Search PubMed⌕ Search

Biomedical subjects

E Hecker

Publications and source records attributed to E Hecker.

At least 73 records · Page 4Linked to original sources
PubMed1984

Co-carcinogens of the initiation-(or tumor)promoter type as environmental risk factors of cancer in man, experimental analysis of an etiologic model situation of life style cancer and current problems of assessment of cancer risk in multifactorial carcinogenesis.

The identification of so-called co-carcinogens i.e. "per se essentially non-carcinogenic amplifiers" of carcinogenesis - especially promoters of initiation(or tumors) - as a new, non-classical group of risk factors has added a new dimension to the etiology of cancer in man. Indeed, in real human life, multifactorial causation of cancer may be considered the rule and classical unifactorial causation the exception. This comprehensive and current concept of the etiology of cancer in man and certain prototype experimental models of multifactorial carcinogenesis allow for proposals of a standardized terminology which may be adequate for common use in both, experimental and epidemiological oncology. On the background of a recent experimental analysis of life style esophageal cancer the current situation regarding the scientific basis of classification and grading of carcinogenic risk factors will be reviewed. It may be helpful in legislation aiming at more environmental safety.

Beverages↗
PubMed1984

Specific lipid components in membrane receptors of 12-O-tetradecanoylphorbol-13-acetate as revealed by direct photoaffinity labelling.

The use of [20-3H]-12-O-tetradecanoylphorbol-13-acetate (3H-TPA) as a direct photoaffinity probe of receptors was investigated. When membrane receptors in a particulate fraction from mouse brain were loaded with the high-affinity agonist 3H-TPA, irradiation of such preparations with ultraviolet (UV) light resulted in specific irreversible binding of the label to the membrane lipids phosphatidylethanolamine (PE) and phosphatidylserine (PS); evidence for labelling of proteins was lacking. The labelled lipids were tentatively identified by co-chromatography; they corresponded to selected reference lipids obtained by photoaffinity labelling. When a variety of natural and synthetic reference lipids was irradiated in the presence of 3H-TPA, photoadducts were obtained primarily from natural lipids containing unsaturated acyl chains in position 2. The synthetic 1,2-dipalmitoyl derivatives of phosphatidylcholine (PC), PE and phosphatidyl glycerol were refractory. When the photoadducts from PC and PE were treated with phospholipases A2 and C, the chromatographic pattern of cleavage products obtained was in accordance with that of phospholipids carrying the 3H-TPA label on the acyl moiety in the 2-position. Since previous evidence had suggested that a lipid-protein complex was the phorbol ester receptor, it may, therefore, be concluded that the receptor(s) contain PE and PS in specific interaction with protein(s). Accordingly, PE- and PS-dependent enzymes (or other proteins) are considered prime candidates for phorbol ester receptors.

Affinity Labels↗
PubMed1984

Cocarcinogens of the tumour-promoter type as potential risk factors of cancer in man. A first complete experimental analysis of an etiological model situation and some of its consequences.

The black and Creole population of the Caribbean island of Curaçao (Netherlands Antilles) is burdened by an exceedingly high rate of oesophageal cancer. As a part of the local diet, the fresh green leaves of the aromatic bush Croton flavens L., known locally as 'welensali', are used to prepare a 'bush tea' drunk commonly as a beverage. Additional habitual uses of the leaves and of other parts of the plant are widespread. Investigations of soluble extracts of roots and leaves of welensali and of welensali tea revealed the presence of a multitude of irritant 'welensali factors', of which there are essentially two activity types, F and F'. F-types exhibit strong initiation (or tumour)-promoting activity on the back skin of the mouse, qualitatively and quantitatively comparable with that of the chemically related and well established promoter 12-O-tetradecanoyl-phorbol-13-acetate. F'-types are less active than the corresponding F-types, yet they are 'cryptic promoters' operationally. F- and F'-types are, respectively, diterpene di- and triesters, with polyfunctional tigliane structures, e.g., welensali factor F1. Together, they comprise a minimum content of 0.32 and 0.04% in roots and fresh green leaves, respectively. Welensali tea contains two mixtures of F- and of F'-types, each comprising three welensali factors, irritant and promoting in mouse skin. The estimated total minimum content of welensali factors per cup of tea is 1.6 micrograms/L. The estimated content of welensali factors type F in one cup of welensali tea, (the preparation of Croton flavens most frequently consumed on Curaçao) is equivalent to more than 10 times the irritant dose 50 of the typical welensali promoter F1 on the mouse ear. Welensali factors type F' contained in one cup are approximately equivalent to the irritant dose 50 of the typical 'cryptic' welensali promoter F1-20-decanoate. Therefore, the overall exposure of persons at risk on Curaçao exceeds that expected to maintain chronic irritation in the human oesophagus, which is considered an important element of initiation/promotion. After completion of chemical analyses, on the basis of epidemiological hints derived from the local situation, experimental evidence for the involvement in cancer associated with consumption of this plant also of putative initiators of the polycyclic aromatic hydrocarbon type is presented. Thus, for the first time in an epidemiologically established dietary cancer, chronic exposure to well-defined cocarcinogens of the promoter type is shown most likely to represent the principal carcinogenic risk involved ('cocarcinogen hypothesis').(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Inhibition of specific binding of [3H]phorbol-12,13-dipropionate to an epidermal fraction by certain irritants and irritant promoters of mouse skin.

