Vitamin E inhibits the carcinogenicity of N-nitrosomethylbenzylamine.
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Animals↗
Biomedical subjects
R R Watson
Publications and source records attributed to R R Watson.
Effects of supplemental vitamin E on cancer growth and promotion during murine AIDS.
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Animals↗
Inhibitory effects of canthaxanthin on in vitro growth of murine tumor cells.
The antitumorigenic effects of carotenoids, in addition to their immuno-enhancing effects, may occur by their direct action on growing tumor cells. To test this hypothesis the direct inhibitory effect of various concentrations of canthaxanthin (CX; 4,4'-diketo-beta-carotene), a non-provitamin A carotenoid, was tested on the in vitro growth of JB/MS, B16F10 melanomas and PYB6 fibrosarcoma and murine non-transformed NIH-3T3 (ATCC CRL 1658) cells. At concentrations of 1 x 10(-8) M up to 1 x 10(-4) M, CX significantly reduced the overall number of tumor cells. The greatest inhibition was observed at a CX concentration of 1 x 10(-4) M after 72 h and 96 h of incubation. However, CX had no inhibitory effect on the growth of the non-transformed NIH-3T3 cell line; rather it significantly enhanced growth of this cell line (P less than 0.05) after 96 h of incubation. Thus, the inhibitory action of CX on growing tumor cells appears to be due to its direct actions on tumor cells and not via its conversion to vitamin A or its immuno-enhancing effects.
9,10-Dimethyl-1,2-benzanthracene↗
Production of tumor necrosis factor alpha by resident and activated murine macrophages.
Alveolar macrophages (Am phi s), resident peritoneal macrophages (RPm phi s), and thioglycolate-elicited peritoneal macrophages (TGPm phi s) were isolated from C57BL/6 mice and incubated with lipopolysaccharide (LPS), stimulated cell supernatant, or recombinant interferon gamma (IFN-gamma) for 24 h. Tumor necrosis factor (TNF) in cell-free supernatants was measured by enzyme-linked immunosorbent assay. Amo phi s incubated with 10(3) ng/ml LPS produced 50 times more TNF than RPm phi s and 5 times more than TGPm phi s, and LPS alone induced maximum TNF production by Am phi s. Stimulated cell supernatant or recombinant IFN-gamma alone did not induce TNF production. A combination of LPS with stimulated cell supernatant or IFN-gamma had only a limited synergistic effect on TNF production by Am phi s. However, both LPS and stimulated cell supernatant or recombinant IFN-gamma induced maximum TNF production by RPm phi s and TGPm phi s. TGPm phi s showed greater sensitivity to LPS and stimulated cell supernatant or IFN-gamma with regard to TNF production than the other macrophage populations investigated.
Animals↗
Biological monitoring of cancer chemoprevention.
A major limiting factor in the successful implementation of cancer chemoprevention trials has been the determination of endpoints to measure efficacy and success. The use of the ultimate goal of such trials, namely, cancer incidence, as an endpoint has serious feasibility problems, including the need for large numbers of participants, long follow-up periods, and high costs. The application of biological markers as intermediate endpoints to reveal responses to chemopreventive agents within a short time and to act as surrogates for cancer is an attractive concept worthy of intense investigation. This study reviews some potential biological markers, including genetic, cellular, biochemical, and immunological, as well as their possible application to cancer chemoprevention.
Antineoplastic Agents↗
Changes in hepatic lipid composition after infection by LP-BM5 murine leukemia virus causing murine AIDS.
