thymectomized mice and mice both thymectomized and splenectomized showed H-Ig in much higher frequencies (average percentages 31.6 and 36.5 respectively). The highest frequency of H-Ig was observed between 1.5 and 3.5 months after transplantation. H-Ig of the IgG1 and IgG2 subclasses were most frequent in all groups during the first 3.5 months. Later, H-Ig belonging to the IgM class also appeared in somewhat higher numbers. H-Ig of the IgA class was a very rare finding at any time. These results indicate that the presence of the thymus, but not necessarily of the spleen, is an important factor in the regulation of the immunoglobulin heterogeneity during the reconstitution of the immune system in lethally irradiated and bone marrow reconstituted mice. (author)

Effect of selective T cell depletion of host and/or donor bone marrow on lymphopoietic repopulation, tolerance, and graft-vs-host disease in mixed allogeneic chimeras (B10 + B10.D2----B10)

International Nuclear Information System (INIS)

Ildstad, S.T.; Wren, S.M.; Bluestone, J.A.; Barbieri, S.A.; Stephany, D.; Sachs, D.H.

1986-01-01

Reconstitution of lethally irradiated mice with a mixture of T cell-depleted syngeneic plus T cell-depleted allogeneic bone marrow (B10 + B10.D2----B10) leads to the induction of mixed lymphopoietic chimerism, excellent survivals, specific in vivo transplantation tolerance to subsequent donor strain skin grafts, and specific in vitro unresponsiveness to allogeneic donor lymphoid elements as assessed by mixed lymphocyte reaction (MLR) proliferative and cell-mediated lympholysis (CML) cytotoxicity assays. When B10 recipient mice received mixed marrow inocula in which the syngeneic component had not been T cell depleted, whether or not the allogeneic donor marrow was treated, they repopulated exclusively with host-type cells, promptly rejected donor-type skin allografts, and were reactive in vitro to the allogeneic donor by CML and MLR assays. In contrast, T cell depletion of the syngeneic component of the mixed marrow inocula resulted in specific acceptance of allogeneic donor strain skin grafts. Such animals were specifically unreactive to allogeneic donor lymphoid elements in vitro by CML and MLR, but were reactive to third party. When both the syngeneic and allogeneic marrow were T cell depleted, variable percentages of host- and donor-type lymphoid elements were detected in the mixed reconstituted host. When only the syngeneic bone marrow was T cell depleted, animals repopulated exclusively with donor-type cells. Although these animals had detectable in vitro anti-host (B10) reactivity by CML and MLR and reconstituted as fully allogeneic chimeras, they exhibited excellent survival and had no in vivo evidence for graft-vs-host disease. Experiments in which untreated donor spleen cells were added to the inocula in this last group suggest that the presence of T cell-depleted syngeneic bone marrow cells diminishes graft-vs-host disease and the mortality from it

Indomethacin Treatment of Mice with Premalignant Oral Lesions Sustains Cytokine Production and Slows Progression to Cancer.

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Johnson, Sara D; Young, M Rita I

2016-01-01

Current treatment options for head and neck squamous cell carcinoma (HNSCC) patients are often ineffective due to tumor-localized and systemic immunosuppression. Using the 4-NQO mouse model of oral carcinogenesis, this study showed that premalignant oral lesion cells produce higher levels of the immune modulator, PGE 2 , compared to HNSCC cells. Inhibiting prostaglandin production of premalignant lesion cells with the pan-cyclooxygenase inhibitor indomethacin stimulated their induction of spleen cell cytokine production. In contrast, inhibiting HNSCC prostaglandin production did not stimulate their induction of spleen cell cytokine production. Treatment of mice bearing premalignant oral lesions with indomethacin slowed progression of premalignant oral lesions to HNSCC. Flow cytometric analysis of T cells in the regional lymph nodes of lesion-bearing mice receiving indomethacin treatment showed an increase in lymph node cellularity and in the absolute number of CD8 + T cells expressing IFN-γ compared to levels in lesion-bearing mice receiving diluent control treatment. The cytokine-stimulatory effect of indomethacin treatment was not localized to regional lymph nodes but was also seen in the spleen of mice with premalignant oral lesions. Together, these data suggest that inhibiting prostaglandin production at the premalignant lesion stage boosts immune capability and improves clinical outcomes.

Immune selection of tumor cells in TCR β-chain transgenic mice.

Science.gov (United States)

Silaeva, Yulia Yu; Grinenko, Tatyana S; Vagida, Murad S; Kalinina, Anastasia A; Khromykh, Ludmila M; Kazansky, Dmitry B

2014-10-01

The concept of immunological surveillance implies that immunogenic variants of tumor cells arising in the organism can be recognized by the immune system. Tumor progression is provided by somatic evolution of tumor cells under the pressure of the immune system. The loss of MHC Class I molecules on the surface of tumor cells is one of the most known outcomes of immune selection. This study developed a model of immune selection based on the immune response of TCR 1d1 single β-chain transgenic B10.D2(R101) (K(d)I(d)D(b)) mice to allogeneic EL4 (H-2(b)) thymoma cells. In wild-type B10.D2(R101) mice, immunization with EL4 cells induced a vigorous CTL response targeted to the H-2K(b) molecule and results in full rejection of the tumor cells. In contrast, transgenic mice developed a compromised proliferative response in mixed-lymphocyte response assays and were unable to reject transplanted allogeneic EL4 cells. During the immune response to EL4 cells, CD8(+) T-lymphocytes with endogenous β-chains accumulated predominantly in the spleen of transgenic mice and only a small part of the T-lymphocytes expressing transgenic β-chains became CD8(+)CD44(+)CD62L(-) effectors. Then, instead of a full elimination of tumor cells as in wild-type mice, a reproducible prolonged equilibrium phase and subsequent escape was observed in transgenic mice that resulted in death of 90% of the mice in 40-60 days after grafting. Prolonged exposure of tumor cells to the pressure of the immune system in transgenic mice in vivo resulted in a stable loss of H-2K(b) molecules on the EL4 cell surface. Genetic manipulation of the T-lymphocyte repertoire was sufficient to reproduce the classic pattern of interactions between tumor cells and the immune system, usually observed in reliable syngeneic models of anti-tumor immunity. This newly-developed model could be used in further studies of immunoregulatory circuits common for transplantational and anti-tumor immune responses.

Splenocytes cultured in low concentrations of IL-2 generate NK cell specificities toward syngenic and allogenic targets

DEFF Research Database (Denmark)

Nissen, Mogens Holst; Jeppesen, M; Claesson, M H

2000-01-01

Splenocytes cultured in the presence of 30-60 units/ml IL-2 for 5 days develop natural killer activity toward syngeneic and allogeneic tumor cell targets. The IL-2 activated splenocytes, themselves, are partially resistant, whereas concanavalin A-activated T blast cells are completely resistant...... to killing. Surprisingly, major histocompatibility complex (MHC)-I-negative target cells are also resistant to natural killer (NK)-cell-mediated killing. Cells resistant to killing were unable to block NK-cell-mediated killing of sensitive targets as judged from cold target cell inhibition experiments......, and one type of target cells sensitive to killing did generally not cross-block killing of other killing-sensitive target cell types. Alloantigen exposure of splenocytes, i.e., one-way mixed lymphocyte cultures, partially prevents the development of NK-cell activity. Our data suggest that target...

Bovine Lactoferrin and Lactoferricin, a Peptide Derived from Bovine Lactoferrin, Inhibit Tumor Metastasis in Mice

Science.gov (United States)

Watanabe, Shikiko; Watanabe, Ryosuke; Hata, Katsusuke; Shimazaki, Kei–ichi; Azuma, Ichiro

1997-01-01

We investigated the effect of a bovine milk protein, lactoferrin (LF–B), and a pepsin–generated peptide of LF–B, lactoferricin (Lfcin–B), on inhibition of tumor metastasis produced by highly metastatic murine tumor cells, B16–BL6 melanoma and L5178Y–ML25 lymphoma cells, using experimental and spontaneous metastasis models in syngeneic mice. The subcutaneous (s.c.) administration of bovine apo–lactoferrin (apo–LF–B, 1 mg/mouse) and Lfcin–B (0.5 mg/monse) 1 day after tumor inoculation significantly inhibited liver and lung metastasis of L5178Y–ML25 cells. However, human apo–lactoferrin (apo–LF–H) and bovine holo–lactoferrin (holo–LF–B) at the dose of 1 mg/mouse failed to inhibit tumor metastasis of L5178Y–ML25 cells. Similarly, the s.c. administration of apo–LF–B as well as Lfcin–B, but not apo–LF–H and holo–LF–B, 1 day after tumor inoculation resulted in significant inhibition of lung metastasis of B16–BL6 cells in an experimental metastasis model. Furthermore, in in vivo analysis for tumor–induced angiogenesis, both apo–LF–B and Lfcin–B inhibited the number of tumor–induced blood vessels and suppressed tumor growth on day 8 after tumor inoculation. However, in a long–term analysis of tumor growth for up to 21 days after tumor inoculation, single administration of apo–LF–B significantly suppressed the growth of B16–BL6 cells throughout the examination period, whereas Lfcin–B showed inhibitory activity only during the early period (8 days). In spontaneous metastasis of B16–BL6 melanoma cells, multiple administration of both apo–LF–B and Lfcin–B into tumor–bearing mice significantly inhibited lung metastasis produced by B16–BL6 cells, though only apo–LF–B exhibited an inhibitory effect on tumor growth at the time of primary tumor amputation (on day 21) after tumor inoculation. These results suggest that apo–LF–B and Lfcin–B inhibit tumor metastasis through different

Schedule-dependency of doxorubicin and vinblastine in EAT tumours in mice

International Nuclear Information System (INIS)

Auersperg, M.; Pogacnik, A.; Kloboves-Prevodnik, V.; Sersa, G.; Cemazar, M.

2006-01-01

Background. Antitumour schedule-dependency of the doxorubicin and vinblastine combination was explored. Materials and methods. Intraperitoneal Ehrlich ascites tumours (EAT) syngeneic to CBA mice were treated with vinblastine or doxorubicin alone, or in combined treatment schedules. Results. Combinations of doxorubicin and vinblastine administered at 48-h, but not at 24-h interval, regardless of the sequence of drugs, significantly reduced the number of tumour cells in the ascites in comparison with all other treatments. In the combined treatment schedules, the predominant morphological changes as well as DNA distribution pattern were dependent on the first drug applied. Regardless of the sequence of the drugs, median survival times of animals did not significantly differ between the treatment groups. Conclusions. The effect of combination of vinblastine and doxorubicin is schedule-dependent. The time interval, but not the sequence of drugs seems to be crucial for the observed effect. The data from preclinical studies are important for planning combined treatment schedules in clinical setting. (author)

Grizzly bear

Science.gov (United States)

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).

Possible Involvement of Insulin Resistance in the Progression of Cancer Cachexia in Mice.

Science.gov (United States)

Ohsawa, Masahiro; Murakami, Tomoyasu; Kume, Kazuhiko

2016-01-01

Malnutrition is a common problem among cancer patients, affecting up to 85% of patients with certain cancers. In severe cases, malnutrition can progress to cachexia, a specific form of malnutrition characterized by loss of lean body mass and muscle wasting. Although this muscle wasting might be a product of enhanced protein degradation, the precise mechanisms of cancer cachexia are not fully elucidated. Based on basic and clinical research, glucose intolerance and insulin resistance have been postulated to be associated with cancer cachexia. Since insulin in the skeletal muscle inhibits protein degradation and promotes protein synthesis, insulin resistance could be a possible cause of cancer cachexia. Therefore, we investigated the involvement of insulin resistance in the development of cancer cachexia in tumor-bearing mice. The signaling protein in the insulin cascade was attenuated in the skeletal muscle and hypothalamus from tumor-bearing mice. We identified Chrysanthemum morifolium RAMAT., known as Kikuka, as a peroxisome proliferator-activated receptor γ (PPARγ) ligand. Treatment with Kikuka attenuates the skeletal muscle changes in tumor-bearing mice. These results suggest that this natural PPARγ activator might be an attractive candidate for the treatment of cancer cachexia. In the symposium, we presented the PPARγ activator-induced improvement of cancer cachexia.

Natural killer activity and suppressor cells in irradiated mice repopulated with a mixture of cells from normal and 89Sr-treated donors

International Nuclear Information System (INIS)

Levy, E.M.; Kumar, V.; Bennett, M.