Specific binding of [3H]phorbol-12,13-dipropionate ([3H]PDPr) to a particulate fraction of mouse skin is demonstrated (KD = 35 nM; Rt = 1.2 pmol/mg protein). A series of compounds of the diterpene ester, indole akaloid and polyacetate types with different degrees of activity as skin tumor promoters and/or irritants have been tested for their capacity to inhibit specific [3H]PDPr binding. Three main categories are found: (i) compounds which exhibit a positive correlation between their potency as irritants and promoters in vivo and their inhibition of specific binding in vitro: 12-O-tetradecanoylphorbol-13-acetate, 3-O-tetradecanoylingenol, pimelea factor P2, 'teleocidin', dihydroteleocidin B, and lyngbyatoxin are active in vivo and in vitro, whereas phorbol and ingenol are inactive and 4-O-methyl-12-O-tetradecanoyl-phorbol-13-acetate is weakly active; (ii) compounds which are strong irritants and inhibitors of binding but are weak or practically non-promoters: mezerein, 12-O-retinoylphorbol-13-acetate and milliamine C; (iii) strong irritants which are weak or marginally active inhibitors of binding: debromoaplysiatoxin and resiniferatoxin. Some consequences of these findings with respect to interpretations of the biochemical mechanism(s) of tumor promotion are discussed.

Animals↗
PubMed1983

Irritant diterpene ester promoters of mouse skin: contributions to etiologies of environmental cancer and to biochemical mechanisms of carcinogenesis.

One of the most advanced experimental models for investigations of the metabolic fate and of mechanisms of action of initiators and promoters at the cell and/or the molecular level is the three-stage initiation/promotion/progression model of carcinogenesis in mouse skin. In etiologic investigation by experimental analyses of local lifestyle-associated esophageal cancer on the Caribbean island of Curacao, based on this model initiators of the solitary carcinogenic PAH type and promoters of the cocarcinogenic diterpene ester (tigliane) type were suggested as putative principal risk factors. In metabolic investigations it was shown that 7,12-dimethylbenz(a)anthracene (DMBA) requires metabolic activation to yield "ultimate initiator(s)," whereas TPA and its diterpene ester congeners are "ultimate promoters" themselves. Yet naturally occurring "cryptic" forms of diterpene ester irritants and promoters require metabolic activation. To show structure/activity relationships, selected new diterpene structures of the tigliane, ingenane, and daphnane types and their irritant and promoting activities in mouse skin are presented in this paper. Common structural features of the diterpene moieties relevant for interaction with cellular receptors are identified. Synthetic modification of the ester moieties reveals highly unsaturated analogs of 12-O-tetradecanoylphorbol-13-acetate (TPA) allowing for dissection of the promotional stage in the mouse skin model in two operationally defined substages, PI and PII. In many tissues and cells, TPA and congeners induce various different biological effects, e.g., phospholipid synthesis is stimulated in epidermis, virus synthesis is stimulated in human lymphoblastoid cell lines carrying latent genomes of Epstein-Barr virus (EBV), and prostaglandin E2 is rapidly released from mouse peritoneal macrophages. Altogether a remarkable biological and biochemical pleiotropism of diterpene ester promoters is indicated. In investigations of the molecular mechanism of action of diterpene esters, non-promoting short chain phorbol esters, such as phorbol-12,13-dipropionate (PDPr) were shown to inhibit diterpene ester-induced promotion in vivo. In radioligand assays employing (20-3H)PDPr as well as (20-3H)TPA, specific binding to the particulate fractions of mouse skin and other mouse organs, including the brain, is seen. Inhibition of specific binding by a series of diterpene esters is correlated with their irritant and promoting activities.(ABSTRACT TRUNCATED AT 400 WORDS)

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Multistage tumor development in the human esophagus - the first identification of cocarcinogens of the tumor promoter type as principal carcinogenic risk factors in a local life style cancer.

An experimental analysis is described which demonstrates that the epidemiologically established high rate of esophageal cancer among blacks and creoles in Curacao most likely is the result of a multistage process involving initiators and promoters. As part of local lifestyle, the group at risk utilizes for various purposes plant parts of an indigenous bush Croton flavens L. ("Welensali"). Moreover they consume, as an everyday beverage, a "bush tea" made from the leaves of the bush. The roots, leaves and tea are shown to contain a multitude of irritant croton factors which are characterized as diterpene esters of the tigliane type. In mouse skin these exhibit strong promoting activity comparable to that of TPA. As the latter, also the croton factors isolated, show no solitary carcinogenic activity. One cup of Welensali tea contains the equivalent of about 12-times the irritant dose of croton factor F1; in addition, the equivalent of about 1.4-times the irritant dose 50 of the corresponding "cryptic" promoter F1-20-decanoate is present. These amounts are considered sufficient to maintain chronic irritation of the esophagus as an important element of co-carcinogenesis, especially of tumor promotion. Also, persons at risk in Curacao have been exposed at times previously to certain initiators. Mice treated by an initiation/promotion protocol with DMBA (or other initiators) and TPA develop tumors of the forestomach. Therefore, esophageal cancer on Curacao may be considered the first case for cocarcinogens of the tumor promoter type being principal risk factors in a life style cancer.

