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PubMed1970

In vitro stimulation of antibody formation by peritoneal cells. II. Cell interactions and effects of immunochemical or metabolic inhibitors.

Peritoneal cells (PC) from normal, unimmunized mice were placed in ultra-thin monolayer cultures containing carboxymethylcellulose (CMC), sheep red blood cells (SRBC), and complement, and tested for the appearance of plaques of lysis. The behavior of PC from young male mice and from female mice that had given birth to several litters (retired breeder mice) was studied. It was found that cells from spleen, mesenteric lymph node, thymus, bone marrow, thoracic duct lymph, or Peyer's patches could not form plaques in the CMC microcultures. Also, various combinations of these cells did not lead to plaque formation. When cells from any of these sources were mixed with PC, there was either no effect or an actual inhibition of plaque formation, the plaque counts being lower than would have been expected from the number of PC present in the mixture. Optimal plaque formation by peritoneal cells was found to be dependent on an optimal cell concentration, this optimum being around 5 x 10(6)/ml for young male mice and 0.5 x 10(6)/ml for retired breeders. Inhibition of plaque formation was found with either supra- or suboptimal cell concentrations. The inhibition by excess cell concentration may have been a simple nutritional or nonspecific overcrowding effect, as it could also be induced by an addition of an excess of spleen or lymph node cells. The failure of more dilute PC preparations to give adequate numbers of plaques appeared to be more specific, as plaque numbers could not be restored to normal by addition of spleen cells. The suggestion was that some cell to cell interaction between PC was involved. This dependence on cell concentration was not seen with immunized spleen PFC. Plaque appearance could be specifically and reversibly suppressed by placing PC in a medium containing rabbit anti-mouse IgM serum. Anti-IgG serum had no such effect. These experiments strengthened our view, expressed in the accompanying paper, that plaque formation was due to the formation of IgM, hemolytic antibody to SRBC by the PC. Metabolic inhibitors were incorporated into monolayer cultures and had different effects with the different types of PFC used. In the case of spleen cells from mice actively immunized against SRBC 4 days before killing, actinomycin D had no effect on plaque counts and puromycin reduced plaque numbers by a factor of 2. In the case of PC from young male mice, actinomycin D in concentrations above 0.01 microg/ml caused reductions down to < 2% of control values in plaque counts, and puromycin (10 microg/ml) had a similar effect. The PC from retired breeder mice occupied an intermediate position between the two cases just discussed. A compartment of cells, equal to about one-fifth of the total normal PFC compartment, was identified as resistant to high concentrations of either actinomycin D or puromycin, being similar in these respects to PFC from spleens of intentionally preimmunized mice. The mitotic poison, Colcemid, did not affect plaque counts in any situation tested. The theoretical implications of these results are briefly discussed.

Animals↗
PubMed1972

Regulation of the immune system by synthetic polynucleotides. V. Effect on cell-associated immunoglobulin receptors and immunological memory.

Addition of polyadenylic-polyuridylic acid in complex form (poly A:U) without antigen to a suspension of spleen cells obtained from BALB/Aj mice primed 6 wk previously with human gamma-globulin (HGG) resulted in an immediate fourfold increase over background number of anti-HGG rosette-forming cells (RFC). Culture of similar cells in the presence of puromycin for 1-6 hr before poly A:U did not significantly reduce the response. Continued culture of primed spleen cells in the presence of poly A:U, resulted in a decrease of RFC to background levels within an hour followed by an increase again 6 hr later. This later increase in RFC was inhibited by addition of puromycin to the culture medium. The nonspecific stimulation by poly A:U of antibody production by primed spleen cells also was induced in vivo. Increases in splenic RFC were detectable 6 hr after intravenous injection of poly A:U alone, without antigen, into primed mice. The response peaked at 18 hr and had dissipated completely within 3 days. A second injection of poly A:U 24 hr or later after the first injection resulted in a second response, similar to the first with respect to kinetics and intensity. Rosette formation by poly A:U-stimulated cells could not be inhibited by mitotic poisons, but was inhibited by treatment of the cells with goat anti-mouse gamma-globulin serum, suggesting that the antibody involved was a 7S gamma-globulin. The decrease in RFC induced by culture of primed cells for 1 hr in poly A:U paralleled a decrease in secondary responsiveness of the cells to antigen. This poly A:U-induced inhibition of secondary responsiveness could be reversed by suspending the treated cells in supernatant fluids derived from poly A:U-stimulated cultures. The reversal was specific in that supernatant fluids removed from bovine serum albumin (BSA)-primed cells by poly A:U did not stimulate the response of HGG-primed cells to HGG. However supernatant fluids from BSA-primed cells caused the production of anti-HGG RFC if BSA rather than HGG was used as triggering antigen. The active factor in the supernatant fluids appeared to be a 7S gamma-globulin since activity was lost after 45 min incubation of the supernatant fluids in the presence of goat anti-mouse 7S gamma-globulin serum.

