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Query: UMLS:C0920652 (skin irritant)
 188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Palytoxin is a human and mouse skin irritant and complete mouse skin tumor promoter that differs from the well-studied phorbol ester class of tumor promoters in many respects. In this study, we have found palytoxin to stimulate the production of superoxide by isolated human neutrophils using electron paramagnetic resonance (EPR) spectroscopy with the spin-trap DMPO. This stimulation of oxyradical production by palytoxin is relatively weak, however, when compared to that by 12-O-tetradecanoylphorbol-13-acetate (TPA). The maximal amount of oxyradicals produced by palytoxin-stimulated neutrophils is 10(-4) mumols/10(6) neutrophils, and this stimulation requires nanomolar concentrations of palytoxin, with half maximal stimulation at concentrations of approximately 30 nM. In contrast, the tumor promoter TPA causes human neutrophils to generate in excess of 10(-3) mumols oxyradicals/10(6) neutrophils with concentrations as low as 1 nM. Toxicity to cultured human epidermal cells was observed at very low concentrations of palytoxin, with 50% loss of colony-forming efficiency observed at approximately 3 x 10(-13) M. For TPA, 50% loss of colony-forming efficiency for cultured epidermal cells requires approximately 5 nM. Thus, although palytoxin stimulates superoxide production in isolated neutrophils, epidermal cells are sensitive at much lower concentrations and are likely to be the important target cell in vivo. This is in contrast to TPA, where neutrophils are stimulated at concentrations less than those required to produce pathological effects on epidermal cells, suggesting that neutrophils may be an important target cell for TPA in vivo.
Carcinogenesis 1992 Sep
PMID:Measurement of neutrophil activation and epidermal cell toxicity by palytoxin and 12-O-tetradecanoylphorbol-13-acetate. 135 52

The proliferative responses induced in hairless mouse epidermis after application of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the skin irritant cantharidin were investigated. Doses known to give the same degree of hyperplasia were chosen. Mice were pulse-labeled with bromodeoxyuridine (BrdUrd) 30 min prior to or 24 h after a single application of either cantharidin or TPA, and thereafter killed at various time intervals. The basal cells were isolated from epidermis, fixed in 70% ethanol and prepared for bivariate BrdUrd/DNA flow cytometric analysis. Cells pulse-labeled in S phase 30 min prior to treatment with cantharidin or TPA were slightly delayed in their progression through S phase and temporarily blocked in G2 phase. However, they were still able to re-enter S phase 18 h later, indicating a shortening of the G1 phase. Cells pulse-labeled 24 h after treatment had a considerably reduced cell cycle time, i.e. reduced G1 transit time. Hence, the wave of cells entering S phase from 16 h after injury could be explained by an immediate reduction in G1 transit time, without assuming recruitment of temporarily resting G0/G1 cells. Although cantharidin caused the longest initial delay in cell cycle progression, the subsequent proliferative response was less pronounced than that provoked by TPA. Rapid proliferation may allow for clonal expansion of initiated cells. The higher ability of TPA to induce rapid proliferation, apparently without causing any severe initial cell damage, may thus be related to its higher tumor promoting ability.
Carcinogenesis 1991 May
PMID:A comparison between the epidermal regenerative responses provoked by a skin irritant and a tumor promoter using anti-BrdUrd/DNA flow cytometry. 202 47

Bilobol, isolated from ginkgo fruit pulp, has been noted to be a strong skin irritant like 12-O-tetradecanoylphorbol-13-acetate (TPA), a tumor-promoter in the skin. A comparative investigation of morphological changes induced by bilobol and TPA induced in the skin of CD-1 mice, and an assessment of the skin tumor promoting potential of bilobol were therefore performed. In experiment I, mice received a single application of 2.5, 50 or 1000 micrograms of bilobol, or 0.1 or 2.5 micrograms of TPA on the right ear. The 50 or 1000 micrograms bilobol and 2.5 micrograms TPA doses caused ear redness, epidermal thickening and inflammatory infiltration. The dose of 2.5 micrograms of TPA, which is usually used as tumor promoter in skin carcinogenesis, was equivalent to 50 micrograms of bilobol in irritant effect. Thus, 50 micrograms of bilobol was used for the promotion testing (experiment II) in CD-1 mice initiated with 100 micrograms of 7, 12-dimethylbenz[a]anthracene (DMBA). Treatment with either 10 or 50 micrograms bilobol twice a week for 30 weeks did not result in any tumor development, thus suggesting that bilobol is not a complete promoter of skin carcinogenesis, despite generation of inflammation.
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PMID:Comparison of the effects of bilobol and 12-O-tetradecanoylphorbol-13-acetate on skin, and test of tumor promoting potential of bilobol in CD-1 mice. 211 May 95