Animals↗
PubMed1982

Biological assays for irritant tumor-initiating and -promoting activities. I. Kinetics of the irritant response in relation to the initiation-promoting activity of polyfunctional diterpenes representing tigliane and some daphnane types.

The kinetics of the irritant response on the mouse ear [erythema measured quantitatively by the irritant dose 50 (ID50)] and its relation to the initiation-promoting activity on the back skin of NMRI mice of some polyfunctional diterpene esters were investigated: (1) A very rapid and transient erythema response is associated with low or absent promoting activity (2) an early and more persistent erythema response in most cases is associated with moderate-to-high promoting activity, and (3) a relatively late onset but persistence up to at least 24 h of the erythema response is associated with high promoting activity. These results may indicate a relationship between the kinetics of the erythema response and the initiation-promoting activity of diterpene esters. The comparatively low promoting activity of esters carrying polyunsaturated acyl functions may indicate the importance of pharmacological parameters such as bioavailability and stability in the biological system, drug-receptor interaction, and "intrinsic activity" of the diterpene esters.

Animals↗
PubMed1982

On the active principles of the spurge family (Euphorbiaceae). IV. Skin irritant and tumor promoting diterpene esters from Euphorbia ingens E.Mey.

The irritant and tumor-promoting principles of the latex of Euphorbia ingens E. Mey have been isolated together with several nonirritant compounds. The Euphorbia factors I1, I5, and I6 are esters of ingenane-type poly-functional diterpene alcohols. Euphorbia factor I1 is characterized as the 3-hexadecanoate of the polyfunctional parent alcohol ingenol and Euphorbia factor I6 as the 3-deca-2.4.6-trienoic acid ester of ingenol. Euphorbia factor I5 is the 16-angelate-3-deca-2.4.6-trienoate of 16-hydroxyingenol. Nonirritant diterpenes of the latex are I2, the ingenol-20-hexadecanoate - an isomer of Euphorbia factor I1 - and I4, the 3.7.12-triacetate-8-nicotinate of the macrocyclic lathyrane-type polyfunctional diterpene alcohol ingol. The diterpene alcohols ingenol and 16-hydroxyingenol are inactive as irritants and tumor promoters of mouse skin. Compared to croton oil factor A1 (TPA), the Euphorbia factor I1 exhibits about 1/10 of the irritant and tumor-promoting activity in mouse skin. I1 shows no reasonable tumorigenic activity. Compared with I1, Eupohorbia factors I5 and I6 are more potent irritants and less potent tumor promoters.

Animals↗
PubMed1982

Effect of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and its nonpromoting analogue 4-O-methyl-TPA on dorsal dermal melanocytes of the Syrian golden hamster (Mesocricetus auratus).

The effect of the tumor promoter TPA and its inactive structural analogue 4-O-methyl-TPA on the induction of dorsal skin melanosis in the normal Syrian golden hamster and on the promotion of melanomas in DMBA-initiated animals was investigated. Both phenomena were observed in TPA-treated hamsters but could not be detected after exposure of animals to 4-O-methyl-TPA. In contrast to results obtained with a variety of other laboratory animals, neither TPA nor 4-O-methyl-TPA were able to induce epidermal hyperplasia of hamster dorsal skin.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Induction of differentiation in human promyelocytic leukemia cells by tumor promoters.

12-)-Tetradecanoylphorbol-13-acetate (TPA), the prototype polyfunctional diterpene ester tumor promoter of two-step carcinogenesis in mouse skin, induced differentiation of human promyelocytic leukemia cells (HL-60) in culture. Differentiation of HL-60 cells was characterized by increased phagocytosis, increased lysozyme activity (EC 3.2.1.17) in the growth medium, and changes in morphology to those characteristics of more mature cells resembling macrophages. Many of the cells treated with TPA became aggregated, attaching firmly to culture flasks. The average intracellular myeloperoxidase activity (EC 1.11.1.7) per cell decreased during induction of differentiation by TPA. It was also found that TPA enhanced, rather than inhibited, differentiation of HL-60 cells induced by DMSO. In addition to TPA, several polyfunctional diterpene esters of the tigliane, ingenane, and daphnane type have been tested for their ability to induce morphological and functional changes of HL-60 cells. The activities of the compounds to induce these changes correlated well with their activities as tumor promoters in two-step carcinogenesis in mouse skin. In particular, half the concentrations required for induction of adhesion of the cells to flasks were roughly correlated to the potency of these compounds as tumor promoters. Among the compounds tested, phorbol-12,13-didecanoate (PDD), ingenol-3-hexadecanoate, Pimelea factor P1 and Pimelea factor P2 were as active as TPA, while 4-O-methyl-TPA and 4 alpha-PDD were much less active. Phorbol and ingenol were totally inactive up to a concentrations 10,000-fold higher than that of TPA.

Cell Adhesion↗