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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Introduction of the v-Ha-ras gene into primary epidermal keratinocytes, followed by grafting of these cells to animals, leads to the formation of benign epidermal tumors that resemble papillomas induced chemically by a two-stage carcinogenesis protocol. In this study, we investigated v-Ha-ras-induced papillomas for aberrant expression of type I keratin K13, previously described in 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13- acetate (DMBA/TPA)-induced mouse epidermal tumors. Papillomas produced from three independent infection series were removed 3 wk after grafting concomitant with control grafts originating from mock-, neo-, and v-fos-infected primary keratinocytes. Combined analysis of the grafts by western blotting of extracted keratins and immunofluorescence studies of frozen sections with a K13-monospecific antibody revealed K13 expression in all v-Ha-ras-induced papillomas and absence of this keratin in all control grafts. K13-positive cells in papillomas were restricted to the suprabasal cell layers of the lesions and, at this stage of papilloma development, occurred as foci of varying extensions. Analysis of genomic DNA from v-Ha-ras-induced papillomas for the methylation state of a CpG dinucleotide in the distant promoter region of the K13 gene revealed the occurrence of unmethylated DNA copies that were generated at the expense of methylated DNA copies ubiquitously present in normal epidermis. The ratio of unmethylated to methylated DNA copies correlated with the extent of suprabasal K13 protein expression. Thus, all features of aberrant K13 expression previously described in DMBA/TPA-induced papillomas were shared by v-Ha-ras-induced papillomas.
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PMID:v-Ha-ras-induced mouse skin papillomas exhibit aberrant expression of keratin K13 as do their 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate -induced analogues. 172 71

Papillomas induced by DMBA initiation-TPA promotion protocols are necessary precursor lesions of squamous cell carcinomas. The papillomas are heterogeneous in their potential for progression to carcinomas, a property apparently induced at the time of initiation. The probability of conversion to malignancy is highest for the papillomas most easily promoted, by either the first few TPA treatments or by "weak" promoters such as mezerein or chrysarobin. The conversion frequency is lowest for TPA-dependent papillomas and those papillomas which appear late in a TPA promotion protocol. The spontaneous rate of malignant conversion is not altered by continued TPA treatment; TPA promotion may simply expand clones of initiated cells which are already programmed with a given probability of conversion. Treatment of papilloma-bearing mice with a genotoxic agent, such as 4-NQO, urethane or cisplatin, increases the rate of malignant conversion. The properties of active converting agents differ markedly from those of the phorbol ester promoting agents, suggesting differences in the mechanisms of action of these two classes of compounds. A genetic mechanism appears likely to explain conversion. The differences between the two stages are further emphasized by the finding that inhibitors of tumor promotion are not inhibitory when given during malignant conversion. The converting agent urethane also affects the subsequent discrete stage in tumor progression, tumor metastasis. Differences in metastatic potential have been found between carcinomas which progress spontaneously after TPA promotion and carcinomas induced in TPA-promoted papillomas by urethane. The multistage nature of experimental epidermal carcinogenesis is well established. The mouse skin model will continue to be valuable for mechanistic studies since similar stages have been described in other tissues as well as in man.
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PMID:Malignant conversion, the first stage in progression, is distinct from phorbol ester promotion in mouse skin. 181 91