The severe hepatic disorders in patients with acquired immune deficiency syndrome (AIDS) is often attributed to a variety of other factors which could affect hepatic function. To evaluate the mechanism of liver damage in murine AIDS-induced immune-suppressed animal, a murine model of AIDS (MAIDS), caused by infection with LP-BM5 murine leukemia virus was used at a late stage of the disease. Retroviral infection significantly increased hepatic cholesterol, triacylgycerol and the cholesterol/phospholipid ratio. Similarly, the proportions of palmitic, palmitoleic, linoleic, ratios of linoleic to arachidonic and saturated to unsaturated fatty acids were significantly lower while the proportion of oleic, docosatetraenoic and docosahexenoic fatty acids were significantly increased in the retrovirus infected mice. Hepatic dysfunction as evidence by increased serum transaminase levels were also observed in the retrovirus infected animals. The data suggest that the liver damage in murine AIDS is induced by retroviral infection and the desaturase enzymes system necessary to maintain regular balance of the fatty acids in the cells may be affected during retroviral infection.
Animals↗
Modification of thymic cell subsets induced by long-term cocaine administration during a murine retroviral infection producing AIDS.
LP-BM5 murine leukemia virus (MuLV) infection and cocaine administration are known to impair the murine immune system. We have developed a murine model to study the effect of daily cocaine administration and retrovirus infection on the lymphoid cell populations of the thymus. C57BL/6 female mice were studied following chronic cocaine administration for 11 weeks with simultaneous LP-BM5 MuLV infection. Cocaine administration reduced body and thymus weight, significantly reduced the number of CD8+ cells in the thymus, and partially prevented thymus enlargement due to lymphoid cell proliferation induced by LP-BM5 MuLV infection. Retrovirus infection was associated with a decrease in the percentage and absolute number of Thy 1.2+, CD4+, and CD8+ cells in the thymus, an effect potentiated by cocaine administration. Therefore cocaine impairs thymic function by altering the number of cells expressing T cell differentiation markers in MAIDS.
Animals↗
Melatonin induced increase in gamma-interferon production by murine splenocytes.
Previously, we demonstrated that production of gamma-interferon (gamma-IFN) by the mouse splenocytes isolated at night was higher than from those isolated in the morning. In this paper we show that melatonin increased gamma-IFN production by murine splenocytes. Moreover, this stimulating effect was significantly higher (10 times) in the cells isolated at night than in those isolated in the morning (2 times).
Animals↗
Modification of spleen cell subsets by chronic cocaine administration and murine retrovirus infection in normal and protein-malnourished mice.
We have developed an experimental mouse model to study the effect of daily cocaine administration on the immune system during an acquired immune deficiency syndrome (AIDS). Mice were infected with LP-BM5 murine leukemia virus, a retrovirus which causes immunosuppression with the development of functional murine AIDS. Increasing doses of cocaine given by daily intraperitoneal injection for 11 weeks reduced body weight. A daily cocaine injection in some mice as well as a saline injection in others showed a decrease in the percentage of Thy 1.2+, CD4+ and CD8+ cells, while both treatments increased the percentage and absolute numbers of B-cells per spleen. Saline and cocaine treatment induced an increase in gamma-IFN and TNF-alpha production by splenocytes. Cocaine treatment favored a decrease in sIL-2R secretion. Saline and cocaine treatment had slightly different effects on the splenocytes of protein-malnourished mice. Cocaine treatment induced an increase in the percentage of CD8+ cells. Saline and cocaine treatments decreased the number of Mac 1+ cells in the spleen. Moreover, saline- and cocaine-treated protein-malnourished mice splenocytes did not present the increase in gamma-IFN production as well-nourished mice splenocytes showed. Retrovirus-infected mice showed a decrease in the percentage of Thy 1.2+ and CD8+ cells and an increase in the percentage and absolute numbers of CD4+, IL-2R+, Mac 1+ and B-cells. Cocaine partially prevented the enlargement of lymphoid organs due to lymphoid cell proliferation induced by murine retrovirus infection, but had little effect on the elevated percentage of CD4+ cells or B-cells or the depressed numbers of CD8+ cells associated with virus infection. However, cocaine did reduce the number of activated IL-2R+ cells and macrophages (Mac 1+) in addition to reducing the total number of cells per spleen in all subsets in retrovirus-infected mice, but not in uninfected controls. Cocaine treatment and retrovirus infection alone or in combination suppressed the release of sIL-2R into supernatant fluid during in vitro culture of splenocytes. These data illustrate that cocaine treatment modulates cell proliferation in retrovirus-infected mice and thus modifies the absolute number of cells in those subsets already altered by retrovirus infection. Retrovirus-infected and retrovirus-infected cocaine-treated protein-malnourished mice showed similar results.