Animals↗
PubMed1978

Effect of colchicine on the antibody response. I. Enhancement of antibody formation in mice.

Colchicine (CC) enhances the antibody response in mice to protein antigens, like diphtheria toxoid and human gamma globulin, as well as to the 2,4,6-trinitrophenyl hapten. Maximal enhancement was observed when CC was administered to animals on the same day as the injection of antigen. The optimal dose of CC was in the range of 1.0-1.5 mg/kg body weight. The enhanced antibody formation was evident from elevated circulating antibody titers and from an increased number of antibody plaque-forming cells (PFC) of the spleen. The circulating antibody titer of CC-treated animals was higher than that of control animals by a factor of about 3-7 in the primary response, and by a factor of at least 15 in the secondary response. In terms of the number of antibody forming cells, CC enhanced the primary PFC response by approximately equal to 100%, and the secondary PFC response by as high as fivefold. The enhancing effect of CC seemed to be related to its mitosis-blocking capacity since (a) vinblastine another antimitotic drug, was found to be as effective as CC and (b) lumicolchicine, the non-anti-mitotic structural isomer of CC, was ineffective in potentiating antibody responses. The critical timing in the administration of CC on the same day as antigen suggests that most likely, the mitotic poison was acting on antigen-stimulated early dividing suppressor cells.

Animals↗
PubMed2004

Overexpression of DRG2 increases G2/M phase cells and decreases sensitivity to nocodazole-induced apoptosis.

DRG2, a member of the DRG subfamily in the GTP-binding protein superfamily, was identified as a repressed gene product in fibroblasts transformed by SV40. The significance of this down-regulation and the cellular role of DRG2 has not been understood in the past. To investigate the function of DRG2 we made a Jurkat cell line, Jurkat-LNCX2-DRG2, stably transfected with pLNCX2-DRG2 to overexpress human DRG2. Cell cycle distribution analysis revealed an increased accumulation of G(2)/M phase cells in Jurkat-LNCX2-DRG2 cells, indicating a retardation of cell-cycle progression. In addition, an overexpression of DRG2 reduced the sensitivity of Jurkat cells to the mitotic poison nocodazole. Our data suggest that overexpression of DRG2 in Jurkat cells affects genes regulating cell-cycle arrest and apoptosis, and that these molecular changes may be important in the growth or differentiation of cells.

Apoptosis↗
PubMed1993

Antimicrotubule agents induce polyploidization of human leukaemic cell lines with megakaryocytic features.

In most eukaryotic cells the regular alternation of chromosome reduplication and cell division is controlled by interdependent relationships which prevent progression to the next cell-cycle phase unless the preceding phase has been completed. Megakaryocytes become polyploid by allowing many rounds of DNA replication without completion of intervening mitoses. To assess the role of cell-cycle dependencies in megakaryocytopoiesis we examined human cell lines which express megakaryocytic features for their ability to continue DNA synthesis and undergo polyploidization in the presence of mitotic poisons. Treatment of HEL cells with colcemid blocked cell division but not cellular DNA synthesis. DNA content distributions of cells treated with colcemid for 48 h showed a marked increase in the proportion of polyploid cells (57.6% +/- 9.9%, n = 16), an increase in cellular size and nuclear lobation. Identical effects were observed in HEL cells treated with colchicine, nocodazole or taxol but not with the inactive compound lumicolchicine. Induction of polyploidization by antimicrotubule agents was also observed in the megakaryoblastic cell lines MEG-01, DAMI and UT-7 but not in the T-cell line MOLT-4 or the promyelocytic cell line HL-60. These results suggest that dependency of DNA replication on completion of the previous mitosis is suppressed in the megakaryocytic lineage.

