Search PubMed⌕ Search

Biomedical subjects

E Hecker

Publications and source records attributed to E Hecker.

At least 55 records · Page 3Linked to original sources
PubMed1988

Spin-labeled phorbol esters and their interactions with cellular membranes. III. Skin irritant and tumor-promoting activities of spin-labeled phorbol-12,13-diesters and relationships to their particular structures.

Sixteen 'doxyl' spin-labeled 12,13-(acetate, acylates) of phorbol were assayed in NMRI mice for irritant and for tumor-promoting activity. The spin-labeled positionally isomeric (n,m)PA- and AP(n,m)-type esters carry straight aliphatic acyl chains of different overall lengths N (number of C atoms). Within the chains the 'doxyl' label is located in different positions (n,m). The potency of some of the esters as irritants and as promoters is comparable to or even higher than that of the prototype diterpene ester promoter 12-O-tetradecanoylphorbol-13-acetate and its positional isomer 12-O-acetylphorbol-13-tetradecanoate. Their irritancies on the ear and their promoting activities on the back skin depend strongly on the structural features of the acyl chain carrying the spin label. Based upon the bioactivities of individual esters biologically meaningful probes were defined for investigations of the molecular interaction of phorbol-ester-type promoters with cellular targets for electron paramagnetic resonance.

Animals↗
PubMed1987

Screening for cryptorchid boys risking sterility and results of long-term buserelin treatment after successful orchiopexy.

This long-term prospective follow-up study showed that in cryptorchid patients a significant correlation exists between the number of germ cells at the time of orchiopexy (prepuberty) and the spermiogram, and thus a biopsy has a prognostic value. Fifty percent of our patients had a germ cell count of less than 0.1 per tubule and belong to the risk group for sterility. Successful surgery could not induce a significant increase of germ cells in the risk group, although it does prevent secondary testicular damage. Patients with cryptorchidism developed after birth have significantly better chances of fertility than those with primary cryptorchidism. The priming effect of testosterone in the first months of life is important for male fertility. In patients belonging to the risk group treated with buserelin, a significant age-dependent increase in germ cell count occurred.

Adult↗
PubMed1987

Structure/activity relationships of polyfunctional diterpenes of the ingenane type. I. Tumor-promoting activity of homologous, aliphatic 3-esters of ingenol and of delta 7,8-isoingenol-3-tetradecanoate.

Eight skin irritant 3-esters with the homologous even number aliphatic acids (acetic to hexadecanoic acid) of the polyfunctional diterpene alcohol ingenol as well as the non-irritant 3-tetradecanoate of delta 7,8-isoingenol were tested for their initiation or (tumor)-promoting activity in the standardized semi-quantitative initiation/promotion assay on the back skin of NMRI mice. In a corresponding protocol over 48 weeks without preceding initiation, i.e. as a tumorigen, the 3-hexadecanoate of ingenol (3-HI) proved to be practically inactive as compared to the strong response elicited as promoter. Dose/response relations were shown to be positive for both 3-HI and 3-O-tetradecanoylingenol (3-TI), as representative ingenol-3-esters. In assays for structure/activity relations of promoting activity, it turned out that the group of 3-acetate, 3-butyrate and 3-hexanoate of ingenol are very weak to weak promoters. The group of 3-octanoate to 3-HI proved to be strong promoters. Maximal activity was exhibited by 3-TI and it is proposed that this be considered the prototype of the 3-esters of the ingenane type. In semi-quantitative terms it is slightly less active as a skin tumor promoter than the tigliane type 12-O-tetradecanoylphorbol-13-acetate. At the same dose level as 3-TI, the 3-tetradecanoate of delta 7,8-isoingenol was inactive as a promoter.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Three stage carcinogenesis in mouse skin--recent results and present status of an advanced model system of chemical carcinogenesis.

