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Biomedical subjects

E Mihich

Publications and source records attributed to E Mihich.

At least 109 records · Page 6Linked to original sources

Augmentation of the development of immune responses of mice against allogeneic tumor cells after adriamycin treatment.

In C57BL/6J mice, depending on the dose of P815 cells used for immunization, Adriamycin exerted different effects on the cell-mediated lytic response and complement-dependent cytotoxicity. At the dose of 3 X 10(7) P815 cells, Adriamycin treatment had no apparent effect on cell-mediated lytic response regardless of timing of drug treatment. At lower doses of antigen (10(7) or 5 X 10(6) cells), the response was augmented in Adriamycin-pretreated mice. Similarly, under conditions which led to a suboptimal complement-dependent humoral response of untreated control, Adriamycin pretreatment resulted in an augmented response; under conditions of maximal response, Adriamycin was suppressive. Suppression was maximal if the drug was injected at either the same time or shortly before or after antigen. The cell-mediated lytic response was proportional to the dose of antigen used, while the complement-dependent humoral lytic response was inversely proportional to dose of antigen in the range used in these experiments. Secondary cell-mediated lytic response in culture was also augmented if mice had been pretreated with Adriamycin 5 days before the primary immunization. The cell-mediated lytic response of spleen and peritoneal exudate cells from mice immunized with relatively low doses of P815 cells 5 days after treatment with Adriamycin was increased 12 to 15 days after immunization. The cytotoxic effects were present in both plastic adherent and nonadherent fractions of either spleen or peritoneal cell populations. All these effector cells were found to be anti-Thy 1.2 sensitive. The phagocytic activity of spleen cells was increased after immunization, but no drug effect was observed; following 24 hr of culture, however, cells from drug-treated immunized donors had increased phagocytic activity as compared to that of controls. Increased phagocytosis also developed in cells nonadherent to plastic.

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Differential expression of murine leukemia antigen on L1210 parental and drug-resistant sublines.

The different expression of surface antigens on L1210 leukemia DBA/2 and drug-resistant L1210 sublines was investigated. Indirect cytotoxic test, the anti-L1210/v alloantiserum reacted more strongly with subline cells than with parental cells. Absorption of the antiserum with Gross cellular surface antigen-positive AKR leukemia (AKSL-4) cells led to a much greater difference in this reactivity. Quantitative absorption experiments revealed that the drug-resistant sublines had 5 times higher absorption capacity than did the parental line. After complete absorption of antibodies against murine leukemia virus-related antigens, the anti-L1210/v alloantiserum still reacted with L1210 cells. This cytotoxicity could be removed after absorption with C3H mammary tumor (MAC-1) cells but not with normal C3H lymphocytes. These results provide evidence that the major cytotoxic activity of the antiserum against L1210 and L1210 subline cells was due to antibodies against murine mammary tumor virus-related antigen and that the drug-resistant sublines of leukemia L1210 have higher quantitative expression of mammary leukemia antigens.

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The relationship of blood vessel proximity and time after radiolabeled thymidine administration to tumor cell population kinetics in a transplanted mouse mammary tumor.

The relation between the time of administration of tritiated thymidine and the proximity of cells to blood vessels and their labeling index, grain density per labeled cells, mitotic index, and growth fraction have been determined autoradiographically in a transplanted mammary tumor of mice. The tumor was rich in blood vessels, and the cells were densely packed, showing a few glandular structures. Shortly after tritiated thymidine administration, cells closer to the blood vessels (0-70 mu) showed a higher percentage of labeled and mitotic cells, more grains per labeled cells, and a higher growth fraction than the cells located in the outer zone (70-140 mu). Eight days later the values of these parameters were similar in both areas. The cell cycle time, the duration of mitosis, the S phase, the G1 phase and the G2 phase were essentially the same in both zones. These results could be attributed either to reutilization of nucleic acid metabolites or release of the original precursor from cells. It is suggested that label redistribution, which may perturb the measurement of the apparent turnover of labeled proliferating cellular systems in the body should be considered in all cases of autoradiographic or labeled purine-pyrimidine turnover studies.

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Prostaglandin modulation of development of cell-mediated immunity in culture.

Prostaglandins (PGs) have been implicated as possible modulators of the immune response and various inflammatory processes. Various cell components of the immune system are sources of PGs, and mitogen or antigen stimulation of human or murine lymphocytes leads to their enhanced release. They are also released from various human and animal tumours. Thus, as cells of the immune system are both sensitive to and sources of PGs, these factors may be important as physiological immune regulators. For example, PGs of the E series are capable of inhibiting many effector functions. They have also been shown to inhibit the development of the humoral response. Although they inhibit the proliferative response to mitogens, little is known about their effects on the development of the cell-mediated immune response to antigens. The data summarized here implicate PGs, thromboxane A2 (TXA2) and prostacyclin (PGI2) in the regulation of cellular immune responses at the inductive phase. Some of these data have been reported in abstract form.