Cell Division↗
PubMed1968

Effect of the Vinca alkaloids on RNA synthesis in human cells in vitro.

The Vinca alkaloids vinblastine sulfate and vincrystine sulfate, which are mitotic poisons, inhibit RNA synthesis in human (HEp-2) cells cultured in vitro. Analyses of RNA synthesis by cells treated with these drugs by acrylamide gel electrophoresis show that 28s rRNA and to a lesser extent 18s rRNA are preferentially inhibited. The synthesis of tRNA is affected much less than that of rRNA. The present experiments suggest that the drugs inhibit both the synthesis and processing of the nucleolar RNA precursors of rRNA. An explanation is also given for previous reports that these alkaloids preferentially inhibit the synthesis of tRNA in animal cells in vitro.

Antineoplastic Agents↗
PubMed2005

Activation of p53 by MDM2 antagonists can protect proliferating cells from mitotic inhibitors.

Recent studies have shown that activation of cell cycle checkpoints can protect normal proliferating cells from mitotic inhibitors by preventing their entry into mitosis. These studies have used genotoxic agents that act, at least in part, by activation of the p53 pathway. However, genotoxic drugs are known also to have p53-independent activities and could affect the sensitivity of tumor cells to antimitotic agents. Recently, we have developed the first potent and selective small-molecule inhibitors of the p53-MDM2 interaction, the nutlins, which activate the p53 pathway only in cells with wild-type but not mutant p53. Using these compounds, we show that p53 activation leads to G1 and G2 phase arrest and can protect cells from mitotic block and apoptosis caused by paclitaxel. Pretreatment of HCT116 and RKO colon cancer cells (wild-type p53) or primary human fibroblasts (1043SK) with nutlins for 24 hours followed by incubation with paclitaxel for additional 48 hours did not increase significantly their mitotic index and protected the cells from the cytotoxicity of paclitaxel. Cancer cells with mutant p53 (MDA-MB-435) responded to the same treatment with mitotic arrest and massive apoptosis. These results have two major implications for cancer therapy. First, p53-activating therapies may have antagonistic effect when combined with mitotic poisons. Second, pretreatment with MDM2 antagonists before chemotherapy of tumors with mutant p53 may offer a partial protection to proliferating normal tissues.

Antineoplastic Agents, Phytogenic↗
PubMed1990

The metabolism and mode of action of gentian violet.

Gentian violet has been used in medicine for almost 100 years: as an antiseptic for external use, as an antihelminthic agent by oral administration, and more recently, as a blood additive to prevent transmission of Chagas' disease. To date, no serious side effects have been reported when used externally. However, oral administration can cause gastrointestinal irritation, and intravenous injection can cause depression in the white blood cell count. Surprisingly, no acute toxic side effects were reported after administration of large amounts of gentian violet-treated blood. No studies have been done on long-term effects (chronic toxicity, carcinogenicity) of gentian violet-treated blood either in humans or in laboratory animals. Gentian violet is a mutagen, a mitotic poison, and a clastogen. The carcinogenic effects of gentian violet in rodents have been reported recently. In addition, a number of triphenylmethane-classed dyes, of which gentian violet is a member, have been recognized as animal and human carcinogens. A photodynamic action of gentian violet, apparently mediated by a free-radical mechanism, has been described in bacteria and in T. cruzi. However, the main target of gentian violet toxicity in the dark is the mitochondrion. Gentian violet is actively demethylated by liver microsomes from different animals and is reduced to leucogentian violet by intestinal microflora. Although the first process may represent a detoxication reaction, the second pathway may have toxicological significance because the completely demethylated derivative leucopararosaniline has been demonstrated to be carcinogenic in rats. A free-radical derivative of gentian violet is also formed by the action of rat liver microsomes, but whether this radical is involved in the cytotoxic effects of gentian violet in mammalian cells remains to be elucidated. Other pathways of gentian violet metabolism have recently been investigated that involve its oxidative N-demethylation by peroxidases. The N-demethylation of gentian violet by prostaglandin synthetase deserves further study. In this regard, the PGS system is being studied as an alternative activating pathway in xenobiotic metabolism because some carcinogenic intermediates can be formed during this cooxidation reaction.