Oxidative modification of genetic material has been implicated as a factor in carcinogenesis, particularly during promotion and progression, and therefore there is a need for sensitive detection of oxidized DNA bases. We developed a method that can be applied to DNA isolated from any source and used to simultaneously quantify oxidized nucleosides without a need to prelabel the DNA or use destructive hydrolytic procedures. This method is based on: (a) enzymatic DNA digestion; (b) HPLC separation of the resultant nucleosides; (c) acetylation of the oxidized nucleosides with [3H]Ac2O (acetic anhydride); (d) removal of the radioactive debris; and (e) quantitative analysis of tritiated nucleoside acetates by HPLC. Enzymatic DNA digestion was optimized using DNase I in the presence of Mg2+ (pH 7), followed by nuclease P1 in the presence of Zn2+ (pH 5.1) and alkaline phosphatase (pH 7.5). Analysis of DNA oxidized with H2O2 in the presence of Fe2+/EDTA for 30 min showed that the levels of 8-OHdG (8-hydroxy-2'-deoxyguanosine) were increased 2.7-fold, HMdU (5-hydroxymethyl-2'-deoxyuridine) 3.15-fold, and FdU (5-formyl-2'-deoxyuridine) 2.5-fold. Although the (-)-isomer of cis-dTG (cis-thymidine glycol) was enhanced 2.3 times, the (+)-isomer remained virtually unchanged. Analysis of DNA isolated from epidermal cells of mice treated in vivo with the tumor promoter TPA (12-O-tetradecanoylphorbol 13-acetate) showed 4.8-, 2.7-, and 8.7-fold increases in the levels of total cis-dTG, 8-OHdG, and HMdU, respectively, and of some unknown DNA oxidation products. These results prove applicability of the 3H-postlabeling method to the analysis of DNA (and potentially RNA) isolated from many sources, including animals and humans.
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PMID:Quantitative high-performance liquid chromatography analysis of DNA oxidized in vitro and in vivo. 188 26

The metabolism of the phorbol diester [20-3H]12-O-tetradecanoylphorbol-13-acetate [( 3H]TPA) was studied in the back skin of NMRI mice after topical administration of a single tumour-promoting dose, dp. Up to 72 h after administration most of the radioactivity recovered from the skin surface, and from the epidermis and dermis of the treated skin area was unchanged TPA, as determined by silica gel HPLC of extracts obtained from these skin fractions. The major TPA metabolite was less polar than TPA and chromatographed in the range of long-chain TPA-20-acylates. At 72 h, it accounted for about 25, 5 and 30% of total radio-activity extracted from skin surface, epidermis and dermis respectively. Of metabolites more polar than TPA, phorbol-13-acetate (PA) by far predominated over 12-O-tetradecanoylphorbol (TP) in both the epidermis and dermis, and by 72 h its relative amount was 3.9 and 2.4% in these skin fractions. Both phorbol monoesters, PA and TP, were not detected in skin surface extracts. In addition to metabolites, various autoxidation products of TPA were present in small amounts in the extracts from each of the skin fractions. The TPA-20-acylate fraction of metabolites isolated from the extracts of skin fractions at 24 h was separated further into the individual metabolites by the combined use of argentation and reversed-phase HPLC. These individual metabolites were identified by co-chromatography with authentic reference compounds. They were TPA-20-acylates carrying saturated fatty acids (16-26 carbon atoms), cis-mono-unsaturated fatty acids (16-24 carbon atoms), linoleic acid and arachidonic acid. The conjugation of TPA with long-chain fatty acids is the first example of a new route of xenobiotic metabolism in skin. When tested for irritant activity on the mouse ear, TPA-20-acylates were about one to two orders of magnitude less active than TPA. Similarly, when TPA-20-tetradecanoate was tested for tumour-promoting activity on the back skin of NMRI mice over a dose range of dp = 50-200 nmol applied twice weekly according to the computer-assisted standard protocol 16, it was found to be of only intermediate potency as compared to the highly potent tumour promoter TPA. The results of the present investigation indicate that metabolic conjugation of TPA with long-chain fatty acids to yield TPA-20-acylates is another pathway of metabolic deactivation of TPA, thus supporting the hypothesis that TPA itself is the ultimate tumour promoter in mouse skin.
Carcinogenesis 1991 Sep
PMID:Toxicokinetics of tumour promoters of mouse skin. II. Metabolism of the tumour promoter 12-O-tetradecanoylphorbol-13-acetate in mouse skin and biological activities of metabolites. 189 16