Dodecylbenzene in various concentrations, dissolved in acetone to a final volume of 50 microliters, was applied twice a week for 78 weeks to the back skin of hairless mice, with or without pretreatment with 51.2 micrograms 9,10-dimethyl-1,2-benzanthracene (DMBA). A negative control group was painted with acetone only and a positive control group was given a single application of 51.2 micrograms DMBA. A few tumours developed but there was no significant skin tumorigenicity--that is, occurrence of benign or malignant tumours--by acetone alone, or by 16% dodecylbenzene. More tumours developed in the group treated with 80% dodecylbenzene than in the group treated with acetone alone or with 16% dodecylbenzene, but there was no significant difference between treatments with 16% and 80% dodecylbenzene. There was only a suggestive increase in tumorigenesis in the group given 51.2 micrograms DMBA and thereafter painted with 40% dodecylbenzene twice a week compared with the group given 51.2 micrograms DMBA once. As regards histologically malignant tumours--that is, carcinogenicity--the group treated twice a week with 16% dodecylbenzene alone developed two skin malignancies, whereas only one carcinoma was observed in the group treated with 80% dodecylbenzene; both results are non-significant. There was only a suggestive increase in the occurrence of skin malignancies in the group treated with DMBA followed by 40% dodecylbenzene compared with that treated with DMBA alone. As regards other tumours, treatment with 80% dodecylbenzene led to six lymphomas in 56 animals, whereas the acetone control group had two lymphomas in 56 animals, a difference which is only suggestive. DMBA alone and DMBA followed by dodecylbenzene gave five and four lymphomas, respectively. There was no significant difference between controls and dodecylbenzene painted animals for lung adenomas or other tumours. A pronounced epidermal hyperplasia, an increase in melanin pigment ("blue spots"), pigment leakage, and skin ulcerations were seen, mainly after 80% dodecylbenzene and after DMBA followed by 40% dodecylbenzene. There was no obvious increase in amyloidosis after continual treatment with 80% dodecylbenzen. The results indicate that 80% dodecylbenzene alone is weakly tumorigenic but not carcinogenic in the skin of hairless mice, and it tends slightly to enhance DMBA initiated tumorigenesis and carcinogenesis. Dodecylbenzene may be a weak inducer of malignant lymphomas. It is a fairly strong skin irritant and may increase amyloidosis.
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PMID:Studies of the carcinogenesis and tumorigenesis of skin applications of dodecylbenzene on hairless mice. 235 57

Palytoxon, which is a toxin with a molecular weight of 2681 daltons isolated from a marine coelenterate, is a potent skin irritant. However, it did not induce ornithine decarboxylase in mouse skin, or adhesion of human promyelocytic leukemia cells (HL-60). Moreover, it did not inhibit the specific binding of [3H]12-O-tetradecanoylphorbol-13-acetate (TPA) to a mouse skin particulate fraction or activate protein kinase C isolated from mouse brain in vitro. Since palytoxin showed strong irritation on mouse ear in one short-term screening test for a promoter, it was examined in a two-stage carcinogenesis experiment. The incidence of tumors in a group of mice treated with 7,12-dimethylbenz[a]anthracene plus palytoxin was 62.5% in week 25. These tumors were identified histologically as seven papillomas and one carcinoma. This paper reports the potent tumor-promoting activity of palytoxin, which is classified as a non-TPA-type tumor promoter.
Carcinogenesis 1986 May
PMID:Palytoxin is a non-12-O-tetradecanoylphorbol-13-acetate type tumor promoter in two-stage mouse skin carcinogenesis. 287 Aug 23

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.
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PMID:Cell membrane associated protein kinase C as receptor of diterpene ester co-carcinogens of the tumor promoter type and the phenotypic expression of tumors. 300 5

