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

Currently there is no well-defined biological parameter or marker to help define agents, doses, and dose schedules for human cancer chemoprevention trials. Induction of ornithine decarboxylase, the rate limiting enzyme in the polyamine biosynthetic pathway, has been shown to be an essential aspect of mouse skin tumor promotion. Supplementary information suggest that this enzyme is an important aspect of carcinogenesis in other organ systems and in other animals (including humans). We have developed an assay system which effectively measured tumor promoter (TPA)-induced ornithine decarboxylase activity on 3-4 mm skin samples from mice and humans. Using this system we evaluated the doses and dose schedules of retinoic acid and indomethacin needed to effectively inhibit ornithine decarboxylase activity. Our data suggest that the doses and schedules of these compounds needed to inhibit ornithine decarboxylase activity would be toxic in humans.
Carcinogenesis 1985 Nov
PMID:Dose and schedule of oral retinoic acid and indomethacin needed to effectively inhibit phorbol ester-induced epidermal ornithine decarboxylase activity. 405 80

The evolution of a fully malignant tumor is a multistep process resulting from the action of multiple factors, both environmental and endogenous, and involves alterations in the function of multiple cellular genes. Chemical carcinogens that initiate this process appear to do so by damaging cellular DNA. In addition to producing simple point mutations, this damage appears to induce the synthesis of a trans acting factor that can induce asynchronous DNA replication. This response may result in gene amplification and/or gene rearrangement. This phenomenon may also play a role in synergistic interactions between chemicals and viruses in the causation of certain cancers. The primary target of the tumor promoters TPA, teleocidin, and aplysiatoxin appears to be the cell membrane. All three of these agents act, at least in part, by enhancing the activity of the phospholipid-dependent enzyme protein kinase C. We have proposed a stereochemical model to explain the interaction of these amphiphilic compounds with the PKC system. We have found that TPA and teleocidin markedly enhance the transformation of C3H 10T1/2 mouse fibroblasts when these cells are transfected with the cloned H-ras human bladder cancer oncogene. Thus, tumor promoters can act synergistically with an activated oncogene to enhance cell transformation. Furthermore, carcinogen-transformed rodent cells display aberrations in the expression of various endogenous retrovirus-related sequences. Activation of some of these sequences may lead to insertion mutations and further aberrations in gene expression. Thus, multistage carcinogenesis may involve both changes in cellular oncogenes and aberrations in the function of DNA sequences that control gene transcription.
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PMID:Cell culture studies on the mechanism of action of chemical carcinogens and tumor promoters. 406 3

Figure 2 summarizes our current understanding of the signal transduction events that appear to be involved in promotion of transformation in JB6 cells. Among the earliest promotion-relevant events (at least for phorbol esters) appear to be C-kinase activation and superoxide anion elevation. Whether such events regulate expression of pro genes needs to be elucidated. Finally, Fig. 3 presents a model for the role of pro genes and transforming genes in inducing and maintaining neoplastic transformation in mouse JB6 cells. Our current hypothesis is that TPA interacts with its receptor (C-kinase) to trigger one or more promotion-relevant second messages, which then activate expression of pro gene(s). The product of a pro gene is postulated to then activate expression of a transforming gene so that its expression becomes constitutive in the neoplastic cell. In the P- cells the "defect" could be at the level of a missing second messenger signal to activate pro genes or a structural change in pro genes such that they are not expressed or they lack activity even though expressed. Recent evidence to be presented elsewhere indicates that pro genes are not limited to mouse cells but are found in certain human tumor and nontumor cells. If human pro homologues turn out to show biological activity for specifying sensitivity to neoplastic transformation, this finding will add a new dimension to testing the somatic mutation hypothesis of carcinogenesis.
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PMID:Genes and membrane signals involved in neoplastic transformation. 406 6

Carcinogenesis is a multistep process resulting from a complex interaction between multiple factors, both environmental and exogenous. In contract to initiating agents that act by damaging cellular DNA, the primary targets of the phorbol ester tumor promoters are membrane-associated receptors. We have proposed a stereochemical model to explain the interaction of these amphiphilic molecules, and of teleocidin and aplysiatoxin, with this receptor system. The model is consistent with evidence that a complex between protein kinase C and phospholipid is the actual receptor for these compounds. Recent data we have obtained with a compound present in tung oil, 12-O-hexadecanoyl-16-hydroxyphorbol-13-acetate (HHPA), and twelve of its congener's (provided by Y. Ito et al.) are also consistent with our stereochemical model. We have studied phorbol ester receptors in a wide variety of tissue culture cell types. Our data, together with other findings, provide evidence for considerable receptor heterogeneity and this may relate to the pleiotropic effects of these compounds. We have found a case of "masked" receptors in a rat liver cell line and shown that it is due to a cell-associated esterase. Normal human melanocyte cultures contain phorbol ester receptors and this is of particular interest since these cells actually require these or related compounds for optimal growth (in collaboration with M. Eisinger). The receptor studies provide clues to how tumor promoters can, via inductive mechanisms, produce alterations in the structure and function of cell membranes. It is not known, however, how in the multistep carcinogenic process promoters enhance the eventual outgrowth of permanently altered tumor cells. We have found that TPA and teleocidin produce a marked enhancement of transformation of C3H 10T1/2 cells induced by transfection with h-ras human bladder cancer oncogene. These and other results are discussed in terms of the role of alterations in cellular oncogenes and transcriptional enhancer sequences during multistage carcinogenesis.
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PMID:Molecular mechanisms of tumor promotion and multistage carcinogenesis. 609 83