One of the many changes induced by topical application of phorbol ester or calcium ionophore A23187 to mouse skin is the appearance of an enzymic activity which will convert arachidonic acid to its 8-hydroxyeicosatetraenoic acid metabolite (8-HETE) (Gschwendt, M., et al (1986) Carcinogenesis 7, 449-455). Induction of this activity is lower in strains of mice with a weak inflammatory response to TPA, and the 8-HETE may be involved in the inflammation or hyperplasia. To further characterize the activity, we first measured the chirality of the product; it is almost exclusively the 8DS)-hydroxy enantiomer (8S-HETE). The 8(S)-HETE is formed from octadeuterated arachidonic acid with complete retention of deuterium labels, indicating that a keto intermediate is not involved in the biosynthesis. Using arachidonic acids labeled with a prochiral tritium in either the 10DR or 10LS positions, we found that the biosynthesis of 8S-HETE is associated with the stereoselective abstraction of the 10DR hydrogen from the 10-carbon of the substrate. This stereoselective hydrogen removal conforms to the properties of an 8S-lipoxygenase. This is the only lipoxygenase known to catalyze solely 8S-oxygenation of arachidonic acid. The recent characterization of stereoselective biological effects for other HETEs serve as strong precedents to suggest that 8S-HETE has a specific role in the cellular tissue response to TPA.
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PMID:Investigation of the mechanism of biosynthesis of 8-hydroxyeicosatetraenoic acid in mouse skin. 190 Feb 7

Okadaic acid and dinophysistoxin-1 are non-12-O-tetradecanoylphorbol-13-acetate (non-TPA)-type tumor promoters, which enhance chemically induced tumorigenesis on mouse skin through a different mechanism from that of TPA. In the present study, we examined the promoting effects of these okadaic acid class tumor promoters on a two-stage transformation using BALB/3T3 cells which was designed to simulate in vivo two-stage carcinogenesis. Cells were treated first with a low dose of the initiator 3-methylcholanthrene (MCA) and then with a test chemical. Okadaic acid and dinophysistoxin-1 significantly enhanced the MCA-induced cell transformation. Okadaic acid tetramethyl ether, an inactive compound, did not affect the transformation of MCA-treated cells. The okadaic acid class of tumor promoters failed to induce transformation without pretreatment by MCA. Okadaic acid did not show initiating activity in the two-stage transformation assay in which cells were treated first with okadaic acid and then with TPA. These results indicate that this transformation assay with BALB/3T3 cells is useful to predict tumor-promoting activity of non-TPA-type as well as TPA-type tumor promoters, before long-term in vivo two-stage carcinogenesis experiments are carried out.
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PMID:Promotion of BALB/3T3 cell transformation by the okadaic acid class of tumor promoters, okadaic acid and dinophysistoxin-1. 190 99

Cepharanthine, isolated from Stephania cepharantha, is one of the bisbenzylisoquinoline-type alkaloids. We have found that it inhibits tumor promotion after topical application in two-stage carcinogenesis in mouse skin. Epidermal ornithine decarboxylase activities inhibited by topical application of cepharanthine, with an 5 micrograms/mouse) and mezerein (5 micrograms/mouse) were found to be inhibited by topical application of cepharanthine, with a ED50 of 1.2 mumol and 1.4 mumol respectively. These inhibitory effects of cepharanthine are considered to be related to its antitumor activity in two-stage carcinogenesis in mouse skin. Cell-mediated immunosuppression by TPA was unaffected by topical application of cepharanthine. A diet containing 0.005% cepharanthine (about 0.5 mg mouse-1 day-1) slightly suppressed the two-stage promotion of skin tumors by twice-weekly applications of 2.5 micrograms TPA for 2 weeks (first stage) followed by twice-weekly applications of 2.5 micrograms mezerein for 23 weeks (second stage) in ICR mice following initiation by 50 micrograms 7,12-dimethylbenz[a]anthracene. Oral administration of cepharanthine inhibits the tumor promotion in two-stage carcinogenesis in mouse skin.
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PMID:Cepharanthine inhibits two-stage tumor promotion by 12-O-tetradecanoylphorbol 13-acetate and mezerein on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene. 190 98