Animals↗
Cocaine-induced suppression of interferon-gamma secretion in leukocytes from young and old C57BL/6 mice.
The effects of cocaine (0.1-100 micrograms/ml) were studied on interferon-gamma (IFN) secretion in Con A-stimulated splenocytes from young (4 months) and old (18 months) C57BL/6 mice. IFN secretion was significantly suppressed by cocaine in a concentration-dependent manner. Suppression was observed in splenocytes from both young and old mice. Splenocytes from young mice released higher amounts of IFN (23.40 +/- 1.47 ng/ml) than those from old mice (6.10 +/- 0.35 ng/ml) after 24 h in culture. The concentration of Con A used to stimulate IFN secretion significantly affected the suppressive effect of cocaine. Pretreatment of splenocytes with cocaine followed by culture in the absence of cocaine did not affect IFN secretion in old mice, while splenocytes from young mice showed a sustained depression in IFN release. This suggests that cocaine suppresses IFN release in vitro and the susceptibility to this inhibitory effect may be age related.
Age Factors↗
Gas chromatographic detection of cocaine and cocaethylene in hair of mice chronically injected with cocaine or cocaethylene and fed ethanol.
GC and GC/MS analysis was used to detect cocaine and cocaethylene in hair extracts of mice injected with 20 mg/kg cocaine hydrochloride or an equivalent dose of cocaethylene fumarate twice daily for 3 weeks. Some mice were fed liquid Lieber-DeCarli diets containing ethanol (26% of total calories) and injected twice daily with the same doses of cocaine or cocaethylene or combination of cocaine and morphine (5 mg/kg). The average concentrations of cocaine in different experimental groups were in the range of 0.9-2.4 ng/mg of hair and for cocaethylene, 2.4-2.8 ng/mg of hair. There were no significant differences in hair concentrations of cocaine among groups receiving cocaine treatment, nor were there significant difference in cocaethylene concentration in hair in the two groups administered cocaethylene. In hair extracts of mice treated with cocaine and ethanol, levels of cocaethylene were below the limit of detection.
Administration, Oral↗
Effect of murine retroviral infection on hair and serum levels of cocaine and morphine.
LP-BM5 retrovirally infected female C57BL/6J mice were administered cocaine, morphine or both by daily intraperitoneal injection for 9 weeks. Drug concentrations were measured by radioimmunoassay in serum and in hair extracts. Hair samples obtained from all drug-treated mice were positive for the drug injected, while none of the saline-treated mice had detectable drug levels in hair or serum. The average morphine concentration obtained from non-infected mice was 11 ng/mg hair whereas the amount found in the LP-BM5-infected mice was significantly higher (20 ng/mg hair). Mice injected with both morphine and cocaine were given 50% of the regular dose of each drug and drug levels in the hair of these animals were approximately half that of mice injected with the full dose of the single drug. Non-infected mice treated with both drugs had a mean value of 7 ng morphine/mg hair and 374 ng cocaine/mg hair while retrovirus-infected mice had significantly higher concentrations, 10 ng morphine/mg hair and 1160 ng cocaine/mg hair (P less than 0.001). Serum concentrations of cocaine and morphine were significantly higher (P less than 0.01) in the retrovirus-infected animals from 40 min to 1.5 h. The increased concentrations of cocaine and morphine in serum during retrovirus infection are accompanied by a significant increase in the amount of drug incorporated into the hair matrix. This change indicates that retroviral infection may influence the disposition of these drugs in the systemic circulation.
