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Enhancing effect of coenzyme, Q10 on immunorestoration with Mycobacterium bovis BCG in tumor-bearing mice.

Effect of the additional treatment with coenzyme Q10 on immunorestoration with Mycobacterium bovis BCG in tumor-bearing mice was investigated. Cell-mediated cytotoxicity in tumor-bearing mice against alloantigenic tumor cells was determined by 51Cr release assay using spleen cells of C57BL/6N mice which had been inoculated subcutaneously with syngeneic melanoma-B16 and immunized intraperitoneally with alloantigenic mastocytoma P815-X2 cells. The cell-mediated cytotoxicity against mastocytoma P815-X2 cells was gradually depressed with the growth of melanoma-B16. The depressed, cell-mediated cytotoxicity in tumor-bearing mice recovered slightly by the treatment with BCG. The recovery effect of BCG on the depressed, cell-mediated cytotoxicity was significantly enhanced by the additional treatment with coenzyme Q10. Coenzyme Q10 did not have an apparent effect on the depressed, cell-mediated cytotoxicity in tumor-bearing mice. These results show that coenzyme Q10 enhances the immunorestoration with BCG in tumor-bearing mice.

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Tumor-induced immunosuppression.

Three tumor systems, including a mastocytoma, plasmacytomas, and a leukemia-lymphoma were studied for their ability to modify humoral immunity to sheep erythrocytes both in vivo and in vitro. All tumors resulted in a depression of the hemolytic antibody plaque-forming cell response in susceptible mice. These studies indicated that the mechanism(s) of suppression, although not fully defined, were different for each model system investigated.

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Inhibition of the growth of murine tumour cells in vitro by serum from non-immune syngeneic and allogeneic mice.

Sera from DBA/2 and Quackenbush mice (which are non-immune for mastocytoma and Sarcoma 180 respectively) contain a heat-labile (56 degrees for 30 min) component(s) that inhibits the in vitro growth of DBA Mastocytoma P-815 X-2 and Sarcoma 180. Adsorption of the sera with tumour cells at 4 degrees did not eliminate the factor(s), suggesting that it is not an antibody. In liquid suspension cultures inhibitory activity was observed at concentrations of mouse serum of 10--20% and in semisolid agar clonogenic cell assays at concentrations as low as 1%. The influences of the inhibitor(s) for both tumours and in both culture systems were parallel. However, there was a quantitative difference in susceptibility to other environmental factors (FCS concentration, bicarbonate concentration, and O2 tension) between the two tumours. These results parallel the in vivo findings where intravenously injected mastocytoma cells produced more tumours than did Sarcoma 180.

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Relationship of molecular weight to antiviral and antitumor activities and toxic effects of maleic anhydride-divinyl ether (MVE) polyanions.

The molecular weight (MW) and dose dependency of several of the toxic effects and antitumor and antiviral activities of a new series of five maleic anhydride-divinyl ether copolymers (MVE) were established. Each polyanion preparation was relatively homogeneous and exhibited a narrow MW range, from 12,500 (MVE-1) to greater than 52,000 (MVE-5). All of the polyanions were effective as adjuvants to surgery against the metastatic Lewis lung carcinoma, and also exhibited marked antitumor activity against the P815 mastocytoma. MVE-1 retained antitumor activity while losing considerable antiviral activity. This polyanion also exhibited the least toxicity with regard to criteria such as sensitization to the lethal effects of endotoxin, inhibition of reticuloendothelial function, and depression of the microsomal mixed functional oxidase system. The MVE-4 (MW, 32,000) and MVE-5 (MW, 52,600) polyanions exhibited potent antitumor and antiviral activity, but also demonstrated dose-dependent toxic effects.

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In vitro and in vivo production of chemotactic inhibitors by tumor cells.

The ascites fluid or peritoneal washings of DBA/2 mice bearing the P815 mastocytoma have been found to contain a chemotactic factor inactivator (CFI) which inactivates the bacterial chemotactic factor as well as the chemotactic activity associated with the C3 and C5 fragments when assayed on rabbit neutrophils. The amount of CFI is proportional to the number of tumor cells in the peritoneal exudate. The inactivator is also found in tumor cell hemogenates as well as in culture fluid from tumor cells growing in vitro. The activity is heat-labile but is not affected by protease inhibitors. Its molecular weight is greater than 50,000 daltons, based on Sephadex chromatography and sucrose density gradient ultracentrifugation studies. In C57BL/6 mice, which reject the mastocytoma, CFI levels decrease in proportion to the decreasing numbers of tumor cells.

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Overall pathway of mononucleosome production.

Five electrophoretically distinguishable classes of mononucleosomes (MI, MII, ...MV) are produced upon treatment of mammalian nuclear chromatin with micrococcal nuclease. These five forms differ in their initial DNA lengths, relative mass proportions, stability, contents of histone H1, and presence of certain nonhistone proteins. A new "chromatin fingerprinting" technique has been developed in order to trace nuclease-mediated interconversions between these mononucleosomes and their polynucleosomal precursors. Application of this technique, together with earlier findings from this laboratory, has made possible the elucidation of the overall pathway of nuclease cleavage of chromatin which leads to the production and interconversion of these mononucleosomes, and has permitted reconstruction of the organization of these mononucleosomes in undigested chromatin...

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Large animal studies of hyperthermia and irradiation.

Investigators who have studied hyperthermic response of spontaneous animal tumors have reported complete remission for variable periods of 15 to 38% of tumors treated. Normal tissue complications were minimal. Long-term control appears more likely if irradiation is combined with hyperthermia, but information is lacking to date to confirm this. Dose-response assays of radiation alone have been done which would make comparisons with hyperthermia and radiation more meaningful. Probabilities for increasing tumor control without significantly increasing normal tissue response can be estimated better from such assays. Spontaneous tumors in companion animals have advantages over rodent tumor systems of relatively larger treatment fields; longer follow-up times are possible, and serial monitoring of a variety of clinical data can be done. Experience of investigators using these tumors has shown that animal owners and referring veterinarians are most cooperative in reasonable, humane approaches to experimental cancer therapy.

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Further characterization of thymic suppressor cells and a factor that suppress the generation of cells cytotoxic for a syngeneic tumor in DBA/2 mice.

Antigen-specific suppressor cells and suppressive extracts obtained from the thymuses of DBA/2 mice bearing small syngeneic P815 mastocytomas were compared for their immunogenetic properties and requirements. The assay for specific suppression involved the ability of either cells or extracts to inhibit the primary in vitro cytotoxic response of normal DBA/2 splenocytes to mitomycin-treated P815 cells. It was shown that pretreatment of suooressor cell populations with anti-Iad antiserum plus rabbit complement removed the suppressive activity. Similarly, absorption of the suppressor factor with anti-Iad antiserum removed the suppressive properties of the material. It was found that the suppressor cells, generated in DBA/2 tumor bearers, were capable of specifically suppressing the anti-P815 response of B6D2 F1 radiation chimeras possessing lymphoid cells of the H-2b or H-2t2 haplotype equally as well as they could suppress the response of H-2d-bearing effector cells. This indicates that the suppressor cells are not H-2 restricted with respect to K or D markers on the responder cells in this system.

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