A single topical application of 10 nmol TPA to mouse skin caused an increase in epidermal cholesterol sulfotransferase activity, a squamous differentiation associated enzyme. A topical application of indomethacin (1.2 mumol), a cyclooxygenase inhibitor, 10 min before TPA application markedly inhibited the above TPA action. Concurrent application of prostaglandin E2 (PGE2) with indomethacin reversed the inhibitory effect of indomethacin. PGF2 alpha, however, failed to reverse the inhibition caused by indomethacin. Both indomethacin and PGE2 alone did not change epidermal cholesterol sulfotransferase activity significantly. These results indicate that PGE2 plays a significant role in the mechanism of TPA-caused increase in cholesterol sulfotransferase activity in mouse epidermis.
Carcinogenesis 1991 Jun
PMID:Involvement of prostaglandin E2 in the tumor promoter phorbol ester-caused increase in epidermal cholesterol sulfotransferase activity. 204 98

Ultrastructural morphometric characteristics of basal keratinocytes in hairless mouse epidermis were analyzed statistically. The following variables were assessed: (i) low versus physiological osmolality during fixation, (ii) alterations induced by a 2-stage carcinogenesis regimen using DMBA and TPA, (iii) criteria for a cell being dark versus being clear, (iv) inter-observer variation. The results show that with low fixation osmolality most basal cells swell and become electron lucent. The few cells which apparently do not swell stand out as shrunken electron dense dark cells. Morphometrically they are more differentiated than clear cells, but do share many features with the basal cell type which appears after fixation in a buffer of physiological osmolality. Iso-osmolality during fixation seems to induce a homogeneous basal cell population of relatively electron dense cells without typical dark and clear elements. Treatment with DMBA/TPA induces not only intercellular edema and reduced desmosomal contacts, but causes injury to the plasma membrane leading to hydropic changes in the cells. This general intra- and intercellular DMBA/TPA induced hydration might induce secondary compression of some of the cells, leading to an increased number of compressed dark cells. It is, however, only after fixation in low buffer osmolality that these effects of DMBA/TPA are statistically significant and clearly observable. The inter-person variation was, apart from a few instances, either not statistically significant or did not interfere with the other effects. We did not find clear arguments in favor of the view that dark cells are primitive epidermal stem cells. They seem only to reflect non-specific toxic effects of tumor promoters, which appear only under certain fixation conditions, that have been used by most authors. The results suggest that dark and clear cells are mainly a consequence of the degree of cellular hydration.
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PMID:Morphometric evaluation of dark and clear epidermal basal cells during early 2-stage chemical skin carcinogenesis in the hairless mouse using two different fixation methods. 211 28

Six generations of a bidirectional selective breeding model for producing lines of mice susceptible (Car-S) and resistant (Car-R) to two-stage skin carcinogenesis are described. Initiation was with 9,10-dimethyl-1,2-benzanthracene (DMBA single application), and promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA twice weekly). The selective breeding was initiated with a highly genetically polymorph foundation population, produced by the intercrossing of eight inbred mouse strains. The Car-S line was produced by assortative mating of the mice presenting the largest number of tumors induced by low DMBA and TPA doses, the Car-R line by mating tumorless mice or mice showing the smallest number of tumors induced by large DMBA and TPA doses. The character investigated was expressed as per cent tumor incidence and as tumor multiplicity per mouse. The mean heritability of the susceptibility character for the two first generations was 0.84 for tumor incidence and 1.3 for tumor multiplicity; these values decreased to 0.53 and 0.44 respectively for the two consecutive generations. The heritability of the resistance character maintained a constant value of 0.29 +/- 0.04 for tumor incidence, and 0.53 +/- 0.08 for tumor multiplicity. The progressive response to selection indicates that the characters investigated are subject to polygenic regulation, even though some genes may have a major effect on the susceptibility character. The interline separation in F5, challenged with the same initiation and promotion schedule, is very large. In the Car-S line, tumor incidence was 82.5% and tumor multiplicity 4.9/mouse on promotion day 49, whereas the corresponding values for the Car-R line were 4.5% and 0.1/mouse on promotion day 81.
Carcinogenesis 1990 Oct
PMID:Genetics of chemical carcinogenesis. 1. Bidirectional selective breeding of susceptible and resistant lines of mice to two-stage skin carcinogenesis. 211 4


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