Murine lymphocyte comitogenesis by phorbol esters, and its inhibition by retinoic acid and inhibitors of polyamine biosynthesis

Fish, Larry A.; Baxter, C. Stuart; Bash, Jerry A.

doi:10.1016/0041-008x(81)90113-7

Cited by 13 publications

(6 citation statements)

References 10 publications

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“…This activity may result from RA-mediated suppression of ornithine decarboxylase, a key enzyme in polyamine biosynthesis (38). Since polyamines may play a role in some other differentiation systems (8,32), it seemed possible that the RA effect on P19 could be mediated by decreases in intracellular polyamine levels. Cultures of aggregated P19 cells were exposed to the following drugs, both in the presence and absence of RA: 3 x 10-6 M spermidine, a polyamine; 3 x 10-4 M alpha-methylornithine and 10-7 M methylglyoxal-bis-(guanyl-hydrazone), two inhibitors of polyamine biosynthesis; and two tumor promotors, 10 The RAC65 cells grew continuously and rapidly in both the presence and absence of RA (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This is consistent with the observations of Schindler et al (31), who found that a line of RA-nonresponsive PCC4 EC cells lacked cellular RA-binding protein activity. In some systems, RA acts by inhibiting the induction of ornithine decarboxylase, a key enzyme in polyamine biosynthesis (8,19,32,38). However, our data suggest that polyamine biosynthesis is not involved in triggering the neural developmental pathway.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Retinoic acid-induced neural differentiation of embryonal carcinoma cells.

Jones-Villeneuve¹,

Rudnicki²,

Harris³

et al. 1983

Mol. Cell. Biol.

280

200

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Retinoic acid-induced neural differentiation of embryonal carcinoma cells.

Jones-Villeneuve¹,

Rudnicki²,

Harris³

et al. 1983

Mol. Cell. Biol.

280

200

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“…The mixed lymphocyte response (MLR) and mitogen stimulation of lymphocytes are methods of assessing lymphocyte responsiveness. Phorbol esters suppress the MLR [14], and have been shown to be mitogens [15,16] and comitogens with other lymphocyte mitogens [17,18]. Immune cell differentiation is also affected by phorbol esters.…”

Section: Introductionmentioning

confidence: 99%

Suppression of the antibody response by phorbol esters in the mouse is due to an effect on the nylon wool adherent cell population

Shopp

Munson

1985

Agents and Actions

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Phorbol esters, in particular 12-O-tetradecanoyl-phorbol-13-acetate (TPA), have been shown to have profound effects on most biological systems including tumor promotion. Presented here are studies on the acute toxic effects of TPA, and the effects of phorbol esters on the in vivo and in vitro, T cell-dependent, antigen-specific antibody response in the mouse. The LD50 of a single i.v. dose of TPA in the mouse was 309 micrograms/kg. Acute toxic effects included lethargy, hypothermia and enlarged, hemorrhagic spleens at the higher doses. TPA was shown to be a potent inhibitor of the in vivo primary antibody response as measured by the IgM antibody-forming cell (AFC) response to sheep red blood cells (sRBC). The ED50 of a cumulative i.v. dose was 145 micrograms/kg administered the day before and the day of immunization (72.5 micrograms/kg/day). A cumulative dose of 500 micrograms/kg (250 micrograms/kg/day) resulted in a 100% suppression of the response. This in vivo exposure to TPA did not alter B cell/T cell ratio in the spleen. Phorbol ester analogs inactive in other biological systems were also inactive in the in vivo AFC response. The in vitro AFC assay was used to determine what cell type was being affected by TPA. Separation of the adherent spleen cells into B and T cell populations was done using nylon wool columns and anti-theta plus complement treatment. Experiments with these cell populations indicated that TPA produced suppression of the response due to an effect on the nylon wool adherent cell population.

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“…Because of this fact, and of the chemical similarity of these agents to the hydrophobic sidechains of the active phorbol diester-promoting agents, we sought to examine the activities of alkanes in another system which has been shown to be sensitive to membrane-active agents, including plant lectins and phorbol diesters. Since studies in the above-mentioned system, namely the mitogenic response of lymphocytes in culture, have suggested a role for the immune system in tumor promotion by phorbol diesters [5][6][7][8][9], we sought to examine whether similar considerations would also be applicable to the mechanism of action of alkanes. In all our studies the experimental animal employed was the mouse, in which the model of tumor promotion has best been established.…”

Section: Introductionmentioning

confidence: 99%

Comitogenic activity of n‐alkane and related tumor promoters in murine lymphocytes

Baxter

Fish

Bash

1981

Teratog Carcinog Mutagen

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Linear alkanes of specific chain length were found to enhance differentially the mitogenic response of murine spleen lymphocytes to the lectin phytohemagglutinin. Within the homologous series of compounds having between six and eighteen carbon atoms, a biphasic structure-function relationship was found, with maximum comitogenic activity occurring for tetradecane, and none or little for octane and octadecane. No alkane was mitogenic per se, and no alkane displaced the optimum mitogenic concentration of the lectin. The concentration of tetradecane having equivalent comitogenic activity was similar to that of methyl myristate, a simple alkyl ester of equal alkyl chain length, but approximately four orders of magnitude less that of the potent promoter 12-0-tetradecanoy1phorbo1-13-acetate (TPA). A similar ratio of potencies of TPA and the alkane dodecane, also a lymphocyte comitogen, has previously been found for promotion of mouse epidermal tumorigenesis. Maximum comitogenic activity was found when alkane and lectin were added to cultures simultaneously, the effect decreasing sharply when alkane addition was delayed relative to lectin. These findings suggest the existence of a cellular receptor with specificity for hydrophobic functions with chain lengths lying within a restricted range. Binding to this receptor also appears to be a common early event in tumor promotion, comitogenicity, and comutagenicity by agents of several chemical types.

show abstract

Murine lymphocyte comitogenesis by phorbol esters, and its inhibition by retinoic acid and inhibitors of polyamine biosynthesis

Cited by 13 publications

References 10 publications

Retinoic acid-induced neural differentiation of embryonal carcinoma cells.

Retinoic acid-induced neural differentiation of embryonal carcinoma cells.

Suppression of the antibody response by phorbol esters in the mouse is due to an effect on the nylon wool adherent cell population

Comitogenic activity of n‐alkane and related tumor promoters in murine lymphocytes

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