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Biomedical subjects

E Hecker

Publications and source records attributed to E Hecker.

At least 91 records · Page 5Linked to original sources
PubMed1982

Tumor-promoting diterpene esters prevent macrophage activation and suppress macrophage tumoricidal capacity.

The efficacy of varied diterpene ester type tumor promoters in suppressing the acquisition as well as the manifestation of cytolytic activity by macrophages was investigated. These mechanisms, believed to be basic to natural antitumor resistance, were markedly suppressed not only by the phorbol ester, TPA, but also by several other tumor promoters of the polyfunctional diterpene ester type covering tigliane, ingenane, and daphnane derivatives. The promoters were particularly effective in preventing the lymphokine-induced enhancement of natural cytolytic activity in resting macrophages. Moreover, the same promoters suppressed the manifestation of cytotoxicity by previously activated macrophages. Their influence on the effector phase was less pronounced than on the activation phase. In sharp contrast, typical solitary carcinogens of the polycyclic aromatic hydrocarbon type exerted little or no activity in the macrophage test systems. Since TPA had already been shown to suppress the natural killer activity in vitro and to abrogate host tumor resistance in vivo, the present findings lend further support to the interpretation that tumor promoters, apart from directly stimulating the outgrowth of transformed cells, may function via interference with natural antitumor effector systems.

Animals↗
PubMed1982

Spin-labeled phorbol esters and their interaction with cellular membranes.

A series of homologous spin-labeled fatty acid analogs of the type 12-O-FASL (n,m)-phorbol-13-acetate [(n,m)PA] of 12-O-tetradecanoylphorbol-13-acetate (TPA) with variable chain length N of the fatty acid moiety and various positions of the nitroxide group were synthesized. Their irritant doses 50 (ID50) on the ear and their initiation-promoting activities on the back skin of NMRI mice were determined. The irritancy 1/ID50 of the (n,m)PA follows the simple linear relation ln(1/ID50) = alpha N + beta. In an "equilibrium" approach, the electron paramagnetic resonance (EPR) spectra measured in absence and in presence of erythrocytes (E) were used to determine the partition coefficients KM,0 between the erythrocyte membrane (M) and the extracellular solution (o). The KM,0 depend on the chain length N of the fatty acid moieties following the equation ln KM,0 = aN + b and show that the (n,m)PA are accumulated preferentially in the erythrocyte membrane. In a "kinetic" approach, the decay rate J(t)/J(o) of the EPR signal intensity of (n,m)PA molecules in absence and in presence of equilibrated E was measured during oxidation with ferricyanide and reduction with ascorbate, respectively. From the data obtained by the "kinetic" approach, a "two-compartmental model" is shown to be the most simple approximation to describe the system, in which finite concentrations of the (n,m)PA are postulated for the extracellular and the membrane compartment only. EPR data indicate that generally the (n,m)PA are buried with their acyl chain in the E membrane with the phorbol moiety close to the outer membrane surface. Apparently only in case of (1,12)PA is the acyl chain long enough to be anchored in the lipid layer of the membrane in a way similar to the tetradecanoyl residue of TPA. A possible relationship with biological activities is discussed.

Animals↗
PubMed1982

Suppression of natural tumor resistance by tumor promoters.

The findings of the present and other studies (4,7) show that TPA and other tumor-promoting esters suppress various in vitro manifestations of natural cell-mediated tumor resistance: (a) prevention of enhancement of macrophage cytocidal activity; (b) suppression of cytocidal capacity by activated macrophages; and (c) suppression of cytolytic activity of NK cells. Moreover, they abrogate host tumor resistance in vivo. These suppressive effects of tumor promoters on natural antitumor effector systems may constitute a fundamental mechanism in carcinogenesis.

Animals↗
PubMed1982

Preparation of retinoic acid esters of phorbol derivatives.

The synthesis of 12-O-retinoylphorbol-13-acetate (RPA), an incomplete tumor promoter (second stage promoter) is described. The preparation starts with phorbol-13-acetate-20-tritylether which is acylated by a carbodiimide method to yield its 12-retinoate. The latter is detritylated by acidic methanol to give RPA. Following an analogous procedure, the 4-methyl-ether of RPA is prepared from 4-O-methylphorbol-13-acetate-20-tritylether.