1981-01-01

Mice that have been injected with 89 Sr have fairly normal B and T cell function, but are abnormal in that they lack natural killer (NK) activity and other functions that require an intact bone marrow. These mice also have an increased potential for suppressor cell activity. We had previously shown that spleen cells from 89 Sr-treated mice could transfer low NK activity and increased suppressor cell function to lethally irradiated syngeneic recipients. To investigate the mechanisms involved in perpetuating these defects, groups of normal spleen or bone marrow cells. Recipients were assayed for their NK activity and suppressor cell function 5 to 14 wk later. it was found that the addition of normal cells in the donor inoculum resulted in normal NK activity. This indicates that low NK activity in 89 Sr-treated mice was not due to the presence of a suppressor cell that prevented NK cell generation. It was additionally found that low NK activity in recipient mice could be boosted by interferon inducers. This would indicate that NK activity in the recipients was not due to a lack of interferon-sensitive pre-NK cells. Suppressor cell function in recipient mice depended on the type and number of normal cells in the donor inoculum. Bone marrow cells were very efficient in overcoming the tendency to produce suppressor cells. It took approximately 20 times more normal spleen cells to produce the same results. The implications of these findings are discussed

Possible Effect of 5, 6- Dimethyl -4 Isothiocyanate Thieno [2, 3-d] Pyrimidine and I or Irradiation on Ehrlich Carcinoma in Mice

International Nuclear Information System (INIS)

Mansour, S.Z.; Anis, L.M.

2010-01-01

Considerable attention has been devoted to the construction of new derivatives of [2,3-d] pyrimidines on the account of their reported biological activities. The aim of the present work is to evaluate the antitumour activity of 5, 6- dimethyl -4- isothiocyanate- thieno [2,3-d] pyrimidine (DMITCTP) in solid Ehrlich carcinoma (SEC) bearing mice. DMITCTP was administered on the 10th day after tumor inoculation at a dose of 150 mg/kg BW, day after day, during a period of 3 weeks. Whole body exposure to one dose of 2Gy gamma irradiation was carried out two weeks after DMITCTP administration. Biochemical analysis in the blood of solid Ehrlich carcinoma (SEC) bearing mice showed significant increase in MDA content and GSH-Px activity level a significant decrease in GSH content and SOD activity level, IL 10 concentration and TNF- α concentration was detected associated with significant alteration in kidney and liver functions, as compared to control. Administration of DMITCTP alone or in combination with gamma-irradiation has significantly decrease MDA content and GSH-Px activity level associated with significant increase in GSH content, SOD activity level, IL-10 concentration and TNF-a concentration, compared to SEC bearing mice. These results supported by significant improvement in liver and kidney functions. Treatment solid Ehrlich carcinoma (SEC) bearing mice with gamma-irradiation or DMITCTP combined with y-irradiation showed significant increase in MDA content, GSH-Px and GST activities levels and in amount of metabolites of CYP450 and significant decrease in GSH content, and SOD activity level, as compared to SEC bearing mice. Administration of DMITCTP alone or combined with gamma- irradiation has significantly decreased tumor volume

Suppressive versus augmenting effect of the same pretreatment regimen in two murine tumor systems with distinct effector mechanisms

International Nuclear Information System (INIS)

Fujiwara, Hiromi; Hamaoka, Toshiyuki; Kitagawa, Masayasu

1978-01-01

The effect of presensitization with x-irradiated tumor cells on the development of host's immune resistance against the tumor-associated transplantation antigens (TATA) was investigated in two syngeneic tumor systems with distinct effector mechanisms. When X5563 plasmacytoma, to which immune resistance was mediated exclusively by killer T lymphocytes, was intravenously inoculated into syngeneic C3H/He mice with lower number after 7000 R x-irradiation, the mice failed to exhibit any protective immunity against the subsequent challenge with viable tumor cells. Moreover, these mice lost their capability to develop any immune resistance even after an appropriate immunization procedure. The immunodepression induced by such a pretreatment regimen was specific for X5563 tumor. While no suppressor cell activity was detected in the above pretreated mice, serum factor(s) from these mice was virtually responsible for this suppression. When the serum factor mediating this tumor-specific suppression was fractionated on the Sephadex G-200 column, the suppressive activity was found in albumin-corresponding fraction, free of any immunoglobulin component. In contrast, in MM102 mammary tumor system, in which immune resistance is solely mediated by tumor-specific antibody, the pretreatment with x-irradiated MM102 cells augmented the induction of anti-tumor immunity. These results indicate that while tumor antigens given in the form of x-irradiated tumor cells suppress the induction of killer T cell-mediated immunity in one system, the same presensitization regimen of tumor antigens augments the antibody-mediated immunity in another system, thus giving a divergent effect on the distinct effector mechanisms of syngeneic tumor immunity. (author)

Combined effect of aerobic interval training and selenium nanoparticles on expression of IL-15 and IL-10/TNF-α ratio in skeletal muscle of 4T1 breast cancer mice with cachexia.

Science.gov (United States)

Molanouri Shamsi, M; Chekachak, S; Soudi, S; Quinn, L S; Ranjbar, K; Chenari, J; Yazdi, M H; Mahdavi, M

2017-02-01

Cancer cachexia is characterized by inflammation, loss of skeletal muscle and adipose tissue mass, and functional impairment. Oxidative stress and inflammation are believed to regulate pathways controlling skeletal muscle wasting. The aim of this study was to determine the effects of aerobic interval training and the purported antioxidant treatment, selenium nanoparticle supplementation, on expression of IL-15 and inflammatory cytokines in 4T1 breast cancer-bearing mice with cachexia. Selenium nanoparticle supplementation accelerated cachexia symptoms in tumor-bearing mice, while exercise training prevented muscle wasting in tumor-bearing mice. Also, aerobic interval training enhanced the anti-inflammatory indices IL-10/TNF-α ratio and IL-15 expression in skeletal muscle in tumor-bearing mice. However, combining exercise training and antioxidant supplementation prevented cachexia and muscle wasting and additionally decreased tumor volume in 4T1 breast cancer mice. These finding suggested that combining exercise training and antioxidant supplementation could be a strategy for managing tumor volume and preventing cachexia in breast cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

77 FR 70423 - Black Bear Hydro Partners, LLC and Black Bear Development Holdings, LLC and Black Bear SO, LLC...

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2012-11-26

... Bear Hydro Partners, LLC and Black Bear Development Holdings, LLC and Black Bear SO, LLC; Notice of..., 2012, Black Bear Hydro Partners, LLC, sole licensee (transferor) and Black Bear Development Holdings, LLC and Black Bear SO, LLC (transferees) filed an application for the partial the transfer of licenses...

Labeling transplanted mice islet with polyvinylpyrrolidone coated superparamagnetic iron oxide nanoparticles for in vivo detection by magnetic resonance imaging

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Huang Hai; Xie Qiuping; Kang Muxing; Zhang Bo; Wu Yulian [Department of Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 (China); Zhang Hui; Chen Jin; Zhai Chuanxin; Yang Deren [State Key Lab of Silicon Materials and Department of Materials Science and Engineering, Zhejiang University, Hangzhou 310027 (China); Jiang Biao, E-mail: wuyulian@medmail.com.c, E-mail: yulianwu2003@yahoo.c [Department of Radiology, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 (China)

2009-09-09

Superparamagnetic iron oxide nanoparticles (SPIO) are emerging as a novel probe for noninvasive cell tracking with magnetic resonance imaging (MRI) and have potential wide usage in medical research. In this study, we have developed a method using high-temperature hydrolysis of chelate metal alkoxide complexes to synthesize polyvinylpyrrolidone coated iron oxide nanoparticles (PVP-SPIO), as a biocompatible magnetic agent that can efficiently label mice islet {beta}-cells. The size, crystal structure and magnetic properties of the as-synthesized nanoparticles have been characterized. The newly synthesized PVP-SPIO with high stability, crystallinity and saturation magnetization can be efficiently internalized into {beta}-cells, without affecting viability and function. The imaging of 100 PVP-SPIO-labeled mice islets in the syngeneic renal subcapsular model of transplantation under a clinical 3.0 T MR imager showed high spatial resolution in vivo. These results indicated the great potential application of the PVP-SPIO as an MRI contrast agent for monitoring transplanted islet grafts in the clinical management of diabetes in the near future.

Labeling transplanted mice islet with polyvinylpyrrolidone coated superparamagnetic iron oxide nanoparticles for in vivo detection by magnetic resonance imaging

International Nuclear Information System (INIS)

Huang Hai; Xie Qiuping; Kang Muxing; Zhang Bo; Wu Yulian; Zhang Hui; Chen Jin; Zhai Chuanxin; Yang Deren; Jiang Biao

2009-01-01

Superparamagnetic iron oxide nanoparticles (SPIO) are emerging as a novel probe for noninvasive cell tracking with magnetic resonance imaging (MRI) and have potential wide usage in medical research. In this study, we have developed a method using high-temperature hydrolysis of chelate metal alkoxide complexes to synthesize polyvinylpyrrolidone coated iron oxide nanoparticles (PVP-SPIO), as a biocompatible magnetic agent that can efficiently label mice islet β-cells. The size, crystal structure and magnetic properties of the as-synthesized nanoparticles have been characterized. The newly synthesized PVP-SPIO with high stability, crystallinity and saturation magnetization can be efficiently internalized into β-cells, without affecting viability and function. The imaging of 100 PVP-SPIO-labeled mice islets in the syngeneic renal subcapsular model of transplantation under a clinical 3.0 T MR imager showed high spatial resolution in vivo. These results indicated the great potential application of the PVP-SPIO as an MRI contrast agent for monitoring transplanted islet grafts in the clinical management of diabetes in the near future.

Phylogeography of mitochondrial DNA variation in brown bears and polar bears.

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Shields, G F; Adams, D; Garner, G; Labelle, M; Pietsch, J; Ramsay, M; Schwartz, C; Titus, K; Williamson, S

2000-05-01

We analyzed 286 nucleotides of the middle portion of the mitochondrial cytochrome b gene of 61 brown bears from three locations in Alaska and 55 polar bears from Arctic Canada and Arctic Siberia to test our earlier observations of paraphyly between polar bears and brown bears as well as to test the extreme uniqueness of mitochondrial DNA types of brown bears on Admiralty, Baranof, and Chichagof (ABC) islands of southeastern Alaska. We also investigated the phylogeography of brown bears of Alaska's Kenai Peninsula in relation to other Alaskan brown bears because the former are being threatened by increased human development. We predicted that: (1) mtDNA paraphyly between brown bears and polar bears would be upheld, (2) the mtDNA uniqueness of brown bears of the ABC islands would be upheld, and (3) brown bears of the Kenai Peninsula would belong to either clade II or clade III of brown bears of our earlier studies of mtDNA. All of our predictions were upheld through the analysis of these additional samples. Copyright 2000 Academic Press.

Phylogeography of mitochondrial DNA variation in brown bears and polar bears

Science.gov (United States)

Shields, Gerald F.; Adams, Deborah; Garner, Gerald W.; Labelle, Martine; Pietsch, Jacy; Ramsay, Malcolm; Schwartz, Charles; Titus, Kimberly; Williamson, Scott

2000-01-01

We analyzed 286 nucleotides of the middle portion of the mitochondrial cytochrome b gene of 61 brown bears from three locations in Alaska and 55 polar bears from Arctic Canada and Arctic Siberia to test our earlier observations of paraphyly between polar bears and brown bears as well as to test the extreme uniqueness of mitochondrial DNA types of brown bears on Admiralty, Baranof, and Chichagof (ABC) islands of southeastern Alaska. We also investigated the phylogeography of brown bears of Alaska's Kenai Peninsula in relation to other Alaskan brown bears because the former are being threatened by increased human development. We predicted that: (1) mtDNA paraphyly between brown bears and polar bears would be upheld, (2) the mtDNA uniqueness of brown bears of the ABC islands would be upheld, and (3) brown bears of the Kenai Peninsula would belong to either clade II or clade III of brown bears of our earlier studies of mtDNA. All of our predictions were upheld through the analysis of these additional samples.

Short-term modern life-like stress exacerbates Aβ-pathology and synapse loss in 3xTg-AD mice.