The long-term (34 weeks) topical administration of 7,12-dimethylbenz(a)anthracene (DMBA) to the skin of male and female Mastomys induced a broad spectrum of benign and malignant tumors in all animals treated. In a two-stage carcinogenesis experiment with topical initiation with DMBA and topical promotion with TPA, 50% of the animals developed both benign and malignant skin tumors. In general, benign tumors occurred between weeks 15 and 25, whereas malignant tumors were seen 40 weeks after initiation. In contrast to the situation in Mus musculus, the benign tumors consisted mainly of keratoacanthomas instead of fibroepitheliomas. In the non-initiated, TPA-treated, control group four benign and four malignant tumors were seen, whereas animals of the DMBA-initiated, acetone-treated control group were free of tumors. The promotion of virus transformed cells with TPA is discussed.
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PMID:Chemical carcinogenesis by the two-stage protocol in the skin Mastomys natalensis (Muridae) using topical initiation with 7,12-dimethylbenz(a)anthracene and topical promotion with 12-0-tetradecanoylphorbol-13-acetate. 611 33

Long-term animal experiments with prenatally X-irradiated offspring have so far not unequivocally settled the question of elevated tumor susceptibility. We have pursued this problem further in a modified 2-stage carcinogenesis-Berenblum/Mottram experiment. Prenatal X-irradiation of mice has thus been regarded as a possible initiator stimulus, with a postnatal promotion stimulus being given by applying the phorbol ester TPA to the offsprings' skin. This treatment has, however, not produced a higher tumor yield, neither of the skin nor of the internal organs, than that produced by X-irradiation in utero alone. This failure seems partly due to the dysplastic nature of the epidermis of prenatally X-irradiated mice, which also fails to respond to TPA application by way of hyperplasia or by an increased inflammation tendency and ulcer formation. We suggest that a decrease in prostaglandin synthesis after prenatal X-irradiation is an important factor for the unchanged tumor susceptibility, especially of the skin.
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PMID:Can prenatal X-irradiation in mice act as an initiator stimulus in a modified 2-stage Berenblum/Mottram experiment with postnatal promotion with phorbol ester TPA? 625 23

Short term assays for potential carcinogenic factors must take into account the fact that carcinogenesis is usually a multistep process and that most human cancers probably result from a complex interaction between multiple factors, both environmental and endogenous. Thus, although extremely valuable, simple in vitro mutagenesis assays have major limitations. Cell culture studies with TPA and other phorbol esters provide clues to tumor promotion and the multistep nature of carcinogenesis. These effects can be divided into three categories: 1) mimicry of transformation in normal cells, and enhancement of transformation by chemical carcinogens or oncogenic viruses; 2) modulation (inhibition or induction) of differentiation; 3) membrane and receptor effects. Current evidence suggests that TPA acts by binding to specific high affinity cell surface membrane receptors and that this leads to alterations in the composition of membrane phospholipids. Presumably, these changes in the lipid matrix of cell membranes produce signals or mediators which lead to the subsequent cytoplasmic and nuclear effects of TPA. Thus, whereas the critical target in the action of initiating carcinogens appears to be cellular DNA, the critical target of the phorbol ester tumor promoters appears to be cell membranes. As a unifying concept of two-stage carcinogenesis, we postulate that during the initiation phase in carcinogenesis the covalent binding of carcinogens in DNA induces abberations in the commitment of the target cells. We believe that this involves highly ordered genetic events, for example, gene transpositions, rather than random point mutations. Certain oncogenic viruses achieve a similar effect thru integration of exogenous DNA sequences into inappropriate sites in the host genome. Tumor promoters, via their effects on growth, gene expression and differentiation, enhance the selective outgrowth of these initiated cells and induce them to express their newly acquired by previously dormant committed state. Rapid in vitro assays for the detection of the phorbol ester tumor promoters and for synergistic interactions between oncogenic viruses and chemical now exist. However, simple assays for other classes of tumor promoters and cofactors remain to be developed.
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PMID:Cell culture systems for studying multifactor interactions in carcinogenesis. 627 1