Age Factors↗
Vitamin E inhibition of lipid peroxidation and ethanol-mediated promotion of esophageal tumorigenesis.
Promotion of chemically induced esophageal cancer by ethanol may include the generation of highly reactive free radicals and thus may be preventable by the antioxidant vitamin E. In the present study, female C57BL/6 mice received N-nitrosomethylbenzylamine (NMBzA, 0.2 mg/kg ig) three times a week for three weeks. After this esophageal carcinogenic treatment, mice were fed a nutritionally adequate liquid diet with 30% of the calories supplied by ethanol or an isocaloric carbohydrate with or without supplemental alpha-tocopherol (142 mg/kg diet). As a marker of in vivo lipid peroxidation, exhaled ethane was collected and measured 24 hours "before" the mice were killed after 20 weeks of dietary treatment. Hepatic malondialdehyde, lipid fluorescence, and conjugated dienes were determined as markers of products of lipid peroxidation and serum aminotransferases as indexes of liver toxicity. Hepatic liver concentrations of vitamins A and E and the size and frequency of esophageal tumors were also assessed. Ethanol consumption after NMBzA administration significantly increased (p less than 0.05) the size and frequency of esophageal tumors. These ethanol-promoted effects were accompanied by increases in indexes of in vivo and accumulated products of lipid peroxidation. Similarly treated animals that received supplemental dietary vitamin E showed significant reductions (p less than 0.05) in mean tumor size and frequency of tumors as well as a decrease in the indexes of hepatic lipid peroxidation. The results suggest that promotion of NMBzA-induced esophageal tumors by ethanol may in part result from increased lipid peroxidation and that vitamin E reduces carcinogenicity of NMBzA or ethanol promoter effects by inhibiting lipid peroxidation.
Animals↗
Vitamin E protection against nitrosamine-induced esophageal tumor incidence in mice immunocompromised by retroviral infection.
Retrovirally induced immunosuppression may elevate the incidence of chemically induced cancers. A proposed hypothesis to explain this relationship is the increased free radical activity observed during retroviral infection and carcinogen activation. We previously found that vitamin E retarded growth of esophageal tumors accompanied by reductions of free radical products. This study investigated the contribution that retroviral immunosuppression has on esophageal cancer induced by the carcinogen N-nitrosomethylbenzylamine (NMBzA), and the response that increased levels of dietary vitamin E has on this induced carcinogenesis. Female C57BL/6 mice received NMBzA or vehicle (corn oil) i.p. weekly for 3 weeks. Then some of the mice were infected with LP-BM5 murine retrovirus and fed diets containing 30 IU vitamin E or 172 IU vitamin E/kg of diet. As an assessment of free radical activity, exhaled ethane was measured prior to killing the animals at 26 weeks. Esophagi from the various mice groups were assessed for size and frequency of tumors. Livers homogenates were analyzed for vitamins A and E, lipid fluorescence, conjugated dienes and malondialdehyde. Hepatic levels of vitamin A and E were decreased (P < 0.05) and indices of lipid peroxidation were greater (P < 0.05) in NMBzA-treated mice relative to controls. Lipid peroxidation and serum transaminases (ALT and AST) were greatest in mice given NMBzA and infected with the retroviruses. Incidence of esophageal tumors were also greatest in the NMBzA-treated, immunocompromised animals. Mice fed vitamin E-supplemented diets showed increased (P < 0.05) hepatic concentrations of vitamin E and vitamin A, decreased activities of serum transaminases, decreased indices of lipid peroxidation, and decreased size and frequency of esophageal tumors in both the immunocompromised and non-immunocompromised mice. These results suggest that vitamin E plays an antioxidant function that retards the incidence of esophageal cancers in immunocompromised and non-immunocompromised animals.
