Cancer research
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The effect of anticoagulant drugs on formation of experimental tumor metastases after i.v. inoculation of BL6 melanoma or Lewis lung carcinoma (3LL) cells was studied in mice with stimulated or depressed natural killer (NK) cell activity. When mice were treated with anticoagulants (warfarin or heparin) or when NK cell activity was stimulated by polyinosinic-polycytidylic acid, significant antimetastatic effects were observed; these effects were substantially augmented when the treatments were combined. However, when NK reactivity of mice was suppressed by anti-asialo GM1 serum or cyclophosphamide, the antimetastatic effects of warfarin and heparin were diminished or completely abrogated. ⋯ Warfarin treatment increased the elimination of radiolabeled BL6 melanoma cells from the lungs of normal mice, and the rate of tumor cell elimination was further potentiated when NK cell activity was stimulated by polyinosinic-polycytidylic acid. In contrast, after anti-asialo GM1 treatment, warfarin had no effect on the survival of i.v. administered tumor cells. Covering of YAC-1 or 3LL tumor cells with fibrin after in vitro exposure with fibrinogen and thrombin substantially protected them from the in vitro cytotoxic action of NK or lymphokine-activated killer cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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Because of potential significance of fecal mutagens and secondary bile acids in the pathogenesis of colonic cancer and of inverse association between dietary fiber and colonic cancer risk, the effect of dietary wheat and rye fiber on fecal mutagenic activity and bile acid levels was studied in 15 healthy men and women who were consuming high fat/moderately low fiber diets and excreting high levels of fecal mutagens and bile acids. Each participant provided two 24-h stool specimens and a 3-day diet record while consuming their normal diet (control). All subjects were then asked to consume their normal diet plus 11 g of supplemental fiber per day in the form of whole grain bread for 4 weeks. ⋯ The concentration of fecal secondary bile acids was significantly lower during the fiber supplemental period in all subjects. Fiber supplementation also inhibited the fecal mutagenic activity in TA100 and TA98 with and without microsomal activation. Thus, the increased fiber intake in the form of whole wheat and rye bread may reduce the production and/or excretion of fecal mutagens and decrease the concentration of fecal secondary bile acids in humans.
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Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was tested in patients with refractory, solid tumors. Twenty patients received 25 evaluable courses. HMBA was given by continuous i.v. infusion for 5 consecutive days with courses repeated every 4 wk, provided there was acceptable, reversible toxicity. ⋯ Once Css was achieved, daily variation was generally less than or equal to 10% from the mean Css. HMBA plasma Css increased linearly with dose, but there was variation in the Css achieved in individual patients at each dose. Doses of 24 to 33.6 g/m2/day consistently produced plasma HMBA Css of 1 to 2 mM matching concentrations required for differentiation in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)
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Ribonucleotide reductase catalyzes the rate-limiting step in the de novo synthesis of 2'-deoxyribonucleoside 5'-triphosphates that is required for DNA replication. The mammalian enzyme consists of two nonidentical protein subunits that are both required for enzyme activity. In leukemia L1210 cells, enriched in G1-phase cells by centrifugal elutriation, it was found that ribonucleotide reductase activity increased as the cells progressed to S-phase. ⋯ The half-lives of the holoenzyme and its subunits were determined in S-phase cells by treatment with cycloheximide. The half-lives of the holoenzyme and the nonheme iron and EB subunits, as determined by enzyme activity, were 3.5, 7.6, and 4 h, respectively. These half-lives are consistent with the data that indicate that the EB subunit is the limiting component in L1210 cells.
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Both macrophages and natural killer cells have been implicated in the antimetastatic activity of maleic anhydride-divinyl ether (MVE-5). In the present study, we attempted to utilize anti-asialo-GM1 antibody and 2-chloroadenosine, agents that kill natural killer (NK) cells and macrophages, respectively, to determine the relative contribution of each effector cell type to the overall host defense. These agents were tested in the M109 lung metastasis model in syngeneic BALB/c mice, and the cytotoxic activities of both peritoneal macrophages and splenic NK cells were followed. ⋯ By Day 5 after MVE-5 treatment, 2-chloroadenosine only inhibited macrophage tumoricidal activity, and conversely, anti-asialo-GM1 antibody only inhibited NK reactivity. Despite the ability of these agents to increase survival of metastases in control animals, they only slightly abrogated the antimetastatic activity of MVE-5. Our data suggest that caution should be exercised in using these agents to discriminate macrophage and NK responses.