Topical application of prostaglandin E1 or E2 onto the mouse skin results in a 2- to 3-fold increase of the cyclic AMP level in epidermis within 5 min. (15S)-15-methyl-PGE1 is more active in this respect, whereas PGD2 and PGF2 alpha are ineffective. The level of cyclic GMP is not altered by E- or F-prostaglandins. A single PGE2 application desensitizes the cyclic AMP response of mouse epidermis to further treatments in a dose dependent and agonist-specific manner. Delayed and longlasting refractoriness of PGE2-induced cyclic AMP accumulation is also caused by hyperplasiogenic skin irritants such as the phorbol ester tumor promoter TPA or the nonpromoting agents RPA and A23187. The non-irritant skin mitogen 4-O-methyl-TPA does not evoke desensitization. TPA-induced PGE2 refractoriness cannot be prevented by inhibitors of protein synthesis, anti-inflammatory steroids, indomethacin or phentolamine. The development of tachyphylaxis does not seem to be related to endogenous formation of PGE or cyclic AMP. A 2-fold increase of epidermal cyclic AMP observed within 1-2 h of TPA application can be inhibited by indomethacin treatment and correlates with delayed accumulation of PGE2 in TPA-treated epidermis, whilst immediate PGE accumulation (5-10 min after TPA application) which has been shown to be critical for development of TPA-induced epidermal hyperplasia is not accompanied by any change of the intraepidermal cyclic AMP level. It is concluded that mouse epidermis contains two types of PGE-regulated effector systems, one of which is coupled to adenylate cyclase, one of which is not. Only the latter system is involved in the induction of hyperplasia. At least as far as the mitogenic effect is concerned, cyclic AMP does not seem to be involved in TPA action.
Carcinogenesis 1983 Nov
PMID:Prostaglandins, cyclic nucleotides and the effect of phorbol ester tumor promoters on mouse skin in vivo. 631 56

Nonmelanoma skin cancers, like most malignancies, increase in incidence with increasing age. However, in general they are not due to the aging process but are primarily due to solar radiation. Clinically, squamous cell carcinomas and basal cell epitheliomas are the most common cancers that occur in the Caucasian population in the United States. The role of radiation from the sun was suggested by a number of astute clinical observations reported around 1900 and subsequently has been established by epidemiologic and experimental studies. Action spectrum evaluations indicate that the ultraviolet B (UVB) rays are the most carcinogenic. However, recent studies indicate that the UVA rays can augment the cancer-producing effects of UVB rays. Other physical stimuli, including heat and wind, can also accelerate UVB carcinogenesis. Chemicals such as the polycyclic hydrocarbons, the nitrosoureas, and nitrogen mustard have an additive carcinogenic effect with UVB radiation. Also, some chemicals such as croton oil, the phorbol ester--TPA, and all-trans-retinoic (RA) acid can promote UVB-initiated carcinogenesis. RA can also inhibit UVB-induced cancer formation. The role of the immune status has received a great deal of attention. Both in experimental and clinical situations, nonspecific immune suppression results in increased cancer formation. Also, recent studies indicate that a specific T cell suppressor population can be induced in experimental animals with UVB which will inhibit rejection of tumors produced by UVB radiation. Finally, damage to DNA by UVB radiation is well established. Studies with the genetic disease xeroderma pigmentosum support the concept that such damage, if not repaired, will lead to cancer formation. It also has been suggested that unrepaired damage to deoxyribonucleic (DNA) and other macromolecules is at least in part responsible for the aging process in general.
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PMID:Photocarcinogenesis, skin cancer, and aging. 635 13

Skin carcinogenesis can be operationally and mechanistically divided into at least three stages; tumor initiation, stage I and stage II of promotion. Current information suggests that reactive intermediates of skin tumor initiators are mutagenic and bind convalently to DNA of epidermal stem cells (dark basal keratinocytes) leading to some irreversible alteration in the differentiation capacity of these cells. Inhibitors of skin tumor initiation by polycyclic aromatic hydrocarbons (PAH) decrease the level of the PAH diol-epoxide bound to specific DNA adducts. The tumor promoters have been shown to have many cellular and biochemical effects in the skin. Recent data suggests that free radicals may be important in skin tumor promotion. The first stage of promotion is partially irreversible and can be accomplished by a single treatment of a tumor promoter such as TPA or by non-promoting agents such as 4-0-methyl-TPA, calcium ionophore A23187, and hydrogen peroxide, as well as wounding. These agents increase the number of dark basal keratinocytes, which suggest that these cells are important in the first stage of promotion. Prostaglandin E2 was found to specifically enhance stage I of promotion whereas the protease inhibitor tosyl phenylalanine chloromethylketone (TPCK) specially inhibited stage I of promotion and the TPA-induced dark basal keratinocytes. The second stage of promotion is initially reversible but later becomes irreversible. The weak promoting agent mezerein is an effective stage II promoter. Polyamines and epidermal cell proliferation appear to be important events in stage II of promotion. Putrescine was found to specifically enhance stage II, whereas retinoic acid (RA), diflouromethylornithine (DFMO), and butylated hydroxyanisole (BHA) specially inhibited stage II of promotion and the mezerein-induced polyamine levels. Floucinolone acetonide (FA) was found to inhibit both stages but was more effective in counteracting stage I of promotion. Although, TPA can cause a decrease in the number of glucocorticoid receptors during promotion, FA can effectively prevent this loss. Recent data suggest that skin tumor promotion can be effectively inhibited by a combination of stage I and II inhibitors. Furthermore, skin carcinogenesis can be counteracted by a combination of low and nontoxic doses of BHA, TPCK, DFMO and vitamin E.
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PMID:Multistage skin carcinogenesis: a useful model for the study of the chemoprevention of cancer. 638 17


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