In the three stage model of carcinogenesis in mouse skin, to a certain compartment of normal cells new and adverse biological properties are imposed by the initiator DMBA yielding 'potential tumor cells,' or 'initiated cells.' These initiated cells exhibit a selective advantage of growth over surrounding normal cells if exposed to DTE promoters. The new properties may result from a genomic mutation associated with an increase of density, affinity or cooperativity of certain membrane receptors as compared to normal cells. Complete promoters, such as TPA, but not incomplete promoters such as RPA may impose a second additional genomic or epigenomic insult onto initiated cells ('conversion'). As a consequence, initiated cells become ready to respond to unspecific mitogenic stimuli ('propagation'), as provided by hyperplasiogenic agents. The initiation/promotion model of mouse skin presents new and attractive possibilities to apply the oncogene approach for further in-depth analysis of the molecular mechanisms of its stages. It remains to be seen to what extent molecular events demonstrated causative for the stages in the mouse skin model are applicable also to stages in multistage models of chemical carcinogenesis operational in other target tissues.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Presence of tumor promoters in the seed oil of Jatropha curcas L. from Thailand.

The seed oil of Jatropha curcas L. was shown to contain skin tumor promoters in a two-stage mouse carcinogenesis experiment. By using the irritant test on mouse ear to monitor activity, the "irritant fraction" was partially purified from the methanol extract of the seed oil by column chromatographies on Florisil and Sephadex LH-20. The irritant fraction obtained induced ornithine decarboxylase in mouse skin and inhibited the specific binding of 3H-12-O-tetradecanoylphorbol-13-acetate to a particulate fraction of mouse skin. After initiation with 7,12-dimethylbenz[a]anthracene (DMBA), this "irritant fraction" induced tumors in the skin of 36% of the mice tested in 30 weeks. Tumor incidences in the groups treated with DMBA alone and "irritant fraction" alone were 7% and 13% in week 30, respectively. Since the skin of Thai people comes into direct contact with this seed oil, an epidemiological study on human skin cancer in Thailand is indicated.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

Tumour-promoting effect of chilli extract in BALB/c mice.

In 50% of BALB/c mice pretreated with atropine, tongue tumours were induced by fortnightly application of DMN-OAc (2 mg/kg) on the tongue. When DMN-OAc + TPA was used for the initiation-promotion protocol, tumours were observed on the tongue, the site of application, in only 10% of animals. In the same group, stomach tumours were obtained in 63% of mice, denoting that initiation-promotion could be successfully used to induce stomach tumours. Using a protocol of DMN-OAc + chilli as a promoter, we observed induction of stomach tumours. The promoter effect of chilli extract was also seen in the BHC-induced hepato-carcinogenesis system. It thus appears that, in BALB/c mice, chilli acts as a promoter in stomach and liver carcinogenesis.

Administration, Topical↗
PubMed1986

Comparative DNA binding of 7,12-dimethylbenz[a]anthracene and some of its metabolites in mouse epidermis in vivo as revealed by the 32P-postlabeling technique.

The binding of some mouse skin metabolites and related derivatives of the tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA) was investigated by 32P-postlabeling analysis after its topical administration. DMBA and trans-3,4-dihydro-3,4-dihydroxy-DMBA (DMBA-3,4-dihydrodiol) both led to the formation of four DNA adducts, which showed a very similar pattern of spots on thin-layer chromatograms. With trans-8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz[a]anthracene (DMBA-8,9-dihydrodiol) one major adduct was obtained which was chromatographically indistinguishable from one of the DMBA adducts. In contrast, 7-hydroxymethyl-12-methylbenz[a]anthracene (7-OHM-12-MBA) gave rise to two major adducts which were separable from DMBA adducts. 3-hydroxy-7,12-dimethylbenz[a]anthracene (3-OH-DMBA) and 7,12-dimethylbenz[a]anthracene-7,12-epoxide (DMBA-O2) did not lead to detectable amounts of adducts. Quantitative determination of DNA binding showed that an initiating dose (i = 100 nmol) of DMBA yielded approximately 12 adducts/10(7) normal nucleotides. Adduct formation with the same dose of DMBA-3,4-dihydrodiol was 7-8 times higher. At a 4-fold higher dose level, DMBA-8,9-dihydrodiol exhibited a 3- to 6-times weaker binding and 7-OHM-12-MBA a slightly stronger binding than DMBA. Chromatography of the DMBA and DMBA-3,4-dihydrodiol adducts with a solvent containing borate showed a decreased mobility of two out of four adducts in each case. These adducts were also sensitive to oxidation by periodate. The results suggest that two DMBA adducts carried vicinal cis-hydroxyl groups and thus were probably derived from the anti-3,4-dihydrodiol-1,2-oxide(s) of DMBA. The other two adducts were probably derived from the syn-stereoisomer(s). When the DNA-modifying capabilities and initiating activities of the more prominent mouse-skin metabolites are considered in relation to DMBA, DMBA-3,4-dihydrodiol is postulated to be a proximate and DMBA-3,4-dihydrodiol-1,2-oxide(s) to be ultimate initiators.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Phospholipids involved in specific binding of 12-O-(5-azido-2-nitrobenzoyl)phorbol-13-acetate to epidermal microsomes, a photolabeling study.