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Baglietto-Vargas, David; Chen, Yuncai; Suh, Dongjin; Ager, Rahasson R; Rodriguez-Ortiz, Carlos J; Medeiros, Rodrigo; Myczek, Kristoffer; Green, Kim N; Baram, Tallie Z; LaFerla, Frank M

2015-09-01

Alzheimer's disease (AD) is a progressive neurological disorder that impairs memory and other cognitive functions in the elderly. The social and financial impacts of AD are overwhelming and are escalating exponentially as a result of population aging. Therefore, identifying AD-related risk factors and the development of more efficacious therapeutic approaches are critical to cure this neurological disorder. Current epidemiological evidence indicates that life experiences, including chronic stress, are a risk for AD. However, it is unknown if short-term stress, lasting for hours, influences the onset or progression of AD. Here, we determined the effect of short-term, multi-modal 'modern life-like' stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aβ levels by augmenting AβPP processing. Thus, short-term stress simulating modern-life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers. Epidemiological evidence indicates that life experiences, including chronic stress, are a risk for Alzheimer disease (AD). However, it is unknown if short stress in the range of hours influences the onset or progression of AD. Here, we determined the effect of short, multi-modal 'modern-lifelike'stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aβ levels by

Regeneration of hemopoietic precursor cells in spleen organ cultures from irradiated mice: influence of genotype of cells injected and of the spleen microenvironment

International Nuclear Information System (INIS)

von Melchner, H.; Lieschke, G.J.

1981-01-01

The regeneration of hemopoietic precursor cells was monitored in spleen organ cultures from lethally irradiated mice injected with 10(7) normal syngeneic or allogeneic bone marrow cells. The important role of the microenvironment in supporting hemopoiesis was confirmed by the failure of mutant Sl/Sld spleens to support CFC regeneration in organ cultures. However, the extent and quality of the CFC regeneration was clearly dependent on the genetic properties of the injected cells. Evidence for this was obtained from the regeneration patterns of various CFC types in organ cultured spleens derived from different mouse donor-recipient strain combinations that maintained the differences in the bone marrow frequency of various CFC types characteristic of the donor strain

Suppression of humoral response during the course of Candida albicans infection in mice.

Science.gov (United States)

Valdez, J C; Meson, O E; de Valdez, G A; Sirena, A

1984-10-30

This paper aims at demonstrating the non-specific immunosuppression as regards thyme-dependent antigens sheep erythrocytes (SRBC) during the course of Candida albicans systemic infection. Three lots of syngeneic/BALB/c mice, 8-12 weeks of age, were used. The first normal lot was inoculated via the intraperitoneal route with a (SRBC) suspension (4 X 10(8) cells ml) in a Hank's balanced saline solution. The primary response of antibodies formed by splenic cells was measured from 4 to 8 days after inoculation using the direct plaque forming cells technique. The second lot was infected by the same route with a suspension of Candida albicans (1 X 10(7) cells). Positive retrocultures from the blood and kidneys of these infected mice were obtained. These yeasts cultivated in a Sabouraud medium were harvested after 20 h at 37 degrees C. Following the same methodology the immune response to SRBC was determined. The serum obtained from infected mice was transferred to a third lot of mice at different intervals during the course of the infection. The immune response to SRBC was done by the direct plaque-forming cells technique. Controls were carried out using normal donors and recipients. A suppression of the immune response was obtained as from the 2nd day of inoculation up to the 28th day. It was not possible to transfer such suppression passively by means of the serum. These results suggest that the systemic infection by Candida albicans induce a non-specific immunosuppression in the organism, already demonstrated in viral infections, bacteria, protozoaria and metazoaria in mammals. In some way, this will contribute to explain the mechanisms of immune response to Candida albicans.

An immunological analysis of natural resistance to moise hepatitis virus (JHMV strain) infection in C3H mice

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Pereira, C A; Pickel, K [Wurzburg Univ. (Germany, F.R.). Inst. fuer Virologie und Immunbiologie

1987-01-01

Since the development of resistance against mouse hepatitis virus (JHMV strain) coincides with the maturation of the immune system, we studied the possible role of distinct immunological components in the resistance of adult mice during JHMV infection. Adult C3H mice naturally resistant to JHMV were rendered susceptible to infection by lethal {sup 60}Co-irradiation and were subsequently reconstituted with limiting numbers of syngeneic bone marrow cells or spleen cells. Resistance or susceptibility dependend on the number of cells used for reconstitution and the interval between reconsitution and infection. Spleen cells from suckling mice affected neither resistance nor susceptibility and peritoneal cells from adult mice and thymus cells reduced resistance. Persistence of JHMV was demonstrated by virus reactivation. Animals infected with JHMV only once before being rendered immunoincompetent showed a different pattern of resistance. One to four months after infection, 15 to 35% of the animals died after reconstitution without having been reinfected, and persisting JHMV was found in their liver, spleen and peritoneal exudate. The survivors (47 to 87%) were resistant to further JHMV infection during immunodeficiency. Animals immunized 3 times with JHMV before irradiation did not show virus reactivation and were fully resistant to JHMV reinfection after reconstitution. The level of neutralizing anti JHMV serum antibodies in the group of mice immunized only once was comparable with the level of those immunized 3 times. The role of macrophage activation and cell-mediated immunity in this model are discused as an explanation for the resistance to, and persistence of, JHMV. (author).

An immunological analysis of natural resistance to moise hepatitis virus (JHMV strain) infection in C3H mice

International Nuclear Information System (INIS)

Pereira, C.A.; Pickel, K.

1987-01-01

Since the development of resistance against mouse hepatitis virus (JHMV strain) coincides with the maturation of the immune system, we studied the possible role of distinct immunological components in the resistance of adult mice during JHMV infection. Adult C3H mice naturally resistant to JHMV were rendered susceptible to infection by lethal 60 Co-irradiation and were subsequently reconstituted with limiting numbers of syngeneic bone marrow cells or spleen cells. Resistance or susceptibility dependend on the number of cells used for reconstitution and the interval between reconsitution and infection. Spleen cells from suckling mice affected neither resistance nor susceptibility and peritoneal cells from adult mice and thymus cells reduced resistance. Persistence of JHMV was demonstrated by virus reactivation. Animals infected with JHMV only once before being rendered immunoincompetent showed a different pattern of resistance. One to four months after infection, 15 to 35% of the animals died after reconstitution without having been reinfected, and persisting JHMV was found in their liver, spleen and peritoneal exudate. The survivors (47 to 87%) were resistant to further JHMV infection during immunodeficiency. Animals immunized 3 times with JHMV before irradiation did not show virus reactivation and were fully resistant to JHMV reinfection after reconstitution. The level of neutralizing anti JHMV serum antibodies in the group of mice immunized only once was comparable with the level of those immunized 3 times. The role of macrophage activation and cell-mediated immunity in this model are discused as an explanation for the resistance to, and persistence of, JHMV. (author) [pt

Protective immunization with B16 melanoma induces antibody response and not cytotoxic T cell response

International Nuclear Information System (INIS)

Sarzotti, M.; Sriyuktasuth, P.; Klimpel, G.R.; Cerny, J.

1986-01-01

C57BL/6 mice immunized with three intraperitoneal injections of syngeneic, irradiated B16 melanoma cells, became resistant to B16 tumor challenge. Immunized mice had high levels of serum antibody against a membrane antigen of B16 cells. The B16 antigen recognized by the anti-B16 sera formed a major band of 90 KD in gel electrophoresis. The anti-B16 antibody was partially protective when mixed with B16 cells and injected into normal recipient mice. Surprisingly, B16 resistance mice were incapable of generating cytotoxic T cells (CTL) specific for the B16 tumor. Both spleen and lymph node cell populations from immunized mice did not generate B16-specific CTL. Allogeneic mice (DBA/2 or C3H) were also unable to generate B16-specific CTL: however, alloreactive CTL produced in these strains of mice by immunization with C57BL/6 lymphocytes, did kill B16 target cells. Interestingly, spleen cells from syngeneic mice immunized with B16 tumor produced 6-fold more interleukin-2 (IL-2) than normal spleen cells, in vitro. These data suggest that immunization with B16 tumor activates a helper subset of T cells (for antibody and IL-2 production) but not the effector CTL response

Introgressive hybridization: brown bears as vectors for polar bear alleles.

Science.gov (United States)

Hailer, Frank

2015-03-01

The dynamics and consequences of introgression can inform about numerous evolutionary processes. Biologists have therefore long been interested in hybridization. One challenge, however, lies in the identification of nonadmixed genotypes that can serve as a baseline for accurate quantification of admixture. In this issue of Molecular Ecology, Cahill et al. (2015) analyse a genomic data set of 28 polar bears, eight brown bears and one American black bear. Polar bear alleles are found to be introgressed into brown bears not only near a previously identified admixture zone on the Alaskan Admiralty, Baranof and Chichagof (ABC) Islands, but also far into the North American mainland. Elegantly contrasting admixture levels at autosomal and X chromosomal markers, Cahill and colleagues infer that male-biased dispersal has spread these introgressed alleles away from the Late Pleistocene contact zone. Compared to a previous study on the ABC Island population in which an Alaskan brown bear served as a putatively admixture-free reference, Cahill et al. (2015) utilize a newly sequenced Swedish brown bear as admixture baseline. This approach reveals that brown bears have been impacted by introgression from polar bears to a larger extent (up to 8.8% of their genome), than previously known, including the bear that had previously served as admixture baseline. No evidence for introgression of brown bear into polar bear is found, which the authors argue could be a consequence of selection. Besides adding new exciting pieces to the puzzle of polar/brown bear evolutionary history, the study by Cahill and colleagues highlights that wildlife genomics is moving from analysing single genomes towards a landscape genomics approach. © 2015 John Wiley & Sons Ltd.

Characterization of a water-soluble polysaccharide from Boletus edulis and its antitumor and immunomodulatory activities on renal cancer in mice.

Science.gov (United States)

Wang, Dong; Sun, Shu-Qing; Wu, Wei-Zhen; Yang, Shun-Liang; Tan, Jian-Ming

2014-05-25

A polysaccharide (BEP, Mw=113,432Da) was purified from Boletus edulis, which had a backbone consisting of (1→6)-linked-α-d-glucopyranosyl, (1→2,6)-linked-α-d-galactopyranosyl, (1→6)-linked-α-d-galactopyranosyl, and (1→3)-linked-α-d-rhamnopyranosyl residues, which were branched at O-2 position of (1→2,6)-linked-α-d-galactopyranosyl residue with a single terminal (1→)-linked-α-l-arabinofuranosyl residue. After 32 days' BEP administration to Renca tumor bearing mice, the tumor mass of Renca transplanted in mice was significantly repressed. Furthermore, BEP could significantly increase the spleen and thymus indices, stimulate splenocytes proliferation, augment NK cell and CTL activities in spleen, and promote the secretion of the cytokines IL-2 and TNF-α in Renca tumor bearing mice. Meanwhile oral administration of BEP (100 and 400mg/kg) restored all the altered hematological and biochemical parameters of tumor-bearing mice to normal levels. Thus, these data demonstrate that BEP possesses potential immunomodulatory activity and might be employed as effective therapeutic agents for the prevention of renal caner. Copyright © 2014 Elsevier Ltd. All rights reserved.

In vivo assessment of 111In-labeled hematoporphyrin derivative in breast tumor-bearing animals

International Nuclear Information System (INIS)

Wong, D.W.; Mandal, Ashis; Brown, Jerry; Reese, I.C.; Siegler, Richard; Hyman, Shigeyo

1989-01-01

The biological behavior of 111 In-labeled HPD has been investigated in tumor-bearing animals. Mice mammary adenocarcinomas and 7,12-dimethylbenz(a)anthracine induced breast tumors in Sprague-Dawley female rats were clearly visualized by 111 In-HPD nuclear scintigraphy. Optimal scans were obtained after a 48 h delay. In normal and tumor-bearing animals, the highest uptake of 111 In-HPD 72 h post-injection was found in the liver, the spleen and the kidneys. Depending on the size and the extent of necrosis, the uptake of 111 In-HPD by malignant breast tumors varied from 2.5% injected dose (ID) in mice to 1% ID in rats. Benign breast tumor uptake of 111 In-HPD was less than 1% ID. No significant amount of the radiopharmaceutical was found in pulmonary abscesses and abdominal cysts. Scintigrams of these infectious or inflammatory lesions were normal. Malignant tumor to blood, heart and lung ratios averaged 50:1, 10:1 and 3:1 respectively. Tumor to brain ratio ranged from 72 to 444:1. (author)

Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice.