Animals↗
PubMed1981

Polycyclic aromatic hydrocarbons and possible metabolites: convertogenic activity in yeast and tumor initiating activity in mouse skin.

The diploid respiratory-deficient strain of yeast D4-RDII was used to assay PAH and urethane as well as some oxygenated derivatives of PAH and the (aliphatic) epoxide hydrolase inhibitor TCPO for convertogenic (mutagenic) activity. As a positive control, the convertogenic ultimate rat liver carcinogen NOAcAAF was used. PAH and urethane were found inactive as convertogens, TCPO was weakly active, whereas oxygenated electrophilic derivatives of PAH, such as K-region oxides, were found strong convertogens. For comparison, some convertogenic key compounds were assayed for their tumor-initiating activity in mouse skin in the standardized system using TPA as a promotor. PAH were stronger initiators than all oxygenated derivatives of PAH tested. TCPO alone exhibited very weak, if any, initiating activity. It was unable to modify initiation to any significant extent, if administered 5 min prior to administration of an initiator. In the absence of correlation between convertogenic and initiating activity the question of the chemical nature of "ultimate initiators" of mouse skin carcinogenesis awaits further investigation.

Animals↗
PubMed1981

Specific binding of the tumor promoter TPA in various mouse organs as measured by a "cold acetone-filter assay'.

Rapid, specific, saturable and partially reversible binding of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate ([3H]TPA) to a particulate fraction of mouse brain can be demonstrated by means of a "cold acetone-filter assay'; by washing with cold acetone at -20 degree C, nonspecific binding of the highly lipophilic [3H]TPA to membranes can be reduced to approximately 10% of the total binding. A comparative study of homogenates of several organs with this test revealed specific [3H]TPA binding/microgram DNA in the order brain much greater than lung approximately equal to spleen approximately equal to liver approximately equal to kidney approximately equal to thymus approximately equal to ovaries. Specific binding sites were also detected in 600 x g supernatant fractions of homogenates from epidermis, forestomach, glandular stomach and small intestine. Competition experiments showed displacement of [3H]TPA by TPA greater than phorbol-12,13-didecanoate greater than 12-deoxyphorbol-13-tetradecanoate greater than phorbol-12,13-dibutyrate (PDBu) greater than phorbol-12,13-diacetate greater than 4-O-methyl-TPA greater than 4 alpha-phorbol-12,13-didecanoate in the brain particulate fraction. Specific [3H]TPA binding is sensitive to heat, periodate and dithiothreitol, but is relatively insensitive to urea or to 1-5% solutions of several common detergents. It is estimated that the present binding test is approximately 500 times more sensitive than the widely-accepted [3H]PDBu assay; perhaps more important, the present method employs TPA, which is extremely effective both as a tumor promoter in vivo and as a pleiotropic effector of cells in vivo and in vitro.

Animals↗
PubMed1980

Plasminogen activator induction and platelet aggregation by phorbol and some of its derivatives: correlation with skin irritancy and tumor-promoting activity.

Phorbol and eight of its derivatives were investigated for their ability to stimulate the synthesis of the enzyme plasminogen activator in cultured chick embryo fibroblasts and to aggregate human blood platelets and have been assayed for tumor, promoting and skin, irritant activities. Over a range of concentrations, elevation in the levels of plasminogen activator activity induced by phorbol derivatives correlates well with their promoting and irritant properties. In the platelet aggregation assay however, the parallelism between the activities measured in different biological assays was less complete. While strong promoters, such as TPA, are potent aggregating agents, and weak promoters, such as PDA, are poor or ineffective inducers of aggregation, two derivatives, PDD and PDB, deviate from this general result. Platelets must be exposed to PDD in relatively high concentrations before they will aggregate, and PDB was found to be the most potent aggregating agent of all the derivatives tested.

Animals↗
PubMed1980

Extent of skin tumour initiation in mice by 7,12-dimethylbenz[alpha]anthracene and induction of arylhydrocarbon monooxygenase are not causally related.