Animals↗
A preliminary trial of beta-carotene in subjects infected with the human immunodeficiency virus.
beta-Carotene is a nontoxic carotenoid with immunomodulating properties in animals and humans. Based on our observations in normal immunocompetent subjects, we studied the effects of this compound in 11 patients infected with the human immunodeficiency virus (HIV). Each subject received 60 mg of beta-carotene daily for 4 mo. Clinical and laboratory studies were obtained at baseline, every month while on treatment and for 2 mo after treatment. Increases in the percent of cells expressing Leu 11 (natural killer cells), Ia antigen and transferrin receptor (activated lymphocytes) were observed after 3 mo of treatment with beta-carotene and diminished thereafter. Major changes were not seen in total lymphocyte count or in the percent of cells expressing CD11, CD8 or CD4 antigens. No clinical toxicity was observed. These data suggest that beta-carotene can modulate certain immune markers in HIV-infected subjects. Further study of this compound in HIV infection may be warranted.
Adult↗
Role of alcohol abuse in nutritional immunosuppression.
Nutritional status is an important determinant of the host resistance against infections and tumors. Alcohol interferes in various ways with the complex system of nutritional immunomodulation. Alcohol acts directly on mechanical barriers in the gastrointestinal tract and increases permeability of intestinal walls, which results in a reduced exclusion of immunogenic material in the intestine. Alcohol further affects granulocytopoiesis and suppresses various immune functions. Indirect effects on the immune response are caused by alcohol-induced malnutrition. Heavy alcohol abuse is associated with a high energy intake derived by alcohol and an inadequate intake of protein, vitamins and minerals. In addition, alcohol abuse impairs absorption, utilization, storage and excretion of nutrients, which together with inadequate nutrient intakes results in nutritional immunosuppression. The high incidence of infections in alcoholics could be one consequence of the alcohol-induced immunosuppression.
Alcoholism↗
LP-BM5, a murine model of acquired immunodeficiency syndrome: role of cocaine, morphine, alcohol and carotenoids in nutritional immunomodulation.
Potential immunomodulation by nutritional excesses and deficiencies can act as cofactors in human immunodeficient virus infection. The role of nutrition in the development and expression of acquired immunodeficiency syndrome (AIDS) is suggested and evaluated. LP-BM5 murine retroviral infection causes immune changes yielding an acquired immune deficiency syndrome with functional similarities to human AIDS. The value of the murine AIDS model to evaluate, rapidly, immune changes caused by potential cofactors, including nutritional changes, is illustrated.
Animals↗
Modification of resistance to Streptococcus pneumoniae by dietary ethanol, immunization, and murine retroviral infection.
Hallmarks of the acquired immune deficiency syndrome (AIDS) are immunologic alterations, frequently associated with opportunistic infections. To study such associations, LP-BM5 murine retrovirus infection was used as a murine model of AIDS. Retrovirally infected and uninfected mice were fed a 5% (v/v) ethanol diet for 55 days and then fed a 7% v/v ethanol diet for the final 7 days to assert the role of ethanol as a cofactor in development of murine AIDS. There was a reduction in polymorphonuclear neutrophils count in ethanol-fed groups. Neutrophils increased in retrovirus-infected groups, except those vaccinated 10 days before challenge with live bacteria. The percentage of splenic lymphocytes in the retrovirus-infected group was reduced in comparison with controls. Survival of the mice challenged intraperitoneally with Streptococcus pneumoniae was increased by vaccination and suppressed by dietary alcohol. Retrovirus infection caused a much faster death rate after bacterial challenge than nonretrovirus infected controls. Vaccination played an important role in delaying the death rate in all treated groups. Transferring spleen cells from healthy, unimmunized mice also enabled the retrovirally infected mice to survive the bacterial infection longer. Enhancement of resistance to S. pneumoniae by vaccination and transfer of immunocompetent cells to mice immunosuppressed by retroviral infection show the potential to use immunomodulation to affect disease resistance in AIDS.
AIDS-Related Opportunistic Infections↗