The effect of tumor-promoting and non-promoting skin mitogens on the induction of matrix degradation in the dermis of mouse skin has been examined. A stimulation of active collagenolytic and proteolytic enzyme levels was observed after application of the tumor promoters 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and 12-O-retinoylphorbol-13-acetate (RPA) as well as the non-promoting skin irritant Ca-ionophore A 23187, but not with the non-irritant mitogen 4-O-methyl-TPA. It therefore appears that the enhancement of collagenolytic and proteolytic enzymes after tumor promoter treatment is mainly due to the inflammation that is always caused by the promoter. However, a subfraction of collagenolytic enzymes that is not extracted from the dermis with 0.5 M NaCl but only with 5 M urea is specifically increased after treatment with TPA and RPA. This fraction is absent in A 23187- or 4-O-methyl-TPA-treated dermis. This indicates that apart from inflammation-induced matrix degradation there is also stimulation of enzymes which are directly related to tumor promotion.
Carcinogenesis 1986 May
PMID:Enhancement of collagen-degrading enzymes in the dermis after one topical application of tumor-promoting phorbol esters. 308 15

Recent evidence shows that stage I of tumor promotion in NMRI-mouse skin induced by a single dose of 12-O-tetradecanoylphorbol-13-acetate (TPA) can be effected not only after initiation by 7,12-dimethylbenz[a]anthracene (DMBA) but also several weeks prior to initiation. In view of this partial inversion of the initiation-promotion sequence we proposed to replace the term 'stage I of promotion' by the term 'conversion'. The convertogenic effectivity of a single dose of TPA applied after DMBA can be suppressed in a rather characteristic and non-toxic fashion by hydroxyurea (HU). In the present study we asked whether HU might also interfere with the converting effectivity of a single dose of TPA given prior to DMBA. NMRI mice received a single dose of TPA 3 weeks prior to initiation by DMBA which was followed by twice weekly application of skin irritant 12-O-retinoylphorbol-13-acetate (RPA) in order to effect stage II of promotion. A single dose of HU given i.p. at different times after TPA was found to interfere with tumor formation exhibiting an almost complete inhibition if administered 18 h after TPA. This inhibition did not prevent a subsequent promotion by repetitive TPA treatment. The data indicate that conversion can be inhibited by HU in the same characteristic fashion regardless of whether TPA was administered after or prior to initiation. The data also support the autonomous character of the conversion process for which epidermal DNA synthesis appears to be obligatory.
Carcinogenesis 1986 May
PMID:Three-stage tumorigenesis in mouse skin: DNA synthesis as a prerequisite for the conversion stage induced by TPA prior to initiation. 308 18

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.
Carcinogenesis 1987 Jan
PMID: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. 310 81

Okadaic acid is a polyether compound of a C38 fatty acid, isolated from a black sponge, Halichondria okadai. Previous studies showed that okadaic acid is a skin irritant and induces ornithine decarboxylase (OrnDCase; 3-hydroxyl-L-glutamate 1-carboxy-lyase, EC 4.1.1.17) in mouse skin 4 hr after its application to the skin. This induction was strongly inhibited by pretreatment of the skin with 13-cis-retinoic acid. A two-stage carcinogenesis experiment in mouse skin initiated by a single application of 100 micrograms of 7,12-dimethylbenz[a]anthracene (DMBA) and followed by application of 10 micrograms of okadaic acid twice a week revealed that okadaic acid is a potent additional tumor promoter: tumors developed in 93% of the mice treated with DMBA and okadaic acid by week 16. In contrast, tumors were found in only one mouse each in the groups treated with DMBA alone or okadaic acid alone. An average of 2.6 tumors per mouse was found in week 30 in the group treated with DMBA and okadaic acid. Unlike phorbol 12-tetradecanoate 13-acetate (TPA), teleocidin, and aplysiatoxin, okadaic acid did not inhibit the specific binding of [3H]TPA to a mouse skin particulate fraction when added up to 100 microM or activate calcium-activated, phospholipid-dependent protein kinase (protein kinase C) in vitro when added up to 1.2 microM. Therefore, the actions of okadaic acid and phorbol ester may be mediated in different ways. These results show that okadaic acid is a non-TPA-type tumor promoter in mouse skin carcinogenesis.
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PMID:Okadaic acid: an additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter. 312 94


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