Animals↗
PubMed1981

Synthesis and binding to tubulin of an allocolchicine spin probe.

A spin probe for the colchicine binding site on tubulin has been synthesized from allocolchicine. The probe is competitive to colchicine with an apparent inhibition constant of 11 microM while allocolchicine has an inhibition constant of 2 microM. Microtubule assembly is inhibited to 50% by 7 microM of the spin probe. As a mitotic poison the spin probe is less potent than colchicine. These data suggest that the probe binds to the same site on tubulin as colchicine and in spite of the somewhat lower efficiency, it seems to be a valuable tool for the study of the microtubule system.

Animals↗
PubMed1976

Differentiation of host-mediated antitumor agents from mitotic posons by the antitumor foot-pad reaction in Ehrlich carcinoma-ddY mouse system.

The effect of antitumor agents (lentinan, PS-K, Mitomycin-C, 6-mercaptopurine, etc.) on the antitumor delayed hypersensitivity reaction (DHR) measured by the foot-pad test was compared with their effect on tumor growth in ddY mice with Ehrlich tumor. These agents all inhibited growth of Ehrlich carcinoma. Lentianan and PS-K enhanced the antitumor DHR, but Mitomycin-C and 6-mercaptopurine did not. By plotting the effect of agents on the anti-tumor DHR against these effects on tumor weight, host-mediated antitumor agents could be differentiated from mitotic poisons. Attempts to distinguish these two types of agents by the same method using a syngeneic tumor system were unsuccessful.

Animals↗
PubMed1999

[Frequency of embryonal lethality in various strains of Drosophila melanogaster under conditions of destabilization of microtubule apparatus and as affected by heat shock].

Efficiency of heat shock and three compounds belonging to a group of mitotic poisons (colchicine (Cl), griseofulvin (Gf) and vinblastine (Vb)) in induction of dominant lethal mutations (DLM) in the Canton S wild type strain and the l(l)ts403 temperature-sensitive strain was shown. The mutagen-sensitive strain, mus(2)201Gl, displays no sensitivity to these drugs according to the DLM criterion. Heat shock followed by the Vb and Gf treatment leads to a reduction in the frequencies of DLM. Conversely, a combination of Cl with heat shock increases the yield of DLM.

Animals↗
PubMed1999

[Frequency of sex chromosome nondisjunction as affected by microtubule destabilization and heat shock in various lines of Drosophila melanogaster].

Vinblastine (Vb), a drug belonging to a group of mitotic poisons, was shown to induce sexual chromosome nondisjunction and loss (SCNL) in oogenesis of different strains of Drosophila melanogaster. Heat shock (37 degrees C, 45 min) decreases the frequency of these events. The highest level of nondisjunction was demonstrated in the temperature-sensitive strain both after heat shock and Vb treatment. No increase of SCNL frequency in oocytes of females treated with griseofulvin (Gf) and Colchicine (Cl), analogues of Vb.

Animals↗
PubMed2002

[Variability of the number of chloroplasts in a population of stoma guard cells in the sugar beet (Beta vulgaris L.)].

Diploid sugar beet plants demonstrate a broad variability of the number of chloroplasts in stoma guard cells, which is related to myxoploidy of cell populations in leaf apical meristems (epigenomic variability). In addition to random organelle segregation between daughter cells, this variability is affected by factors disrupting the mitotic cycle: (1) plant treatment with a mitotic poison, such as colchicine; (2) duration of the life cycle of a plant; the variability in second-year plants is greater than in first-year ones; (3) the mode of plant reproduction; the variability in inbred plants is greater than in the initial population. Treatment of germinating seeds with a diluted colchicine solution increases the number of organelles in cells in the myxoploid generation (generation C0) and the variance of the distributions in the first vegetation year. The variability in the organelle number in stoma cells correlates with that in maternal meristem cells. It is concluded that the epidermal cell monolayer (including stoma guard cells) keeps record of the epigenomic and epiplastome variability in meristem cells. The variability of the number of chloroplasts in stoma guard cells is approximated by binomials with negative powers.