Science.gov (United States)

Urzua, Ulises; Chacon, Carlos; Lizama, Luis; Sarmiento, Sebastián; Villalobos, Pía; Kroxato, Belén; Marcelain, Katherine; Gonzalez, María-Julieta

2017-10-01

Aging intersects with reproductive senescence in women by promoting a systemic low-grade chronic inflammation that predisposes women to several diseases including ovarian cancer (OC). OC risk at menopause is significantly modified by parity records during prior fertile life. To date, the combined effects of age and parity on the systemic inflammation markers that are particularly relevant to OC initiation and progression at menopause remain largely unknown. Herein, we profiled a panel of circulating cytokines in multiparous versus virgin C57BL/6 female mice at peri-estropausal age and investigated how cytokine levels were modulated by intraperitoneal tumor induction in a syngeneic immunocompetent OC mouse model. Serum FSH, LH and TSH levels increased with age in both groups while prolactin (PRL) was lower in multiparous respect to virgin mice, a finding previously observed in parous women. Serum CCL2, IL-10, IL-5, IL-4, TNF-α, IL1-β and IL-12p70 levels increased with age irrespective of parity status, but were specifically reduced following OC tumor induction only in multiparous mice. Animals developed hemorrhagic ascites and tumor implants in the omental fat band and other intraperitoneal organs by 12 weeks after induction, with multiparous mice showing a significantly extended survival. We conclude that previous parity history counteracts aging-associated systemic inflammation possibly by reducing the immunosuppression that typically allows tumor spread. Results suggest a partial impairment of the M2 shift in tumor-associated macrophages as well as decreased stimulation of regulatory B-cells in aged mice. This long term, tumor-concurrent effect of parity on inflammation markers at menopause would be a contributing factor leading to decreased OC risk.

Supplementation of Magnolol Attenuates Skeletal Muscle Atrophy in Bladder Cancer-Bearing Mice Undergoing Chemotherapy via Suppression of FoxO3 Activation and Induction of IGF-1.

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Meng-Chuan Chen

Full Text Available Skeletal muscle atrophy, the most prominent phenotypic feature of cancer cachexia, is often observed in cancer patients undergoing chemotherapy. Magnolol (M extracted from Magnolia officinalis exhibits several pharmacological effects including anti-inflammatory and anticancer activities. In this study, we investigated whether magnolol supplementation protects against the development of cachexia symptoms in bladder cancer-bearing mice undergoing chemotherapy. Combined treatment of magnolol with chemotherapeutic drugs, such as gemcitabine and cisplatin (TGCM or gemcitabine (TGM, markedly attenuates the body weight loss and skeletal muscle atrophy compared with conventional chemotherapy (TGC. The antiatrophic effect of magnolol may be associated with inhibition of myostatin and activin A formation, as well as FoxO3 transcriptional activity resulting from Akt activation, thereby suppressing ubiquitin ligases MuRF-1 and MAFbx/atrogin-1 expression, as well as proteasomal enzyme activity. Notably, magnolol-induced insulin-like growth factor 1 (IGF-1 production and related protein synthesis may also contribute to its protective effects. The decreased food intake, and intestinal injury and dysfunction observed in the mice of TGC group were significantly improved in the TGCM and TGM groups. Moreover, the increased inflammatory responses evidenced by elevation of proinflammatory cytokine formation and NF-κB activation occurred in the atrophying muscle of TGC group were markedly inhibited in mice of combined treatment with magnolol. In summary, these findings support that magnolol is a promising chemopreventive supplement for preventing chemotherapy-induced skeletal muscle atrophy associated with cancer cachexia by suppressing muscle protein degradation, and inflammatory responses, as well as increasing IGF-1-mediated protein synthesis.

Radioresistant CD4+ T cells in normal, unprimed mice, with verification of the Bergonie-Tribondeau law

International Nuclear Information System (INIS)

Makidono, Reiko; Ito, Akira.

1997-01-01

This is the first report on radioresistant CD4+ T cells found in normal, unprimed mice. After sublethal whole body irradiation, regular CD4+ as well as primitive NK1.1+ CD4+ T cells were enriched in the spleen. Since it has been well established that virgin T and B cells are highly radiosensitive, these cells were once assumed to be a unique lymphocyte population for which radiosensitivity does not follow the general law of radiation sensitivity for mammalian cells (Bergonie-Tribondeau law). These cells exhibited higher proliferative response to accessory cells than the non-irradiated control cells in the syngeneic mixed leukocyte reaction (SMLR). This indicated that virgin CD4+ T cells sensitized to, and readily respond to self-MHC class II molecules are radioresistant, and that their radioresistance, as activated cells, is consistent with the Bergonie-Tribondeau law. (author)

Negligible colon cancer risk from food-borne acrylamide exposure in male F344 rats and nude (nu/nu mice-bearing human colon tumor xenografts.

Directory of Open Access Journals (Sweden)

Jayadev Raju

Full Text Available 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.

Protective specific immunity induced by doxorubicin plus TNF-alpha combination treatment of EL4 lymphoma-bearing C57BL/6 mice.

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Ehrke, M J; Verstovsek, S; Maccubbin, D L; Ujházy, P; Zaleskis, G; Berleth, E; Mihich, E

2000-07-01

The therapeutic efficacy of a single (day 8), moderate dose (4 mg/kg, i.v.) of doxorubicin (DOX, Adriamycin) combined with recombinant human TNF-alpha (3 different doses and 5 different schedules, i.v.) was evaluated in C57BL/6 mice bearing an implant (s.c.) of the DOX-sensitive, TNF-alpha-resistant EL4 lymphoma. In parallel to monitoring survival, the levels of several host anti-tumor cytolytic effector functions of splenocytes and thymocytes were evaluated throughout the treatment period and in long-term survivors (LTS). DOX treatment alone resulted in a moderate (approx. 20%) increase in life span but no cures. TNF-alpha alone, at any tested dose or schedule, had little or no positive effect on survival. The combinations of DOX and TNF-alpha were only slightly better than DOX alone with respect to the time to death of mice that died (approx. 29% increase); however, each of the combinations involving 1,000 U TNF-alpha/injection produced a fraction (20% to 80%) of LTS. The host defense activities examined included those of splenic and thymic cytolytic T lymphocytes (CTL) and lymphokine-activated killer cells as well as splenic tumoricidal macrophages. Although most activities were modulated by tumor growth and/or treatment, only CTL responsiveness appeared to correlate with survival. CTL activity in the treated groups with LTS was significantly higher than in control groups late in the treatment period. Finally, ex vivo analyses of splenocytes and thymocytes together with the rejection of implanted tumor at 17 months established that LTS displayed specific long-term immune memory. Copyright 2000 Wiley-Liss, Inc.

Functional antigen binding by the defective B cells of CBA/N mice.

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Snippe, H; Merchant, B; Lizzio, E F; Inman, J K

1982-01-01

CBA/N mice have an X-linked B cell defect which prevents them from responding to nonmitogenic thymic independent (TI-2) antigens such as dinitrophenylated DNP-Ficoll (1,2). The F1 male progeny of CBA/N female mice express the same defect. Spleen cell suspensions from such defective mice (CBA/N X C3H/HeN F1 males) could not respond to DNP-Ficoll following in vitro immunization and subsequent transfer into irradiated, syngeneic, F1 male recipients as expected. In contrast, normal CBA/N X C3H/HeN F1 female spleen cells could respond and effect a "rescue"; they mounted strong plaque-forming cell responses 7 days after in vitro exposure to DNP-Ficoll and subsequent transfer into irradiated F1 male recipients. Defective F1 male spleen cells, however, could bind significant quantities of 125I-DNP-Ficoll after in vitro exposure. Extensive washing of these spleen cells could not reverse this binding. Such DNP-Ficoll-exposed and washed F1 male spleen cells could, after transfer, aid normal untreated F1 female cells in their rescue function. The defective F1 male spleen cells could convey immunogenic quantities of DNP-Ficoll to the "rescuing" F1 female cells. Mitomycin treatment of F1 male cells did not interfere with their conveyor function. Goat anti-mouse mu serum impeded the passive antigen conveyor function of defective F1 male cells as did prior exposure to high concentrations of free DNP hapten. Our data support the view that the B cell defect of CBA/N X C3H/HeN F1 male mice does not relate to antigen binding, but rather to an inability to be effectively triggered by certain cell-bound polymeric antigens.

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

Directory of Open Access Journals (Sweden)

Fakhry S. Salem

2011-01-01

Full Text Available 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.

The influence of whole body 60Co-irradiation on distribution of 67Ga in tumor-bearing mice

International Nuclear Information System (INIS)

Wakao, Hiromi; Shimura, Akira; Higashi, Tomomitsu

1981-01-01

Since the initial findings that 67 Ga has a preferential affinity for soft tissue tumors, in humans numerous suggestions have been advanced for the basic mechanism involved. The effects produced by whole-body X-irradiation on the excretion and tissue distribution of 67 Ga have been reported by Swartzendruber and others. Bradley and coworkers have shown that these irradiation effects were associated with an increase in serum iron. The present investigation was undertaken in order to study the relationships between the change in the serum iron concentration and 67 Ga accumulation in the tumor and soft tissues in mice bearing Ehrlich's ascites tumor. The following results were obtained. (1) The serum iron concentration was significantly decreased between 3 and 6 hours after 10 Gy (1,000 rad) dose of whole-body 60 Co-irradiation. Subsequently, the serum iron levels were slowly elevated. (2) The uptake of 67 Ga in the tumor and soft tissues was increased if the serum iron concentration was decreased by whole-body 60 Co-irradiation during the early phase. On the contrary, if the serum iron concentration was high, the uptake of 67 Ga in the tumor was decreased. (3) The excretion of 67 Ga from the body was delayed if the serum iron concentration was decreased by whole-body 60 Co-irradiation. However, if the serum iron concentration was high, the excretion of 67 Ga from the body significantly increased. (author)

The Spleen Is an Ideal Site for Inducing Transplanted Islet Graft Expansion in Mice.

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Takeshi Itoh

Full Text Available Alternative islet transplantation sites have the potential to reduce the marginal number of islets required to ameliorate hyperglycemia in recipients with diabetes. Previously, we reported that T cell leukemia homeobox 1 (Tlx1+ stem cells in the spleen effectively regenerated into insulin-producing cells in the pancreas of non-obese diabetic mice with end-stage disease. Thus, we investigated the spleen as a potential alternative islet transplantation site. Streptozotocin-induced diabetic C57BL/6 mice received syngeneic islets into the portal vein (PV, beneath the kidney capsule (KC, or into the spleen (SP. The marginal number of islets by PV, KC, or SP was 200, 100, and 50, respectively. Some plasma inflammatory cytokine levels in the SP group were significantly lower than those of the PV group after receiving a marginal number of islets, indicating reduced inflammation in the SP group. Insulin contents were increased 280 days after islet transplantation compared with those immediately following transplantation (p<0.05. Additionally, Tlx1-related genes, including Rrm2b and Pla2g2d, were up-regulated, which indicates that islet grafts expanded in the spleen. The spleen is an ideal candidate for an alternative islet transplantation site because of the resulting reduced inflammation and expansion of the islet graft.

Suppression of a thymus dependent humoral response in mice by Concanavalin A in vivo

International Nuclear Information System (INIS)

Egan, H.S.; Ekstedt, R.D.

1975-01-01

Mice treated with Concanavalin A prior to immunization with sheep erthyrocytes exhibit a markedly reduced plaque forming spleen cell response. This immunosuppressive effect could be reversed by using higher doses of antigen or priming the animals with nonimmunizing doses of antigen prior to Concanavalin A injection designed to either by-pass or enhance thymus derived lymphocyte functions. It was also demonstrated that Concanavalin A in vivo activated the thymus derived lymphocyte subpopulation in the spleen, and this activation was dose dependent and correlated with the immunosuppression observed. Animals injected with Concanavalin A at various times prior to whole body lethal irradiation would not support the plaque forming cell response of adoptively transferred normal syngeneic spleen cells. This effect was shown to be time and dose of Concanavalin A dependent. It was also shown that the route of injection of Concanavalin A prior to irradiation determined the results observed, in that the intravenous route resulted in the suppression of transferred cells, while the intraperitoneal route showed no effect. It is suggested that Concanavalin A induced immunosuppression of the humoral, thymus dependent immune response in mice results for the activation of a subpopulation of thymus derived suppressors cells, and that the effect is short lived, radiation resistant, and dose of Concanavalin A and antigen dependent

Endocrine therapy of human breast cancer grown in nude mice

DEFF Research Database (Denmark)

Brünner, N; Osborne, C K; Spang-Thomsen, M

1987-01-01

mice bearing transplanted human breast tumors have been proposed as such a model. This review therefore discusses the use of the athymic nude mouse model of the study of human breast cancer biology, and focuses on four subjects: 1. biological characteristics of heterotransplanted breast tumors; 2...