The preparation of 12-O-(5-azido-2-nitro)benzoylphorbol-13-acetate (NABPA) is described. It is used as a photoaffinity probe to study the biochemical components involved in the specific binding of phorbol esters to an epidermal particulate fraction (microsomes) from NMRI mice: without irradiation NABPA binds in a saturable and high affinity manner (KD = 12 nM; Rt = 2.6 pmol/mg protein) to microsomes; after irradiation (at 350 nm) specific photolabeling (representing specific binding of NABPA) is found of phospholipids (phosphatidyl-serine (PS) and -ethanolamine(PE)), but not of protein. The results are discussed in the context of protein kinase C being a receptor for phorbol esters.

Affinity Labels↗
PubMed1985

Cell membrane associated protein kinase C as receptor of diterpene ester co-carcinogens of the tumor promoter type and the phenotypic expression of tumors.

For investigations of biochemical and molecular mechanism(s) involved in carcinogenesis the three stage initiation/promotion/progression approach in mouse skin provides one of the most developed experimental models. As initiators (and as progressors), solitary carcinogenic polycyclic aromatic hydrocarbons (PAH), such as 7,12-dimethylbenz [a]anthracene (DMBA), are used. As promoters in the last about 15 years, cocarcinogenic skin irritant polyfunctional diterpene esters of plant origin have become most powerful tools. Their low activity "cryptic forms" are activated metabolically by hydrolases yielding highly active skin irritants and cocarcinogens of the "ultimate promoter" type such as the phorbol-12,13-diester TPA and congeners of the ingenane- and daphnane type. In their target cells the ultimate promoters are bound to specific binding sites both through their ester moieties as well as through their diterpene moieties as revealed by structure/activity relationships. In such investigations most recently, also fine structural comparison of threedimensional computergraphs of prototype promoters were included. In correlation with their irritant and promoting activities, diterpene ester promoters exhibit agonist type specific (non-covalent) binding to the particulate fraction of epidermis and other organs or cells. The specifically bound portion of certain electron spin and photoaffinity labeled phorbol ester analogs indicates their distinct molecular orientation in membranes and, in their microenvironment, presence of phospholipids essential for activity of the Ca++ dependent proteinkinase C (PKC). Specific bindings to and activation of PKC was shown for TPA and congeners particularly also in mouse epidermis as one of the target organs of initiation/promotion by DMBA/TPA. Diterpene ester promoters are postulated to interact with the second messenger system operated by inositolphospholipid/diacylglycerol which is linked to (i) receptors of certain (endocrine) hormones or growth factors and (ii) to certain oncogene derived (autocrine) molecular signals. In this way, diterpene ester promoters, mostly taylor-made by partial syntheses, have lead to new dimensions the investigations of specific mechanistic problems of processes of carcinogenesis. Interlinkage of parts of these processes with receptor research opens up new and fascinating aspects of mechanisms of carcinogenesis at the cell and/or molecular level. They will provide important leads in gaining a more differentiated system of assessment of environmental risk factors of cancer for cancer prevention and in developing more purposeful and selective antineoplastic drugs for clinical use.

Animals↗
PubMed1985

Stability of the "second stage" promoter 12-O-retinoylphorbol-13-acetate.