Beta vulgaris↗
PubMedDate not supplied

Study of in vitro drug sensitivity on a newly established cell line from a primary bronchial epidermoid carcinoma of human origin (NSCLCN6).

We studied a cell line established from a primary non-small-cell lung cancer (non-SCLC) of human origin and characterized by midly differentiated epidermoid carcinoma, a human karyotype and keratin expression. Doubling time was about 48 h in vitro and 12 days when transplanted into nude mice. In vitro, this cell line was mainly sensitive to dactinomycin and mitotic poisons such as Vinca alkaloids. Most chemotherapeutic drugs proved ineffective. Our findings are comparable to previous results in patients who showed 30% objective response and less than 5% complete response regardless of the therapeutic associations used against non-SCLC. Our line would also seem to provide a good model for studying new potentially antitumor substances.

Aged↗
PubMed1991

Effects of daunomycin on the microtubular network: a cytochemical study on a human melanoma cell line.

The interaction of daunomycin (DAU), an anthracyclinic antibiotic employed as antitumoral agent, with microtubules, has been investigated by cytochemical and morphological methods on a human melanoma cell line (H14). Results obtained indicated that DAU was able to modulate the microtubule reassembly in cells treated with colcemid; such an effect proved to be dose-dependent. In particular, it has been observed that a low dose of DAU (0.05 microM) seemed to favor the microtubule reassembly whereas a higher dose (0.10 microM) impaired this process. In addition, when the anthracyclinic antibiotic was employed together with colcemid, both the cell detachment and the depolymerization of microtubules induced by the mitotic poison were hampered. These effects were dose-dependent and were better accomplished when DAU was used at an equimolar or at higher dose than that employed for the antimicrotubular agent. Moreover, the treatment of cells with DAU alone induced the stabilization of the microtubules, making them more resistant to the action of antimicrotubular agents. This effect could in part explain the antagonistic action exerted by DAU against colcemid. These observations seem to confirm that the microtubular network is an important target involved in the mechanism of action of the anthracyclinic antibiotics.

Cell Adhesion↗
PubMed1990

[Effect of alloxans on pancreatic B-cells with special regard to the alloxan-metal-complex theory. I. Effects of alloxan, alloxan-zinc chelates, dilauric acid and colchicine on blood sugar and rate of mitosis of B-cell Langerhans islets].

Alloxan, alloxan-zinc-chelate, sodium salt of dialuric acid, and colchicine significantly raised the blood sugar level under the previously mentioned experimental conditions 28 h after the application. The typical three-phase blood sugar curve development after alloxan (initial hyperglycemia, hypoglycemia, permanent hyperglycemia) was only approximately reached by dialuric acid which initiated, however, instead of the initial hyperglycemia a more pronounced hypoglycemic phase within the first 6 h. Alloxan-zinc-chelate protractedly and significantly made the blood sugar's increase up to the 7th d post injectionem, without being able to maintain a permanent hyperglycemia with half-normal dosage in comparison with alloxan. Non-diabetogenic alloxan doses (19 mg/kg i. v.) and the appropriate alloxan-zinc-chelate dosage (35 mg/kg) led to a significant increase of the blood sugar only in the chelate group with the long-term test up to 10 d, suggesting an increased and prolonged effect of the metal-chelates by stabilization of alloxan. The tested substances differently acted on the mitotic frequency of B-cells. The mitosis did not increase in the alloxan-zinc- and dialuric acid treated animals and was similar to normal animals far below the fractions of 1/10(6). A 4- and 5-fold increase of the mitotic frequency in the colchicine or alloxan treated animals as well as an accumulation of delayed metaphases suggest an impeded transition to the anaphase and include alloxan among the mitotic poisons.

Alloxan↗