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Biomedical subjects

E Mihich

Publications and source records attributed to E Mihich.

At least 127 records · Page 7Linked to original sources
PubMed1978

Cell population kinetics of fast- and slow-growing transplantable tumors derived from spontaneous mammary tumors of the DBA/2 Ha-DD mouse.

The proliferation kinetics of a fast-growing spontaneous mouse mammary tumor subline (SMT-F) and a slow-growing spontaneous mouse mammary tumor subline (SMT-S) tumor have been determined autoradiographically at 2 different stages of tumor growth. The length of the cell cycle and the growth fraction for SMT-F were 11.2 hr and 0.85, respectively, on Day 14 and 12.1 hr and 0.78 on Day 28. For SMT-S these same parameters were 15.6 hr and 0.50 on Day 14 and 16. 1 hr and 0.45 on Day 28. On Days 14 and 28 the mitotic indices were 1.3 and 1.0%, respectively, for SMT-S, compared to 2.2 and 1.9% for SMT-F. The cell loss rate, cell loss factor, and cell loss were significantly higher for SMT-F than for SMT-S. The difference in the growth rates for these 2 tumor lines was attributable to a slight prolongation of the length of the cell cycle and a reduction in the growth fraction of SMT-S.

Adenocarcinoma↗
PubMed1977

Multiple basis of combination chemotherapy.

In combination chemotherapy, the type of drug interactions can be divided into three broad categories: 1) combinations based on cooperative effects of active drugs; 2) combinations in which the effectiveness of an active drug is increased by the concurrent administration of an inactive agent; and 3) combination of an active drug with an agent capable of selectively reversing the toxicity of the first drug. Many concepts have been proposed to explain the synergistic interaction between two active drugs at the level of the target cell. These include multiple inhibition of a single enzyme, enhanced activation, decreased inactivation, increased drug uptake, sequential blockade, concurrent inhibition, complimentary inhibition, and concerted inhibition. The therapeutic advantage of combination chemotherapy may reside in the whole organism, reflecting increased bioavailability of drug, reduced dose-limiting toxicity or reduced impairment of host defenses; it may reside in the tumor cells, reflecting the multiple molecular mechanisms of interaction mentioned above. Examples discussed include among others methotrexate plus citrovorum factor, thymidine or allopurinol, araC plus tetrahydrouridine and 3-deazauridine plus testosterone.

Animals↗
PubMed1977

Studies on the structure--activity relationship among aliphatic and aromatic bisguanylhydrazones and some related compounds.

A total of 18 compounds consisting of 7 alphatic and 7 aromatic bis(guanylhydrazones), p-quinone-bis(guanylhydrazone), one monoguanylhydrazone, one diamidine and one diguanidine were studied spectrophotometrically to determine their ability to interact with native calf-thymus DNA and the possible correlation of binding with biological activity. In each case, the ability of a compound to bind to DNA correlate with its ability to inhibit the activity of DNA-dependent DNA polymerase (EC 2.7.7.7) extracted from mouse leukemia L1210 cells. For example, all the aromatic bis-guanylhydrazones and diamidine (hydroxystilbamidine), which were good inhibitors of the enzyme activity, showed a biphasic interaction with DNA. All the aliphatic compounds displayed no detectable interaction with DNA in the Tris buffer used, and were also poor inhibitors of the polymerase activity. Interaction of decamethylene diguanide (Synthalin with DNA could not be determined because the compound does not absorb light in the UV-VIS region. However, in similarity with other aliphatic compounds, this agent was a poor inhibitor of DNA polymerase reduction. The p-quinone-bis(guanyl-hydrazone) and p-phenylbenzaldehyde-monoguanylhydrazone showed only a monophasic interaction with DNA and caused an intermediate inhibition of the enzyme activity. When tested for possible anti-leukemic activity against i.p. L1210 leukemia in syngeneic DBA/2J mice, all the aromatic bis-guanylhydrazones as well as hydroxystilbamidine caused prolongation of survival of tumor-bearing mice. Among the aliphatic bisguanylhydrazones, all of which showed no binding to DNA and caused at the most only a very slight inhibition of DNA polymerase, only methylglyoxal-bis(guanylhydrazone) (CH3--G) had antileukemic activity. Synthalin also inhibited leukemia growth. Evidences presented indicate that the mechanisms of action of aliphatic and aromatic bisguanylhydrazones may be quite different. Furthermore, the ability to bind to DNA may be a useful criterion to predict the antileukemic activity of aromatic guanylhydrazones and possibly other aromatic-bis-cationic compounds, but not that of aliphatic congeners.