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Synthesis, biologic effects, and biochemical properties of some 2'-azido- and 2'-amino-2'-deoxyarabinofuranosyl pyrimidines and purines.

Various 2'-azido- and 2'-aminoarabinofuranosyl purine and pyrimidine nucleosides have been synthesized. Among these, the derivatives of cytosine and of adenine inhibit the growth of some tumor cell lines in vitro and in vivo. 2'-Azidoarabinofuranosyl cytosine also interferes with the replication of herpes simplex virus types I and II. Whereas 2'-azidoara-C is resistant to deamination by a partially purified CdR deaminase from KB cells, the adenine derivatives are substrates for aminohydrolases partially purified from calf and mouse intestines. Both azido- and aminoara-C are phosphorylated by partially purified CdR kinases from leukemia L1210 and from human AML blast cells. The accumulated data encourage exploration of the clinical utility of the more potent of these analogues.

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Selective imbalances of cellular immune responses by adriamycin.

It has been demonstrated that spleen cells from mice treated with adriamycin not only develop an increased cell-mediated immune response during culture with allogeneic tumor cells, but also have increased phagocytic activity following culture, respond to heat-treated (45 degrees C) alloantigen, develop an increased suppressor cell function, and are less sensitive to a suppressor cell activity. Thus, changes in spleen cell subpopulations occurring in the donor mice consequent to drug treatment result in demonstrable selective imbalances of cellular functions involved in the immune response. One cell type which has been implicated as being necessary in the expression of all these functions is the monocyte-macrophage, and it is suggested that an effect of adriamycin on progenitors of this cell type may lead to the imbalances.

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Biochemical pharmacological determinants of drug action in cancer therapeutics.

Based on the hypothesis that the selectivity of the antitumor action of a drug is dependent on a multiplicity of systemic and target cell factors, the role of pharmacokinetics and biotransformation in determining drug bioavailability and the target cell determinants of the action of arabinosylcytosine and of methotrexate are briefly discussed. The modulation of the action of an antimetabolite by a modification of the bioavailability of certain metabolites is mentioned as an approach towards the development of more selective chemotherapy.

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Modification of mouse immune responses against allogeneic tumor by pretreatment of antigen with mitomycin C or X-irradiation.

Treatment of P815 mastocytoma cells with mitomycin C or X-irradiation prior to their inoculation into an allogeneic host resulted in a shift in the appearance of the peak of the T-killer cell population from day 10 to day 6. This finding is discussed in relation to the caution that must be exerted in extrapolating data obtained in studies in vitro using one-way mixed lymphocyte cultures to in vivo model systems involving proliferating tumor cells as immunogens.

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Reversal of the in vitro methotrexate suppression of cell-mediated immune response by folinic acid and thymidine plus hypoxanthine.

The development of a primary complement-independent cellular cytotoxic immune response in culture by C57BL/6J spleen cells stimulated with X-irradiated allogeneic P815 tumor cells was inhibited more than 50% in the presence of 1.5 X 10(-8) M methotrexate. This immunosuppression by methotrexate was time and dose dependent. Equimolar folinic acid administered at either -4, 0, +4, or +24 hr relative to 1.5 X 10(-8) M methotrexate reversed immunosuppression by more than 50%. Increased folinic acid concentration (5 to 10-fold) completely restored the immune response only if added 4 hr prior to methotrexate. Thymidine plus hypoxanthine (100 microM each) when present throughout the 4-day culture period gave total reversal of immunosuppression. The reversal was also obtained with hypoxanthine alone and was dose dependent. These results indicate that reversal of the methotrexate-induced impairment of cellular immune function depends on several parameters including the concentration of methotrexate and of the reversing agents as well as the time of exposure of relevant target cells to these agents.

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Temporal specificity of procarbazine in the inhibition of mouse immune responses to allogeneic tumor.

The inhibition of the cellular response of C57Bl/6 mice against allogeneic P815 mastocytoma by procarbazine was shown to be uniquely dependent upon time of administration with respect to antigen. If the drug was given 4 or 6 days after antigen, the development of the T cell effectors was inhibited; if it was given earlier (2 hr or 1 or 2 days after antigen), the response was affected less. In contrast to the immunosuppressive effectiveness of delayed administration of procarbazine, the inhibition of the T cell response by daunorubicin was greatest when the agent was given 2 days after antigen, and that by cyclophosphamide, at the concentrations used, was relatively time independent. Under similar conditions the effects of the three agents on the humoral response were found to be less selective. The inhibition of both responses by procarbazine was shown to be dose dependent and relatively independent of the route of administration.

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