Expression of DAI by an oncolytic vaccinia virus boosts the immunogenicity of the virus and enhances antitumor immunity

Directory of Open Access Journals (Sweden)

Mari Hirvinen

2016-01-01

Full Text Available In oncolytic virotherapy, the ability of the virus to activate the immune system is a key attribute with regard to long-term antitumor effects. Vaccinia viruses bear one of the strongest oncolytic activities among all oncolytic viruses. However, its capacity for stimulation of antitumor immunity is not optimal, mainly due to its immunosuppressive nature. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI to boost the innate immune system and to activate adaptive immune cells in the tumor. We showed that infection with DAI-expressing VV increases expression of several genes related to important immunological pathways. Treatment with DAI-armed VV resulted in significant reduction in the size of syngeneic melanoma tumors in mice. When the mice were rechallenged with the same tumor, DAI-VV-treated mice completely rejected growth of the new tumor, which indicates immunity established against the tumor. We also showed enhanced control of growth of human melanoma tumors and elevated levels of human T-cells in DAI-VV-treated mice humanized with human peripheral blood mononuclear cells. We conclude that expression of DAI by an oncolytic VV is a promising way to amplify the vaccine potency of an oncolytic vaccinia virus to trigger the innate—and eventually the long-lasting adaptive immunity against cancer.

Fibromodulin deficiency reduces collagen structural network but not glycosaminoglycan content in a syngeneic model of colon carcinoma.

Science.gov (United States)

Olsson, P Olof; Kalamajski, Sebastian; Maccarana, Marco; Oldberg, Åke; Rubin, Kristofer

2017-01-01

Tumor barrier function in carcinoma represents a major challenge to treatment and is therefore an attractive target for increasing drug delivery. Variables related to tumor barrier include aberrant blood vessels, high interstitial fluid pressure, and the composition and structure of the extracellular matrix. One of the proteins associated with dense extracellular matrices is fibromodulin, a collagen fibrillogenesis modulator expressed in tumor stroma but scarce in normal loose connective tissues. Here, we investigated the effects of fibromodulin on stroma ECM in a syngeneic murine colon carcinoma model. We show that fibromodulin deficiency decreased collagen fibril thickness but glycosaminoglycan content and composition were unchanged. Furthermore, vascular density, pericyte coverage and macrophage amount were unaffected. Fibromodulin can therefore be a unique effector of dense collagen matrix assembly in tumor stroma and, without affecting other major matrix components or the cellular composition, can function as a main agent in tumor barrier function.

Antitumour and Antioxidant Activities of Activin in Kidney Tissue of Mouse Bearing Murine Mammary Adenocarcinoma and Exposed to Gamma Radiation

International Nuclear Information System (INIS)

EI-Tahawy, N.A.; Hanafi, N.; Said, U.Z.

2009-01-01

Activin (a grape seed-derived proanthocyanidins extract) possess a broad spectrum of biological, pharmacological and therapeutic activities. The present study performed to investigate the preventive and modulating effects of dietary activin in radiation or murine mammary adenocarcinoma (MMA) induced damage in kidneys of albino mice throughout in vitro and in vivo studies. Activin was orally administered to mice for 5 consecutive days (100 mg/ kg body wt) before and 10 days post tumour inoculation. In irradiated group, animals were exposed to 6 Gy whole body gamma-radiations on the fifth day of tumour inoculation. Biochemical and histopathological studies were investigated. In vitro studies using MMA cells revealed that activin increase non viable tumour cell counts. In vivo studies, either MMA or gamma-irradiation resulted in biochemical, and histopathological changes leading to kidney damage. Biochemical studies revealed that activin treatment significantly restored the elevated activity of lactate dehydrogenase (LDH), ameliorated kidney functions profile, and depressed the levels of tumour markers, also enhanced glutathione content (GSH) and activities of superoxide dismutase (SOD) and catalase (CAT). It also reduced kidney lipid peroxides and improves serum total protein level. Histopathological changes in the kidney tissues were attenuated by activin treatment either in MMA-bearing mice group or irradiation group. Exposure of MMA-bearing mouse to gamma- radiations slightly improves the above mentioned damage. While dual treatment of MMA-bearing mice with activin and subsequence with gamma-radiation exposure was more effective. It could be concluded that activin through its antioxidant properties might attenuate radiation or MMA induced renal damage suggesting that activin may have a potential benefit in enhancing radiotherapy

EcoBears

DEFF Research Database (Denmark)

Nielsen, Nick; Pedersen, Sandra Bleuenn; Sørensen, Jens Ager

2015-01-01

In this paper, we introduce the EcoBears concept that aims to augment household appliances with functional and aesthetic features to promote their "use'' and "longevity of use'' to prevent their disposal. The EcoBears also aim to support the communication of environmental issues in the home setting....... We present our initial design and implementation of the EcoBears that consist of two bear modules (a mother and her cub). We also present our preliminary concept validations and lessons learned to be considered for future directions....

Cellular analysis of the phenotypic correction of the genetically controlled low immune response to the polyproline determinant by macrophages

International Nuclear Information System (INIS)

Falkenberg, F.W.; Sulica, A.; Shearer, G.M.; Mozes, E.; Sela, M.

1974-01-01

SJL mice are high responders to the polyproline region of poly(Tyr,Glu)-polyPro-polyLys, (T,G)-Pro-L and of poly(Phe,Glu)-polyPro-polyLys, (Phe,G)-Pro-L, whereas DBA/l mice are the low responders to this moiety. The low responsiveness of DBA/l mice to polyproline could be enhanced by immunization with (T,G)-Pro-L 4 days after stimulation of peritoneal cells by thioglycolate. The same effect was observed when DBA/l mice were immunized with 10 7 syngeneic peritoneal exudate cells (PEC) preincubated in vitro with the immunogen. Similar treatments of SJL mice did not enhance the high response to polyproline, nor did it enhance low responses to other synthetic polypeptides tested. The enhancing effect of PEC on immunocompetent cells was established by transferring graded numbers of spleen cells together with 10 7 PEC into irradiated syngeneic DBA/l recipients. The effective cell type in the PEC was found to be the macrophage as the same results were observed with the adherent-cell population. Furthermore, the effect was not abolished after in vitro irradiation of PEC with 5000 R or by anti-theta treatment. In vivo irradiation of the PEC donors 2 days before the cells were harvested also did not influence the phenotypic correction of the low responsiveness. Transfer experiments in which graded inocula of either marrow cells or thymocytes from DBA/l donors were transferred into syngeneic recipients in the presence of an excess of the complementary cell type together with PEC indicated that the enhancing effect was reflected in the bone-marrow-cell population only

Stable isotopes to detect food-conditioned bears and to evaluate human-bear management

Science.gov (United States)

Hopkins, John B.; Koch, Paul L.; Schwartz, Charles C.; Ferguson, Jake M.; Greenleaf, Schuyler S.; Kalinowski, Steven T.

2012-01-01

We used genetic and stable isotope analysis of hair from free-ranging black bears (Ursus americanus) in Yosemite National Park, California, USA to: 1) identify bears that consume human food, 2) estimate the diets of these bears, and 3) evaluate the Yosemite human–bear management program. Specifically, we analyzed the isotopic composition of hair from bears known a priori to be food-conditioned or non-food-conditioned and used these data to predict whether bears with an unknown management status were food-conditioned (FC) or non-food-conditioned (NFC). We used a stable isotope mixing model to estimate the proportional contribution of natural foods (plants and animals) versus human food in the diets of FC bears. We then used results from both analyses to evaluate proactive (population-level) and reactive (individual-level) human–bear management, and discussed new metrics to evaluate the overall human–bear management program in Yosemite. Our results indicated that 19 out of 145 (13%) unknown bears sampled from 2005 to 2007 were food-conditioned. The proportion of human food in the diets of known FC bears likely declined from 2001–2003 to 2005–2007, suggesting proactive management was successful in reducing the amount of human food available to bears. In contrast, reactive management was not successful in changing the management status of known FC bears to NFC bears, or in reducing the contribution of human food to the diets of FC bears. Nine known FC bears were recaptured on 14 occasions from 2001 to 2007; all bears were classified as FC during subsequent recaptures, and human–bear management did not reduce the amount of human food in the diets of FC bears. Based on our results, we suggest Yosemite continue implementing proactive human–bear management, reevaluate reactive management, and consider removing problem bears (those involved in repeated bear incidents) from the population.

State Space Formulation of Nonlinear Vibration Responses Collected from a Dynamic Rotor-Bearing System: An Extension of Bearing Diagnostics to Bearing Prognostics.

Science.gov (United States)

Tse, Peter W; Wang, Dong

2017-02-14

Bearings are widely used in various industries to support rotating shafts. Their failures accelerate failures of other adjacent components and may cause unexpected machine breakdowns. In recent years, nonlinear vibration responses collected from a dynamic rotor-bearing system have been widely analyzed for bearing diagnostics. Numerous methods have been proposed to identify different bearing faults. However, these methods are unable to predict the future health conditions of bearings. To extend bearing diagnostics to bearing prognostics, this paper reports the design of a state space formulation of nonlinear vibration responses collected from a dynamic rotor-bearing system in order to intelligently predict bearing remaining useful life (RUL). Firstly, analyses of nonlinear vibration responses were conducted to construct a bearing health indicator (BHI) so as to assess the current bearing health condition. Secondly, a state space model of the BHI was developed to mathematically track the health evolution of the BHI. Thirdly, unscented particle filtering was used to predict bearing RUL. Lastly, a new bearing acceleration life testing setup was designed to collect natural bearing degradation data, which were used to validate the effectiveness of the proposed bearing prognostic method. Results show that the prediction accuracy of the proposed bearing prognostic method is promising and the proposed bearing prognostic method is able to reflect future bearing health conditions.

State Space Formulation of Nonlinear Vibration Responses Collected from a Dynamic Rotor-Bearing System: An Extension of Bearing Diagnostics to Bearing Prognostics

Directory of Open Access Journals (Sweden)

Peter W. Tse

2017-02-01

Full Text Available Bearings are widely used in various industries to support rotating shafts. Their failures accelerate failures of other adjacent components and may cause unexpected machine breakdowns. In recent years, nonlinear vibration responses collected from a dynamic rotor-bearing system have been widely analyzed for bearing diagnostics. Numerous methods have been proposed to identify different bearing faults. However, these methods are unable to predict the future health conditions of bearings. To extend bearing diagnostics to bearing prognostics, this paper reports the design of a state space formulation of nonlinear vibration responses collected from a dynamic rotor-bearing system in order to intelligently predict bearing remaining useful life (RUL. Firstly, analyses of nonlinear vibration responses were conducted to construct a bearing health indicator (BHI so as to assess the current bearing health condition. Secondly, a state space model of the BHI was developed to mathematically track the health evolution of the BHI. Thirdly, unscented particle filtering was used to predict bearing RUL. Lastly, a new bearing acceleration life testing setup was designed to collect natural bearing degradation data, which were used to validate the effectiveness of the proposed bearing prognostic method. Results show that the prediction accuracy of the proposed bearing prognostic method is promising and the proposed bearing prognostic method is able to reflect future bearing health conditions.

Fraction From Lycium barbarum Polysaccharides Reduces Immunotoxicity and Enhances Antitumor Activity of Doxorubicin in Mice.

Science.gov (United States)

Deng, Xiangliang; Luo, Shuang; Luo, Xia; Hu, Minghua; Ma, Fangli; Wang, Yuanyuan; Zhou, Lian; Huang, Rongrong

2018-01-01

The aim of the present study was to investigate whether fraction from Lycium barbarum polysaccharide (LBP) could reduce immunotoxicity and enhance antitumor activity of doxorubicin (Dox) in mice. A water-soluble LBP fraction, designated LBP3, was isolated from edible Chinese herbal Lycium barbarum and used in this study. To investigate the effect of LBP3 on Dox-induced immunotoxicity, tumor-free mice were used and treated with either normal saline, Dox, or Dox plus LBP3. To investigate the effect of LBP3 on antitumor activity of Dox, H22 tumor-bearing mice were used and treated with either normal saline, Dox, LBP3, or Dox plus LBP3. The results showed that LBP3 did not protect against the body weight loss caused by Dox, but it promoted the recovery of body weight starting at day 5 after Dox treatment in tumor-free mice. LBP3 also improved peripheral blood lymphocyte counts, promoted cell cycle recovery in bone marrow cells, and restored the cytotoxicity of natural killer cells. Furthermore, in H22 tumor-bearing mice, LBP3 enhanced antitumor activity of Dox and improved peripheral blood lymphocyte counts and the cytotoxicity of splenocytes. In brief, our results demonstrated that LBP3 could reduce the immunotoxicity and enhance antitumor activity of Dox.