Animals↗
PubMed1977

Differential tumor immunogenicity of L1210 and its sublines. I. Effect of an increased antigen density on tumor cell surfaces on primary B cell responses in vitro.

The differential immunogenicity of DBA/2 lymphoma L1210 and three L1210 sublines, each resistant to a different anti-leukemic agent (guanazole, methylglyoxal-bis-guanylhydrazone, and 4,4-diacetyldiphenylurea-bis-guanylhydrazone), was evaluated in vitro. Syngeneic spleen cells from nonimmunized DBA/2 mice were cultured in the presence of graded numbers of irradiated cells of L1210 or its sublines. The stimulation elicited a T-independent primary antibody response in vitro which was measured by determining the number of plaque-forming cells by using the immunizing lymphoma cells as target. Cells of all three sublines exhibited an increased immunogenicity, as compared to that of the parental L1210 cells, in eliciting the response directed to tumor-associated antigens which were common to all sublines. Dose-response experiments showed that high doses of the parental cells did stimulate responses which were detectable with subline cells as target. The results indicated that the differential immunogenicity of L1210 and its sublines, as demonstrated in the present assay system, is primarily quantitative, and was apparently due to increased amount or density of common tumor-associated antigens on the subline cells. The implications of these observations are discussed in relation to the possible mechanisms underlying the emergence of highly immunogenic drug-resistant sublines.

Animals↗
PubMed1977

Increased primary cell-mediated immunity in culture subsequent to adriamycin or daunorubicin treatment of spleen donor mice.

Spleen cell populations from mice treated with Adriamycin or daunorubicin were found to develop a greater complement-independent cellular cytotoxic immune response during culture with allogeneic tumor cells than spleen cells from untreated or cyclophosphamide-treated animals. A temporal and drug dose dependence of this effect was demonstrated. The changes in spleen cell population occurring in the donor mice consequent to drug treatment were evident in the nylon woll-adherent fraction of the spleen cells. The results are consistent with the possibility that the concentration of specific progenitor or accessory cells in the spleen is increased consequent to drug treatment.

Animals↗
PubMed1976

Spectrophotometric studies on the binding with polynucleotides of 4,4'-diacetyldiphenylurea-bis(guanylhydrazone) and methylglyoxal-bis(guanylhydrazone).

4,4'-Diacetyldiphenylurea-bis(guanylhydrazone) (DDUG), an agent very effective against several animal leukemias and tumors, was found, spectrophotometrically, to interact in a biphasic manner with several natural, native and heat-denatured, and synthetic DNAs. The spectrum of DDUG was shifted towards the visible region with a hypochromic shift reaching a maximum hypochromicity at 316 mmu at a 1 : 1 molar ratio of DDUG to DNA nucleotide. Increasing molarity of DNA nucleotide resulted in a further shift towards the visible end, but with hyperchromicity rather than hypochromicity, and reaching its peak at 323 mmu. The interaction with yeast RNA was much weaker than that with DNA. 4,4'-Diacetyldiphenylurea (DDU) did not show any interaction with DNA; its monoguanylhydrazone (DDUM) showed only a hypochromic interaction. In contrast to DDUG, methylglyoxal-bis( guanylhydrazone (CH3-G), an aliphatic bisguanylhydrazone with antileukemic properties, showed only a hypochromic interaction with DNA at low ionic strength. Unlike DDUG, CH3-G was a very weak inhibitor of the DNA polymerase reaction. The hypochromic shift of the DDUG spectrum with DNA was abolished in the presence of 15 mM sodium citrate or 500 mM NaCl but not in the presence of 150 mM NaCl or 100 mM sodium acetate. The hyperchromic shift was abolished in the presence of 8 M urea. From the results obtained with different DNAs, RNA, synthetic polynucleotides and nucleotides, it appears that the total shift of the DDUG spectrum in the presence of intact DNA can not be ascribed to interaction with a single base although a greater shift occurred in the presence of G-C rich DNA.

Antineoplastic Agents↗
PubMed1975

Selection for high immunogenicity in drug-resistant sublines of murine lymphomas demonstrated by plaque assay.