To provide guidelines for handling the very labile phorbol ester, RPA,2 its stability under various laboratory conditions was studied. RPA will remain undecomposed for 8 weeks if stock solutions are made in ethanol, ethyl acetate, or DMSO and stored in absolute darkness at -20 degrees C. When exposed to light RPA readily isomerizes to 13'-cis-RPA. Structure/activity investigations of irritant polyfunctional diterpene esters of phorbol, ingenol, and resiniferonol with saturated and unsaturated aliphatic or with aromatic acids indicate that their irritant activity is a necessary, yet insufficient prerequisite for initiation- (or tumor-) promoting activity (e.g., Refs. 3 and 4). For further testing of this hypothesis, the retinoic acid analogue of the mouse skin irritant and initiation-promoter TPA, i.e., RPA, was designed (7). In initiation/promotion experiments of skin of NMRI mice, it proved to be an irritant almost as active as TPA, but only marginally active as a promoter. In combination with TPA, it turned out to be a "second stage" promoter (PII-promoter) (1, 6) in our strain of mice (2, 7). RPA is a much more labile compound than TPA (5), especially in the solid form. If stored in solution, special precautions have to be taken to ascertain that the concentration or dose intended is represented by undecomposed RPA.

Drug Stability↗
PubMed1984

The value of testicular biopsy in cryptorchidism.

This prospective study conducted on 24 children, who have now reached adulthood, was undertaken to determine the value of testicular biopsies in cryptorchidism relative to fertility prognosis. A significant correlation between the number of germ cells in the biopsy and sperm count was found to exist (p less than 5%). Thus, the testicular biopsy performed during orchiopexy was found to have a prognostic value. The hormonal findings (LH, FSH) suggest that in cryptorchid adults impaired Leydig cell function exists only when serious tubular damage is present. Because of its prognostic value with respect to fertility and the probability of discovering carcinoma in situ cells, it is strongly recommended that a testicular biopsy is performed in cryptorchid boys.

Adolescent↗
PubMed1984

On the active principles of the spurge family (Euphorbiaceae). V. Extremely skin-irritant and moderately tumor-promoting diterpene esters from Euphorbia resinifera Berg.

The irritant and tumor-promoting principles were isolated from the latex of Euphorbia resinifera Berg. and from the resin derived from latex (euphorbium), which is commercially available as a drug. The irritant Euphorbia factors RL 5 (mixture), RL 6, RL 7, RL 8, and RL 10 were identified as tigliane-type 12-deoxyphorbol esters each bearing, in the 13 position, either long-chain, partially methyl-substituted acyl residues (10-16 carbon atoms) or short-chain acyl residues (4 or 5 carbon atoms) or a (substituted) phenylacetyl group with a 20-acetoxy group. Euphorbia factors RL 15 (mixture), RL 16, RL 17, RL 18, and RL 21 are the corresponding 20-deacetylated derivatives thereof. The irritant Euphorbia factors RL 11, RL 12, RL 22, RL 23 were characterized as esters of the tigliane type 12-deoxy-16-hydroxyphorbol, i.e., 13-0-phenylacetyl-16-0-benzoyl-12-deoxy16-hydroxyphorbol-20- acetate (RL 11) and 13, 16-0-phenylacetyl, tigloyl-12-deoxy-16-hydroxy-phorbol-20-acetate (RL 12), RL 22 and RL 23 representing the respective 20-deacetylated derivatives. A mixture of irritant factors, RL 13, was shown to represent long-chain 3-esters of ingenane-type ingenol with similar acyl residues (10-16 carbon atoms, partially methyl-substituted) to RL 5 (RL 15) above. A further group of E. resinifera factors was of the daphnane type: RL 9 was identified as the extremely irritant 9,13,14-orthophenylacetate of resiniferonol-20-(4-hydroxy-3-methoxy)phenylacetate (Resiniferatoxin), RL 14 as the corresponding 9,13,14-orthophenylacetate of resiniferonol, and RL 20 as 14-0-phenylacetylresiniferonol-20-(4-hydroxy-3-methoxy)-phenylacet ate (Proresiniferatoxin). The irritant factors specified below were accompanied by nonirritant esters of the tigliane type 12,20-dideoxyphorbol, i.e., RL 1 and RL 2, and of the lathyrane type ingol, i.e., RL 3 and RL 4. In tumor promotion experiments the mixture of homologous irritant factors RL 13 was equipotent with the standard tumor promoter TPA, but at 10 times the dose of TPA. Several others of the irritant factors had low activity as tumor promotors, but of the few tumors obtained in these experiments a high percentage was malignant. The very high irritant activity of the latex may be ascribed to resiniferatoxin (RL 9), representing a new class of rapidly acting skin irritants. No promoting activity was detected on administration of the highly irritant resiniferatoxin.

Animals↗