Effect of immunomodulation on the fate of tumor cells in the central nervous system and systemic organs of mice. Distribution of [125I]5-iodo-2'-deoxyuridine-labeled KHT tumor cells after left intracardial injection

International Nuclear Information System (INIS)

Conley, F.K.

1982-01-01

The effect of systemic immunomodulation on tumor cell arrest and retention in the central nervous system was studied by following radioactively labeled tumor cells. KHT mouse sarcoma tumor cells were labeled in vitro with [ 125 I]IdUrd, and 1x10 5 tumor cells were injected into the left side of the hearts of syngeneic C3H mice. Experimental groups consisted of untreated normal mice, mice pretreated iv with Corynebacterium parvum, and mice chronically infected with Toxoplasma gondii; in this model both groups of immunomodulated mice are protected from developing systemic metastatic tumor, but only Toxoplasma-infected mice have protection against metastatic brain tumor. At time intervals from 1 to 96 hours, groups of mice from each experimental group were killed, and the brain and other organs were monitored for radioactivity to determine the number of viable tumor cells that had been present at the time of death. Normal mice demonstrated significant retention of tumor cells in the brain and kidneys plus adrenals at 96 hours. By contrast, in both groups of immunomodulated mice tumor cells were rapidly eliminated from systemic organs, but tumor cells were significantly retained in the central nervous system even at 96 hours after tumor cell injections. The results indicated that generalized immunomodulation had more effect in elimination of tumor cells from systemic organs than from the brain and that the elimination of tumor cells from the brain in Toxoplasma-infected mice was a delayed phenomenon

Cancer cell–derived microparticles bearing P-selectin glycoprotein ligand 1 accelerate thrombus formation in vivo

Science.gov (United States)

Thomas, Grace M.; Panicot-Dubois, Laurence; Lacroix, Romaric; Dignat-George, Françoise; Lombardo, Dominique

2009-01-01

Recent publications have demonstrated the presence of tissue factor (TF)–bearing microparticles (MPs) in the blood of patients suffering from cancer. However, whether these MPs are involved in thrombosis remains unknown. We show that pancreatic and lung cancer cells produce MPs that express active TF and P-selectin glycoprotein ligand 1 (PSGL-1). Cancer cell–derived MPs aggregate platelets via a TF-dependent pathway. In vivo, cancer cell–derived MPs, but not their parent cells, infused into a living mouse accumulate at the site of injury and reduce tail bleeding time and the time to occlusion of venules and arterioles. This thrombotic state is also observed in mice developing tumors. In such mice, the amount of circulating platelet-, endothelial cell–, and cancer cell–derived MPs is increased. Endogenous cancer cell–derived MPs shed from the growing tumor are able to accumulate at the site of injury. Infusion of a blocking P-selectin antibody abolishes the thrombotic state observed after injection of MPs or in mice developing a tumor. Collectively, our results indicate that cancer cell–derived MPs bearing PSGL-1 and TF play a key role in thrombus formation in vivo. Targeting these MPs could be of clinical interest in the prevention of thrombosis and to limit formation of metastasis in cancer patients. PMID:19667060

Effects of daily treatment with a radioprotector WR-2721 on Ehrlich's ascites tumors in mice

International Nuclear Information System (INIS)

Ikebuchi, Makoto; Shinohara, Shigeo; Kimura, Hiroshi; Morimoto, Kunio; Shima, Akihiro

1981-01-01

Mice were injected daily with a radioprotector WR-2721 (S-2-[3-aminopropyl-amino]ethylphosphorothioic acid) after inoculation with Ehrlich's ascites tumor cells. Increases in weight of mice, volume of ascitic fluid and number of ascitic cells per mouse were reduced by the daily administration of 5 mg/mouse of the drug, indicating a suppressive effect of WR-2721 on growth of ascitic cells. But daily treatment with 5 mg/mouse of WR-2721 caused earlier death of tumor-bearing mice. (author)

Comparison of Alignment Correction Angles Between Fixed-Bearing and Mobile-Bearing UKA.

Science.gov (United States)

Inoue, Atsuo; Arai, Yuji; Nakagawa, Shuji; Inoue, Hiroaki; Yamazoe, Shoichi; Kubo, Toshikazu

2016-01-01

Good outcomes have been reported with both fixed-bearing and mobile-bearing unicompartmental knee arthroplasty (UKA). However, overcorrected alignment could induce the progression of arthritis on the non-arthroplasty side. Changes of limb alignment after UKA with both types of bearings (fixed bearing: 24 knees, mobile bearing: 28 knees) were investigated. The mean difference between the preoperative standing femoral-tibial angle (FTA) and postoperative standing FTA was significantly larger in mobile bearing UKA group. In fixed-bearing UKA, there must be some laxity in MCL tension so that a 2-mm tension gauge can be inserted. In mobile-bearing UKA, appropriate MCL tension is needed to prevent bearing dislocation. This difference in MCL tension may have caused the difference in the correction angle between the groups. Copyright © 2016 Elsevier Inc. All rights reserved.

Immunopathology of thrombocytopenia in experimental malaria.

Science.gov (United States)

Grau, G E; Piguet, P F; Gretener, D; Vesin, C; Lambert, P H

1988-12-01

An early thrombocytopenia was observed in CBA mice during acute infection with Plasmodium berghei. This was associated with an increase in bone marrow megakaryocytes and a reduction of normal syngeneic 111Indium-labelled platelet life span. Malaria-induced thrombocytopenia was thus considered to be the result of increased peripheral platelet destruction rather than central hypoproduction. The occurrence of thrombocytopenia was modulated by T-cell depletion. Indeed, thymectomized, irradiated or anti-CD4 monoclonal antibody-treated mice failed to develop thrombocytopenia, although they were infected to the same extent. Conversely, a significant thrombocytopenia was observed in thymectomized mice reconstituted with CD4+ T cells. During the course of infection, a significant inverse correlation was found between platelet counts and platelet-associated IgG. Normal mice passively transferred with serum from syngeneic malaria-infected mice developed thrombocytopenia. The possibility to raise monoclonal anti-platelet antibodies from P. berghei-infected animals further suggested a role for an antibody-mediated platelet destruction during acute murine malaria infection. These results indicate that in murine malaria, thrombocytopenia is mediated by immune mechanisms and that CD4+ T cells might be significantly involved.

H-11-linked gene has a parallel effect on Leishmania major and L. donovani infections in mice

International Nuclear Information System (INIS)

Blackwell, J.M.; Hale, C.; Roberts, M.B.; Ulczak, O.M.; Liew, F.Y.; Howard, J.G.

1985-01-01

The courses of visceral infection following intravenous injection of Leishmania donovani amastigotes, or lesion growth following subcutaneous injection of L. major promastigotes, were examined in B10.129(10M) (H-2b, H-11b) mice and compared with disease profiles observed in congenic C57BL/10ScSn(= B10) (H-2b, H-11a) and B10.D2/n (H-2d, H-11a) mice, and in BALB/mice. Possession of alternative alleles at H-11 and closely linked loci transformed the normal curing/healing phenotype of B10 mice into a characteristically different noncuring/nonhealing phenotype affecting both visceral and subcutaneous infections in B10.129(10M) mice. In reciprocal radiation bone marrow chimeras made between the congenic B10 and B10.129(10M) strains, both cure and noncure phenotypes were transferable with the donor hematopoietic system. Although it was possible to demonstrate transfer of suppression with T-enriched spleen cells from day 61 L. donovani-infected B10.129(10M) donor mice into 550 rad syngeneic recipients, the pretreatment of mice with sublethal irradiation did not, as in the earlier studies of Scl-controlled L. major nonhealing or H-2-controlled L. donovani noncure phenotypes, have a clear or consistent prophylactic effect. Together with the progressive disease profile observed even for L. donovani at low parasite doses this suggests that, despite their ability to develop initial delayed-type hypersensitivity reactions to parasite antigen early in L. major infection, B10.129(10M) mice possess some inherent defect in ability to mount a cell-mediated response effective at the level of macrophage neishmanial activity in vivo even when suppressor T cells are not generated. Elucidation of this characteristically different noncuring/nonhealing phenotye may provide important insight into common events involved in the development of the cell-mediated immune response to both visceral and subcutaneous forms of leishmaniasis

Lymphoma induction by heterocyclic amines in Eu-pim-1 transgenic mice

DEFF Research Database (Denmark)

Sørensen, Ilona Kryspin; Kristiansen, E.; Mortensen, Alicja

1997-01-01

The usefulness of transgenic E mu-pim-1 mice bearing in their genome the pim-1 oncogene supplemented with an upstream immunoglobulin enhancer and a downstream murine leukaemia virus long terminal repeat, as sensitive test organisms was studied in two short-term carcinogenicity studies. The mice...... to bacteria and cultured mammalian cells. PhIP is a potent mouse lymphomagen, while IQ is a liver, lung and forestomach carcinogen in mice. We found that transgenic E mu-pim-1 mice are highly susceptible to PhIP induced lymphomagenesis but do not respond to IQ treatment. PhIP feeding of E mu-pim-1 mice...... not only increased the total number of T-cell lymphomas but also decreased the latency time compared to either transgenic or wild-type controls. The effect was most pronounced in the treated female E mu-pim-1 mice, which showed a higher incidence of PhIP induced T-cell lymphomas than transgenic males...

Transient engraftment of syngeneic bone marrow after conditioning with high-dose cyclophosphamide and thoracoabdominal irradiation in a patient with aplastic anemia

International Nuclear Information System (INIS)

Matsue, K.; Niki, T.; Shiobara, S.; Ueda, M.; Ohtake, S.; Mori, T.; Matsuda, T.; Harada, M.

1990-01-01

We describe the clinical course of a 16 year old girl with aplastic anemia who was treated by syngeneic bone marrow transplantation. Engraftment was not obtained by simple infusion of bone marrow without immunosuppression. The patient received a high-dose cyclophosphamide and thoracoabdominal irradiation, followed by second marrow transplantation from the same donor. Incomplete but significant hematologic recovery was observed; however, marrow failure recurred 5 months after transplantation. Since donor and recipient pairs were genotypically identical, graft failure could not be attributed to immunological reactivity of recipient cells to donor non-HLA antigens. This case report implies that graft failure in some cases of aplastic anemia might be mediated by inhibitory cells resistant to cyclophosphamide and irradiation

Associations between the uptake of {sup 111}In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts

Energy Technology Data Exchange (ETDEWEB)

McLarty, Kristin; Cornelissen, Bart; Scollard, Deborah A. [University of Toronto, Department of Pharmaceutical Sciences, Toronto, ON (Canada); Done, Susan J. [University of Toronto, Department of Medical Biophysics, Toronto, ON (Canada)]|[University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, ON (Canada)]|[University Health Network, Department of Pathology, Toronto, ON (Canada); Chun, Kathy [North York General Hospital, Genetics Program, Toronto, ON (Canada); Reilly, Raymond M. [University of Toronto, Department of Pharmaceutical Sciences, Toronto, ON (Canada)]|[University of Toronto, Department of Medical Imaging, Toronto, ON (Canada)]|[University Health Network, Toronto General Research Institute, Toronto, ON (Canada)]|[University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON (Canada)

2009-01-15

The purpose of the study was to investigate the associations between uptake of {sup 111}In-DTPA-trastuzumab, tumour HER2 density and response to trastuzumab (Herceptin) of human breast cancer (BC) xenografts in athymic mice. The tumour uptake of {sup 111}In-DTPA-trastuzumab in athymic mice bearing BC xenografts with increasing HER2 density (0 to 3+) was evaluated. Specific uptake ratios were established in biodistribution (SUR) and imaging studies (ROI-SUR) using {sup 111}In-labeled mouse IgG ({sup 111}In-DTPA-mIgG). Further corrections were made for circulating radioactivity using tumour-to-blood ratios defined as a localization index (LI) and region-of-interest localization index (ROI-LI), respectively. Mice were treated with trastuzumab (Herceptin). A tumour growth inhibition index (TGI) was calculated and relative TGIs calculated by dividing the TGI of control by that of trastuzumab-treated mice. Strong, nonlinear associations with HER2 density were obtained if the uptake of {sup 111}In-DTPA-trastuzumab was corrected for nonspecific IgG localization (i.e., SUR; r{sup 2}=0.99) and circulating radioactivity (i.e., LI; r{sup 2} =0.87), but without these corrections, the association between HER2 density and tumour uptake was poor (r{sup 2}=0.22). There was a strong association between ROI-SUR and ROI-LI values and HER2 expression (r{sup 2}=0.90 and r{sup 2}=0.95), respectively. All tumours were imaged. Relative TGI values were associated with increasing uncorrected tumour uptake of {sup 111}In-DTPA-trastuzumab but not always with HER2 density (i.e., MCF-HER2-18 cells with trastuzumab-resistance). HER2 expression (0 to 3+) can be differentiated using {sup 111}In-DTPA-trastuzumab, but requires correction of tumour uptake for nonspecific IgG localization and circulating radioactivity. The uncorrected uptake of {sup 111}In-DTPA-trastuzumab was associated with tumour response to trastuzumab. (orig.)

Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target.

Science.gov (United States)

Perales-Puchalt, Alfredo; Svoronos, Nikolaos; Rutkowski, Melanie R; Allegrezza, Michael J; Tesone, Amelia J; Payne, Kyle K; Wickramasinghe, Jayamanna; Nguyen, Jenny M; O'Brien, Shane W; Gumireddy, Kiranmai; Huang, Qihong; Cadungog, Mark G; Connolly, Denise C; Tchou, Julia; Curiel, Tyler J; Conejo-Garcia, Jose R

2017-01-15

To define the safety and effectiveness of T cells redirected against follicle-stimulating hormone receptor (FSHR)-expressing ovarian cancer cells. FSHR expression was determined by Western blotting, immunohistochemistry, and qPCR in 77 human ovarian cancer specimens from 6 different histologic subtypes and 20 human healthy tissues. The effectiveness of human T cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T cells. FSHR is expressed in gynecologic malignancies of different histologic types but not in nonovarian healthy tissues. Accordingly, T cells expressing full-length FSHR-redirected chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T cells persisted as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor-transduced T cells away from targeted tumor cells. T cells redirected against FSHR + tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries. Clin Cancer Res; 23(2); 441-53. ©2016 AACR. ©2016 American Association for Cancer Research.

Immune mechanisms in Ehrlich ascites tumor growth in mice

International Nuclear Information System (INIS)

Marusic, M.

1979-01-01

Normal mice immunised with irradiated Ehrlich ascites tumor (EAT) cells rejected EAT challenge given 2 weeks later but T-cell-deficient thymectomised lethally irradiated, and bone-marrow-reconstituted (TIR) mice succumbed. However, when TIR mice were injected i.v. with thymus, lymph node, or spleen cells from normalsyngetic donors immediately following i.p. injection of irradiated EAT cells, they rejected the subsequent tumor challenge. This induction of immunity in TIR mice was shown to be T-cell dependent. Spleen cells from EAT- bearing mice given immediately after irradiated tumor cells were also able to promote rejection of EAT challenge in TIR mice. Spleen cells from EAT-immune mice inhibited EAT growth when admixed with tumor cells prior to i.p. injection into normal recipients, but had no effect on progressive tumor growth when given i.v. immediately after i.p. tumor injection. Immune serum inhibited i.p. EAT growth when given either i.p. or i.v. Whereas inhibition of EAT growth by admixed spleen cells was shown to be T-cell independent. The data indicate that T lymphocytes are required only in the induction phase of the immune reponse of mice against EAT, while the efferent phase of the response is accomplished by serum antibodies, perhaps through an interaction with host macrophages. (author)

Comprehensive study of the drug delivery properties of poly(l-lactide)-poly(ethylene glycol) nanoparticles in rats and tumor-bearing mice.

Science.gov (United States)

Shalgunov, Vladimir; Zaytseva-Zotova, Daria; Zintchenko, Arkadi; Levada, Tatiana; Shilov, Yuri; Andreyev, Dmitry; Dzhumashev, Dzhangar; Metelkin, Evgeny; Urusova, Alexandra; Demin, Oleg; McDonnell, Kevin; Troiano, Greg; Zale, Stephen; Safarovа, Elmira

2017-09-10

Nanoparticles made of polylactide-poly(ethylene glycol) block-copolymer (PLA-PEG) are promising vehicles for drug delivery due to their biodegradability and controllable payload release. However, published data on the drug delivery properties of PLA-PEG nanoparticles are heterogeneous in terms of nanoparticle characteristics and mostly refer to low injected doses (a few mg nanoparticles per kg body weight). We have performed a comprehensive study of the biodistribution of nanoparticle formulations based on PLA-PEG nanoparticles of ~100nm size at injected doses of 30 to 140mg/kg body weight in healthy rats and nude tumor-bearing mice. Nanoparticle formulations differed by surface PEG coverage and by release kinetics of the encapsulated model active pharmaceutical ingredient (API). Increase in PEG coverage prolonged nanoparticle circulation half-life up to ~20h in rats and ~10h in mice and decreased retention in liver, spleen and lungs. Circulation half-life of the encapsulated API grew monotonously as the release rate slowed down. Plasma and tissue pharmacokinetics was dose-linear for inactive nanoparticles, but markedly dose-dependent for the model therapeutic formulation, presumably because of the toxic effects of released API. A mathematical model of API distribution calibrated on the data for inactive nanoparticles and conventional API form correctly predicted the distribution of the model therapeutic formulation at the lowest investigated dose, but for higher doses the toxic action of the released API had to be explicitly modelled. Our results provide a coherent illustration of the ability of controllable-release PLA-PEG nanoparticles to serve as an effective drug delivery platform to alter API biodistribution. They also underscore the importance of physiological effects of released drug in determining the biodistribution of therapeutic drug formulations at doses approaching tolerability limits. Copyright © 2017 The Authors. Published by Elsevier B.V. All

A review of bear farming and bear trade in Lao People's Democratic Republic

Directory of Open Access Journals (Sweden)

E. Livingstone

2018-01-01

Full Text Available This study reviews the bear farming industry in Lao PDR with the objective of documenting the current number of commercial bear facilities (i.e. captive bear facilities judged to be trading in bear bile and/or bears and bear parts and the number of bears contained within these facilities, noting changes since it was last examined between 2000 and 2012 by Livingstone and Shepherd (2014. We surveyed all known commercial bear facilities and searched for previously unrecorded facilities. We compared our records with Livingstone and Shepherd (2014 and corrected some duplicate records from their study. In 2017, we recorded seven commercial facilities; four dedicated bear farms, and three tiger farms that were reportedly also keeping bears. We found that between 2012 and 2017 the recorded number of dedicated bear farms reduced by two, and the recorded number of tiger farms also keeping bears increased by one. Within the same period, the total number of captive bears among all facilities in Lao PDR hardly changed (+one, but the number of bears within each facility did. The northern facilities, owned by ethnic Chinese, have expanded since 2012, and central and southern facilities have downsized or closed. While bear farming appears to be downsizing in Lao PDR overall, efforts to phase it out are undermined by the expansion of foreign owned facilities in the north, within Special and Specific Economic Zones that largely cater to a Chinese market, and where the Lao government's efforts to enforce laws and protect wildlife appear to be lacking. Closing the facilities in the north will require political will and decisive law enforcement. Keywords: Bear farms, Bear bile, Gall bladder, Urso-deoxycholic acid, Bear bile extraction facilities, Lao PDR, Ursus thibetanus

Acanthus ilicifolius plant extract prevents DNA alterations in a transplantable Ehrlich ascites carcinoma-bearing murine model.

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Chakraborty, Tridib; Bhuniya, Dipak; Chatterjee, Mary; Rahaman, Mosiur; Singha, Dipak; Chatterjee, Baidya Nath; Datta, Subrata; Rana, Ajay; Samanta, Kartick; Srivastawa, Sunil; Maitra, Sankar K; Chatterjee, Malay

2007-12-28

To investigate the chemopreventive efficacy of the Indian medicinal plant Acanthus ilicifolius L Acanthaceae in a transplantable Ehrlich ascites carcinoma (EAC)-bearing murine model. Male Swiss albino mice were divided into four groups: Group A was the untreated normal control; Group B was the EAC control mice group that received serial, intraperitoneal (ip) inoculations of rapidly proliferating 2 x 10(5) viable EAC cells in 0.2 mL of sterile phosphate buffered saline; Group C was the plant extract-treated group that received the aqueous leaf extract (ALE) of the plant at a dose of 2.5 mg/kg body weight by single ip injections, once daily for 10, 20 and 30 consecutive days following tumour inoculation (ALE control); and Group D was the EAC + ALE-treatment group. The chemopreventive potential of the ALE was evaluated in a murine model by studying various biological parameters and genotoxic markers, such as tumour cell count, mean survival of the animals, haematological indices, hepatocellular histology, immunohistochemical expression of liver metallothionein (MT) protein, sister-chromatid exchanges (SCEs), and DNA alterations. Treatment of the EAC-bearing mice with the ALE significantly (P decrement (P single-strand breaks (SSBs) by 38.53% (3.14 +/- 0.31 vs 1.93 +/- 0.23, P < 0.01) in EAC-bearing murine liver. Our data indicate that, ALE is beneficial in restoring haematological and hepatic histological profiles and in lengthening the survival of the animals against the proliferation of ascites tumour in vivo. Finally, the chemopreventive efficacy of the ALE is manifested in limiting MT expression and in preventing DNA alterations in murine liver. The promising results of this study suggest further investigation into the chemopreventive mechanisms of the medicinal plant A. ilicifolius in vivo and in vitro.

Molecular phylogeny and SNP variation of polar bears (Ursus maritimus), brown bears (U. arctos), and black bears (U. americanus) derived from genome sequences.

Science.gov (United States)

Cronin, Matthew A; Rincon, Gonzalo; Meredith, Robert W; MacNeil, Michael D; Islas-Trejo, Alma; Cánovas, Angela; Medrano, Juan F

2014-01-01

We assessed the relationships of polar bears (Ursus maritimus), brown bears (U. arctos), and black bears (U. americanus) with high throughput genomic sequencing data with an average coverage of 25× for each species. A total of 1.4 billion 100-bp paired-end reads were assembled using the polar bear and annotated giant panda (Ailuropoda melanoleuca) genome sequences as references. We identified 13.8 million single nucleotide polymorphisms (SNP) in the 3 species aligned to the polar bear genome. These data indicate that polar bears and brown bears share more SNP with each other than either does with black bears. Concatenation and coalescence-based analysis of consensus sequences of approximately 1 million base pairs of ultraconserved elements in the nuclear genome resulted in a phylogeny with black bears as the sister group to brown and polar bears, and all brown bears are in a separate clade from polar bears. Genotypes for 162 SNP loci of 336 bears from Alaska and Montana showed that the species are genetically differentiated and there is geographic population structure of brown and black bears but not polar bears.

Role of Omega 3 Fatty Acids Against Ehrlich Ascites Carcinoma-Induced Hepatic and Brain Dysfunctions in Gamma Irradiated Mice

International Nuclear Information System (INIS)

El-Gharib, M.M.M.

2014-01-01

Cancer is a deadly disease that has touched the lives of many people in the world today. Omega 3 essential fatty acids (ω-3 FAs); found in high concentrations in fish oil, claim a plethora of health benefits. The present study aimed to evaluate the role of ω-3 FAs supplementation either alone or combined with fractionated γ-radiation exposure against Ehrlich solid tumor-induced inflammation, oxidative stress, biochemical alterations and histopathological changes in the liver, brain and tumor tissues of Albino mice. ω-3 FAs were orally administered via gavages to mice for a period of 30 consecutive days at a dose of 300 mg/kg body weight. On the 7th day of experiment, mice were subcutaneously transplanted in the neck region with 0.2 ml of Ehrlich ascites carcinoma cells for solid tumor induction and on the 17th and 25th days, mice were exposed to a fractionated whole body γ-radiation (0.5 Gy/week for two weeks). The results of the present work showed that Ehrlich carcinoma (EC) and/or γ-irradiation led to systemic inflammation (elevated TNF-α, TLC and CRP levels), hepatic oxidative stress (elevated TBARs level, decreased GSH, GSH-Px, CAT and SOD levels) and biochemical alterations in liver (elevated AST, ALT, ALP and LDH activities) and brain (dopamine, EP,NE and serotonin levels) tissues. On the other hand, ω-3 FAs supplementation to the experimentally irradiated EC-bearing mice, significantly reduced tumor size, depressed the concentrations of inflammatory markers, reduced oxidative stress and also ameliorated the biochemical alterations in liver and brain tissues. Histopathological examinations showed that treatment with ω-3 FAs recorded great destruction of tumor tissue, great disappearance of metastatic EC cells from the liver tissue and normal appearance in cerebrum and cerebellum of brain tissue layers in EC-bearing mice. Combined treatment of EC-bearing mice with ω-3 FAs and γ-irradiation showed necrotic cells and remnant tumor cells in tumor

Heritability of body size in the polar bears of Western Hudson Bay.