The immunogenicity of lymphoma L1210 and three L1210 sublines, resistant to methylglyoxal bis(guanylhydrazone), 4,4'-diacetyldiphenylurea bis(guanylhydrazone), or guanazole (L1210/GZL), respectively, was evaluated. Syngeneic DBA/2J mice were given a single i.p. injection of serially diluted suspension of irradiated cells from L1210 or L1210 sublines. Five days later spleen cells from the immunized mice were tested for the presence of plaque-forming cells using the immunizing lymphoma cell lines as target. Sera collected from the animals were examined for cytolytic antibody activity by lysis in gel using the same target cells. For comparison, the H-2 immunogenicity of L1210 and its sublines was investigated in H-2-incompatible allogeneic mice. The following results were obtained. (a) All the sublines showed increased immunogenicity and susceptibility to lysis as compared to L1210 cells. The number of plaque-forming cells/spleen ranged from 100 for L1210 to 4450 for L1210/GZL, the most immunogenic subline, and the antibody titer ranged from 1/8 for L1210 to 1/128 for L1210/GZL. (b) All the sublines carried common tumor-associated antigens that apparently made primary contributions to the increased immunogenicity. (c) The common tumor-associated antigens were also expressed on L1210 cells, although in a lesser defree, as evidenced by the definite, albeit low, capacity of L1210 cells to absorb DBA/2J anti-L1210/GZL antibodies. (d) Spleen and thymus cells of DBA/2J mice as well as unrelated murine ascites tumor cells did not cause significant absorption of these antibodies. (e) Only a partial inverse relationship could be demonstrated between tumor-associated antigens but the lowest for H-2. The above results would seem compatible with the hypothesis that the increased immunogenicity of drug-resistant L1210 sublines is attributable to the selection of preexisting highly immunogenic cells during immunosuppression by treatments selecting for drug resistance.

Animals↗
PubMed1975

Mouse effector functions involved in the antibody-dependent cellular cytotoxicity to xenogeneic erythrocytes.

Mouse spleen cell populations were fractionated by carbonyl iron depletion and nylon wool column separation. The fractions were tested for phagocytic and lytic activity against antibody-coated 51Cr-labeled sheep red blood cells. Carbonyl iron resistant cells had no phagocytic activity but caused lysis at a relatively slow rate. Nylon wool column nonadherent cells had a similar effect. In contrast with the slow lytic action of these cells, nylon wool adherent cells or non-carbonyl iron-treated cells had phagocytic as well as rapid lytic action. Under the conditions studied, both rapid and slow lytic functions were saturable whereas the phagocytic function was not.

Animals↗
PubMed1975

Effect of antimyeloma cell antiserum on immunological enhancement.

Growth of Sarvoma 180 in AKR mice was enhanced by immunization with frozen-thawed homogenates of this tumor. Treatment of host mice with rabbit antimyeloma cell antiserum, either furing immunization or shortly after tumor implantation, resulted in a decreased incidence of tumor rejection or an increased rate of tumor growth. A slow-growing subline from a spontaneous, DBA/2Ha-DD mammary tumor is rejected after initial growth in DBA/2J mice. The incidence of rejection was reduced by treatment with the antiserum studied.

Animals↗
PubMed1975

Fast- and slow-growing transplantable tumors derived from spontaneous mammary tumors of the DBA/2 Ha-DD mouse.

Nineteen transplantable tumor lines were established from individual spontaneous mammary tumors of the DBA/2 Ha-DD mouse. Of these lines, 5 were classified as fast growing, 8 as medium growing, and 6 as slow growing, based on the time required for the tumors to reach a size of 10 mm in average diameter and on the average survival time of tumor-bearing syngeneic hosts. The relative differences in rate of growth among 5 of these lines remained stable during 11 to 19 transplant generations. In DBA/2J mice, a slow-growing and a fast-growing tumor line were cross-immunogenic. The differences in growth rate between these 2 tumor lines were not primarily related to differences in immunogenicity since they were not abolished in preirradiated hosts. The growth of cell populations from these 2 tumor lines in culture was comparable; however, cells from the fast-growing line had a plating efficiency about 4 times higher than those from the slow-growing line.

Animals↗
PubMed1974

Specific inhibition of the enzymic decarboxylation of S-adenosylmethionine by methylglyoxal bis(guanylhydrazone) and related substances.

Methylglyoxal bis(guanylhydrazone) {1,1'-[(methylethanediylidene)-dinitrilo]diguanidine} is a very potent inhibitor of putrescine-activated S-adenosylmethionine decarboxylases from many different mammalian tissues, including sublines of mouse L1210 leukaemia that are resistant to the drug as well as sublines that are sensitive. The inhibition of purified rat ventral prostate S-adenosylmethionine decarboxylase is competitive with respect to the S-adenosylmethionine substrate, and is much greater in the presence than in the absence of the activator putrescine. Inhibition by the drug depends, among other things, on the nature of the aliphatic amines that can serve as stimulators of rat prostate S-adenosylmethionine decarboxylase. Effects of some congeners of methylglyoxal bis(guanylhydrazone) on the enzyme are described.

Amidines↗