In order to clarify further the relation between extent of arylhydrocarbon monooxygenase (AHM) induction and tumour initiation by polycyclic aromatic hydrocarbons, AHM activity and concentration of 7,12-dimethyl-benz[alpha]anthracene (DMBA) equivalents in dorsal epidermis were determined after both intragastric and topical administration of DMBA. Although in each case the dose applied caused comparable tumor incidences, both the extent of AHM induction and the concentration of DMBA equivalents were remarkably different: while topically applied DMBA stimulated AHM several-fold, intragastric instillation led to only a slight increase, if any. The concentration of DMBA equivalents in epidermis was about 100-fold higher after topical DMBA application than after intragastric administration. These data provide further evidence that extent of tumour initiation by DMBA and of AHM induction are not causally related; positive correlations found in certain cases appear to be fortuitous. Induction of AHM seems to be rather a function of DMBA concentration adjustment in epidermis and to indicate, if anything, elevated detoxification.

Administration, Oral↗
PubMed1980

Tumour initiation in mouse skin by 7,12-dimethylbenz[a]anthracene: irrelevance of systemic activation.

The effect was investigated of 7,8-benzoflavone (BF) on tumour initiation by 7,12-dimethylbenz[a]anthracene (DMBA) applied either intragastrically or topically. A single topical application of BF drastically decreased tumour initiation via both routes. This decrease was in both cases inversely proportional to the interval between administration of DMBA and BF. The data suggest that the decisive step of metabolic activation of DMBA is mediated by cytochrome P-448 dependent monooxygenase(s) located within the epidermis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Systemic promoting action and leukemogenesis in SWR mice by phorbol and structurally related polyfunctional diterpenes.

Phorbol and six structurally related compounds representing the polyfunctional diterpenes of the tigliane, ingenane, and lathyrane types were tested for systemic promoting and leukemogenic activity in SWR mice. For systemic initiation soon after birth, 15 microgram dimethylnitrosamine (DMN) was injected s.c. The diterpenes were administered i.p. either with or without prior systemic initiation with DMN. Systemic promotion was expressed for liver by induction of adenomas with all the diterpenes tested, some of them being more potent than phorbol. The relatively high dose of DMN used as initiator prevented an evaluation of promoting action in relation to lung carcinogenesis. The leukemogenic effect of phorbol in SWR mice was confirmed at three different dose levels. The other diterpenes tested had no significant leukemogenic activity. The leukemogenic action of phorbol was totally inhibited by prior DMN injection. The lack of correlation between promoting action in skin, systemic promoting action in liver and leukemogenic action, among the diterpenes tested, is discussed.

Animals↗
PubMed1979

Tumor initiators and promoters in the induction of Epstein-Barr virus.

The effect of various tumor initiators and promoters on induction of persisting Epstein-Barr virus (EBV) in different lines of lymphoblastoid cells was analyzed. Neither five polycyclic aromatic hydrocarbons, amongst them potent tumor initiators (e.g., 7,12-dimethylbenz[a]anthracene), nor the potent (ultimate) liver carcinogen N-acetoxy-N-2-acetylamino-fluorene induced EBV. A series of compounds, representing three classes of tumor-promoting diterpene esters (e.g., 12-O-tetradecanoylphorbol-13-acetate), efficiently induced EBV in persistently infected cells. The concentration required for maximal induction ranged between 0.5 and 100 nM. Some nonpromoting diterpenes (phorbol, 4alpha-phorbol-12,13-didecanoate, and ingenol) did not induce EBV. However, the nonpromoters, resiniferatoxin and 12-deoxyphorbol-13-decatrienoate, were effective, whereas anthralin, a tumor promoter, did not induce EBV. In three lines of EBV genome-carrying cells (Raji, NC-37, and RPMI 64-10) only abortive induction was noted, leading exclusively to synthesis of early antigen. In cells of lines with low spontaneous virus release (P3HR-1, B95-8, and QIMR-Wil), upon treatment with tetradecanoylphorbol acetate, approximately 20-40 times more viral DNA was recovered as compared to untreated controls. Viral DNA from tetradeca-noylphorbol acetate-induced cultures revealed the same restriction endonuclease cleavage pattern as viral DNA obtained from noninduced cells. Within 10 days after induction, release of infectious virus increased approximately by one order of magnitude. Prostaglandins, reported to be released after treatment with tumor promoters, were ineffective in virus induction under the conditions tested.

Carcinogens↗