Science.gov (United States)

Malenfant, René M; Davis, Corey S; Richardson, Evan S; Lunn, Nicholas J; Coltman, David W

2018-04-18

Among polar bears (Ursus maritimus), fitness is dependent on body size through males' abilities to win mates, females' abilities to provide for their young and all bears' abilities to survive increasingly longer fasting periods caused by climate change. In the Western Hudson Bay subpopulation (near Churchill, Manitoba, Canada), polar bears have declined in body size and condition, but nothing is known about the genetic underpinnings of body size variation, which may be subject to natural selection. Here, we combine a 4449-individual pedigree and an array of 5,433 single nucleotide polymorphisms (SNPs) to provide the first quantitative genetic study of polar bears. We used animal models to estimate heritability (h 2 ) among polar bears handled between 1966 and 2011, obtaining h 2 estimates of 0.34-0.48 for strictly skeletal traits and 0.18 for axillary girth (which is also dependent on fatness). We genotyped 859 individuals with the SNP array to test for marker-trait association and combined p-values over genetic pathways using gene-set analysis. Variation in all traits appeared to be polygenic, but we detected one region of moderately large effect size in body length near a putative noncoding RNA in an unannotated region of the genome. Gene-set analysis suggested that variation in body length was associated with genes in the regulatory cascade of cyclin expression, which has previously been associated with body size in mice. A greater understanding of the genetic architecture of body size variation will be valuable in understanding the potential for adaptation in polar bear populations challenged by climate change. © 2018 John Wiley & Sons Ltd.

Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia.

Science.gov (United States)

Delitto, Daniel; Judge, Sarah M; Delitto, Andrea E; Nosacka, Rachel L; Rocha, Fernanda G; DiVita, Bayli B; Gerber, Michael H; George, Thomas J; Behrns, Kevin E; Hughes, Steven J; Wallet, Shannon M; Judge, Andrew R; Trevino, Jose G

2017-01-03

Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu potentially contributing to PC-associated cachexia. Specifically, human PC xenografts were generated by implantation of pancreatic cancer cells, L3.6pl and PANC-1, either in the flank or orthotopically within the pancreas. Mice bearing orthotopic xenografts demonstrated significant muscle wasting and atrophy-associated gene expression changes compared to controls. Further, despite the absence of adaptive immunity, splenic tissue from orthotopically engrafted mice demonstrated elevations in several pro-inflammatory cytokines associated with cancer cachexia, including TNFα, IL1β, IL6 and KC (murine IL8 homologue), when compared to controls. Therefore, data presented here support further investigation into the complexity of cancer cachexia in PC to identify potential targets for this debilitating syndrome.

Teddy Bear Stories

DEFF Research Database (Denmark)

van Leeuwen, Theo; Caldas-Coulthardt, Carmen

2014-01-01

This paper presents a semiotic analysis of a key cultural artefact, the teddy bear. After introducing the iconography of the teddy bear, it analyses different kinds of stories to show how teddy bears are endowed with meaning in everyday life: stories from children's books, reminiscenses by adults...... bears have traditionally centred on interpersonal relations within the nuclear family, but have recently been institutionalized and commercialized....

Enhancement of antinociception by coadminstration of minocycline and a non-steroidal anti-inflammatory drug indomethacin in naïve mice and murine models of LPS-induced thermal hyperalgesia and monoarthritis

Directory of Open Access Journals (Sweden)

Masocha Willias

2010-12-01

Full Text Available Abstract Background Minocycline and a non-steroidal anti-inflammatory drug (NSAID indomethacin, have anti-inflammatory activities and are both used in the management of rheumatoid arthritis. However, there are no reports on whether coadministration of these drugs could potentiate each other's activities in alleviating pain and weight bearing deficits during arthritis. Methods LPS was injected to BALB/c mice intraperitoneally (i.p. to induce thermal hyperalgesia. The hot plate test was used to study thermal nociception in naïve BALB/c and C57BL/6 mice and BALB/c mice with LPS-induced thermal hyperalgesia and to evaluate antinociceptive effects of drugs administered i.p. Monoarthritis was induced by injection of LPS intra-articularly into the right hind (RH limb ankle joint of C57BL/6 mice. Weight bearing changes and the effect of i.p. drug administration were analyzed in freely moving mice using the video-based CatWalk gait analysis system. Results In naïve mice indomethacin (5 to 50 mg/kg had no significant activity, minocycline (25 to 100 mg/kg produced hyperalgesia to thermal nociception, however, coadministration of minocycline 50 mg/kg with indomethacin 5 or 10 mg/kg produced significant antinociceptive effects in the hot plate test. A selective inhibitor of COX-1, FR122047 (10 mg/kg and a selective COX-2 inhibitor, CAY10404 (10 mg/kg had no significant antinociceptive activities to thermal nociception in naïve mice, however, coadministration of minocycline, with CAY10404 but not FR122047 produced significant antinociceptive effects. In mice with LPS-induced hyperalgesia vehicle, indomethacin (10 mg/kg or minocycline (50 mg/kg did not produce significant changes, however, coadministration of minocycline plus indomethacin resulted in antinociceptive activity. LPS-induced RH limb monoarthritis resulted in weight bearing (RH/left hind (LH limb paw pressure ratios and RH/LH print area ratios deficits. Treatment with indomethacin (1 mg/kg or

“Bear-ly” learning: Limits of abstraction in black bear cognition

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Jennifer Vonk

2018-02-01

Full Text Available We presented two American black bears (Ursus americanus with a serial list learning memory task, and one of the bears with a matching-to-sample task. After extended training, both bears demonstrated some success with the memory task but failed to generalize the overarching rule of the task to novel stimuli. Matching to sample proved even more difficult for our bear to learn. We conclude that, despite previous success in training bears to respond to natural categories, quantity discriminations, and other related tasks, that bears may possess a cognitive limitation with regards to learning abstract rules. Future tests using different procedures are necessary to determine whether this is a limit of bears’ cognitive capacities, or a limitation of the current tasks as presented. Future tests should present a larger number of varying stimuli. Ideally, bears of various species should be tested on these tasks to demonstrate species as well as individual differences.

GAS BEARING

Science.gov (United States)

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.

Overexpression of IGF-I in skeletal muscle of transgenic mice does not prevent unloading-induced atrophy

Science.gov (United States)

Criswell, D. S.; Booth, F. W.; DeMayo, F.; Schwartz, R. J.; Gordon, S. E.; Fiorotto, M. L.

1998-01-01

This study examined the association between local insulin-like growth factor I (IGF-I) overexpression and atrophy in skeletal muscle. We hypothesized that endogenous skeletal muscle IGF-I mRNA expression would decrease with hindlimb unloading (HU) in mice, and that transgenic mice overexpressing human IGF-I (hIGF-I) specifically in skeletal muscle would exhibit less atrophy after HU. Male transgenic mice and nontransgenic mice from the parent strain (FVB) were divided into four groups (n = 10/group): 1) transgenic, weight-bearing (IGF-I/WB); 2) transgenic, hindlimb unloaded (IGF-I/HU); 3) nontransgenic, weight-bearing (FVB/WB); and 4) nontransgenic, hindlimb unloaded (FVB/HU). HU groups were hindlimb unloaded for 14 days. Body mass was reduced (P < 0.05) after HU in both IGF-I (-9%) and FVB mice (-13%). Contrary to our hypothesis, we found that the relative abundance of mRNA for the endogenous rodent IGF-I (rIGF-I) was unaltered by HU in the gastrocnemius (GAST) muscle of wild-type FVB mice. High-level expression of hIGF-I peptide and mRNA was confirmed in the GAST and tibialis anterior (TA) muscles of the transgenic mice. Nevertheless, masses of the GAST and TA muscles were reduced (P < 0.05) in both FVB/HU and IGF-I/HU groups compared with FVB/WB and IGF-I/WB groups, respectively, and the percent atrophy in mass of these muscles did not differ between FVB and IGF-I mice. Therefore, skeletal muscle atrophy may not be associated with a reduction of endogenous rIGF-I mRNA level in 14-day HU mice. We conclude that high local expression of hIGF-I mRNA and peptide in skeletal muscle alone cannot attenuate unloading-induced atrophy of fast-twitch muscle in mice.

Dose rate effectiveness in radiation-induced teratogenesis in mice

International Nuclear Information System (INIS)

Kato, F.; Ootsuyama, A.; Norimura, T.

2000-01-01

To investigate the role of p53 gene in tissue repair of teratogenic injury, we compared incidence of radiation-induced malformations in homozygous p53(-/-) mice, heterozygous p53(+/-) mice and wild-type p53(+/+) mice. After X-irradiation with 2 Gy at high dose rate on 9.5 days of gestation, p53(-/-) mice showed higher incidences of anomalies and higher resistance to prenatal deaths than p53(+/+) mice. This reciprocal relationship of radiosensitivity to anomalies and deaths supports the notion that embryos or fetuses have a p53-dependent 'guardian' that aborts cells bearing radiation-induced teratogenic DNA damage. In fact, after X-irradiation, the number of apoptotic cells was greatly increased in p53(+/+) fetuses but not in p53(-/-) fetuses. The same dose of γ-ray exposure at low dose rate on 9.5-10.5 day of gestation produced significant reduction of radiation-induced malformation in p53(+/+) and p53(+/-) mice, remained teratogenic for p53(-/-) mice. These results suggest that complete elimination of teratogenic damage from irradiated tissues requires the concerted cooperation of two mechanisms; proficient DNA repair and the p53-dependent apoptotic tissue repair. When concerted DNA repair and apoptosis functions efficiently, there is a threshold dose-rate for radiation-induced malformations. (author)

A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic mice.

Science.gov (United States)

Buchmann, Pascale; Dembek, Claudia; Kuklick, Larissa; Jäger, Clemens; Tedjokusumo, Raindy; von Freyend, Miriam John; Drebber, Uta; Janowicz, Zbigniew; Melber, Karl; Protzer, Ulrike

2013-02-06

Therapeutic vaccines are currently being developed for chronic hepatitis B and C. As an alternative to long-term antiviral treatment or to support only partially effective therapy, they should activate the patient's immune system effectively to fight and finally control the virus. A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens - besides activation of a humoral immune response. We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg), and the saponin-based ISCOMATRIX™ adjuvant for its ability to stimulate T and B cell responses in C57BL/6 mice and its ability to break tolerance in syngeneic HBV transgenic (HBVtg) mice. In C57BL/6 mice, the vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ, TNFα and IL-2, as well as high antibody titers against both antigens. Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection. Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage. In summary, this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant, chronic HBV infection. Copyright © 2013 Elsevier Ltd. All rights reserved.

Engraftment Site and Effectiveness of the Pan-Caspase Inhibitor F573 to Improve Engraftment in Mouse and Human Islet Transplantation in Mice.

Science.gov (United States)

Pepper, Andrew R; Bruni, Antonio; Pawlick, Rena; Wink, John; Rafiei, Yasmin; Gala-Lopez, Boris; Bral, Mariusz; Abualhassan, Nasser; Kin, Tatsuya; Shapiro, A M James

2017-10-01

Islet transplantation is an effective therapy in type 1 diabetes and recalcitrant hypoglycemia. However, there is an ongoing need to circumvent islet loss posttransplant. We explore herein the potential of the pan-caspase inhibitor F573 to mitigate early apoptosis-mediated islet death within portal and extrahepatic portal sites in mice. Mouse or human islets were cultured in standard media ±100 μM F573 and subsequently assessed for viability and apoptosis via terminal deoxynucleotidyl transferase dUTP nick end labeling staining and caspase-3 activation. Diabetic mice were transplanted with syngeneic islets placed under the kidney capsule (KC) or into the subcutaneous deviceless (DL) site at a marginal islet dose (150 islets), or into the portal vein (PV) at a full dose (500 islets). Human islets were transplanted under the KC of diabetic immunodeficient mice at a marginal dose (500 islet equivalents). Islets were cultured in the presence of F573, and F573 was administered subcutaneously on days 0 to 5 posttransplant. Control mice were transplanted with nontreated islets and were injected with saline. Graft function was measured by nonfasting blood glucose and glucose tolerance testing. F573 markedly reduced human and mouse islet apoptosis after in vitro culture (P islet function when transplanted under the KC (P islet marginal KC transplants. Conversely, F573 significantly improved mouse islet engraftment in the PV and DL site (P islet apoptosis and improves engraftment most effectively in the portal and DL subcutaneous sites.