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

Clinical studies suggest that diabetes mellitus may predispose to the development of pancreatic cancer. The current study investigated the effect of experimental diabetes on the susceptibility of the Syrian hamster to the induction of exocrine pancreatic carcinoma by the carcinogen BOP. Diabetes was induced with the B-cell toxin streptozotocin. Three groups of animals were studied: nondiabetic control animals and animals with streptozotocin-induced diabetes, and a third group of animals in which the diabetogenic effect of streptozotocin was blocked with nicotinamide. Streptozotocin-induced diabetes significantly inhibited the induction of pancreatic carcinoma by BOP, decreasing the incidence of carcinoma to 24 percent compared with an incidence of 75 percent in nondiabetic control animals (p less than 0.002). In diabetic animals, the degree of inhibition of carcinogenesis paralleled the severity of the diabetes. Blocking the diabetogenic effect of streptozotocin with nicotinamide restored the incidence of induced invasive pancreatic carcinoma to that occurring in nondiabetic control animals. In the hamster model, diabetes appears to have a strong influence on susceptibility to the development of pancreatic carcinoma.
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PMID:Influence of diabetes on susceptibility to experimental pancreatic cancer. 296 53

Retinoic acid receptor transcripts (RARalpha and RARgamma) are decreased in benign mouse epidermal tumors relative to normal skin and are almost absent in carcinomas. In this report, the expression of RARalpha and RARgamma proteins was analyzed by immunoblotting in benign skin tumors induced by two different promotion protocols designed to yield tumors at low or high risk for malignant conversion. RARalpha was slightly reduced in papillomas promoted with 12-O-tetradecanoylphorbol-13-acetate (low risk) and markedly decreased or absent in papillomas promoted by mezerein (high risk). However, mezerein also caused substantial reduction of RARalpha in nontumorous skin. RARgamma was not detected in tumors from either protocol and was greatly reduced in skin treated by either promoter. Both RARalpha and RARgamma proteins were decreased in keratinocytes overexpressing an oncogenic v-ras(Ha) gene, and RARalpha was underexpressed in a benign keratinocyte cell line carrying a mutated c-ras(Ha) gene. Introduction of a recombinant RARalpha expression vector into benign keratinocyte tumor cells reduced the S-phase population and inhibited [3H]thymidine incorporation in response to retinoic acid. Furthermore, transactivation of B-RARE-tk-LUC by retinoic acid was markedly decreased in keratinocytes transduced with the v-ras(Ha) oncogene (v-ras(Ha)-keratinocytes). Blocking protein kinase C function in v-ras(Ha)-keratinocytes with bryostatin restored RARalpha protein to near normal levels, reflecting the involvement of protein kinase C in RARalpha regulation. Both RARalpha and RARgamma are down-regulated in cultured keratinocytes by 12-O-tetradecanoylphorbol-13-acetate, further implicating PKC in the regulation of retinoid receptors. Our data suggest that modulation of RARs could contribute to the neoplastic phenotype in mouse skin carcinogenesis and may be involved in the differential promoting activity of mezerein and 12-O-tetradecanoylphorbol-13-acetate, particularly for selecting tumors at high risk for malignant conversion.
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PMID:Loss of retinoic acid receptors in mouse skin and skin tumors is associated with activation of the ras(Ha) oncogene and high risk for premalignant progression. 889 48

Inositol hexaphosphate (InsP6) is the most abundant inositol phosphate found in plants. In mammalian cells, the concentrations of InsP6 are between 10 and 100 microM. Previous work has indicated that InsP6 is an effective cancer chemopreventive and chemotherapeutic agent. However, the molecular mechanisms involved in the inhibition of carcinogenesis by InsP6 remain unclear. In this study, we investigated the influence of InsP6 on tumor promoter-induced cell transformation and signal transduction pathways leading to activator protein 1 activation, which is considered to play a crucial role in tumor promotion. InsP6 markedly blocks epidermal growth factor-induced phosphatidylinositol-3 (PI-3) kinase activity in a dose-dependent manner in JB6 cells and directly in vitro. Blocking PI-3 kinase activity by InsP6 profoundly impairs epidermal growth factor- or phorbol ester-induced JB6 cell transformation and extracellular signal-regulated protein kinases activation, as well as activator protein 1 activation. These results provide the first evidence that the molecular mechanism of InsP6 antitumor promotion effect targets and blocks PI-3 kinase activation and demonstrate that PI-3 kinase can serve as a molecular target for the development of cancer chemopreventive agents.
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PMID:Inositol hexaphosphate inhibits cell transformation and activator protein 1 activation by targeting phosphatidylinositol-3' kinase. 923 Jan 93

Cancer chemoprevention can be defined as prevention of cancer by the administration of one or more chemical entities, either as individual drugs or as naturally occurring constituents of the diet. Based largely on the time period that chemopreventive agents exhibit activity in animal models of carcinogenesis, they can be classified as inhibitors of carcinogen formation, blocking agents, and suppressing agents. The majority of compounds that inhibit the formation of carcinogens prevent the formation of nitrosamines from secondary amines and nitrite in an acidic environment. Blocking agents are inhibitors of tumor initiation, while suppressing agents are inhibitors of tumor promotion/progression. Many well-characterized chemopreventive agents act at one or more steps in both tumor initiation and promotion/progression. The objective of this paper is to provide a general discussion of the mechanisms through which chemopreventive agents inhibit carcinogenesis. Examples of agents that act through these mechanisms are given; however, a complete listing of effective chemopreventive agents is not possible within the context of this paper. At the conclusion is a brief discussion of future prospects in cancer chemoprevention and obstacles to overcome.
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PMID:Perspectives in cancer chemoprevention. 925 86

The cytochrome P450 (P450) enzymes that catalyse metabolism of the estrogen, estrone (E1), to the putative carcinogen 16alpha-hydroxy E1 (16alpha-OHE1) in humans were determined. The potential of the most abundant circulating form of estrogen, estrone 3-sulfate (E1S), to be the substrate was also investigated. Human liver microsomal sulfatases convert E1S to E1, an essential prerequisite for formation of 16alpha-OHE1 from added E1S in this system. E1 metabolism to 16alpha-OHE1 in a panel of 15 human liver microsomal preparations correlated with total P450 concentrations (r2 = 0.63) and with activities associated with P450 forms CYP3A4 and 3A5 (r2 = 0.72). E1 16alpha-hydroxylase activity in human liver microsomes was inhibited by 75% by monoclonal anti human CYP3A4/5 antibodies at 4 mg antibody/nmol total P450, and by troleandomycin, a specific CYP3A4/5 inhibitor. Rates of E1 metabolism to 16alpha-OHE1 were 1.6-fold higher when E1 was generated in situ from E1S than when E1 was added. Microsomal preparations of cDNA expressed CYP3A4 or 3A5, with NADPH-P450-reductase co-expressed, both metabolized E1 to 16alpha-OHE1, and added cytochrome b5 increased the rates 5.1- and 7.5-fold, respectively. In these systems rates of E1 metabolism to 16alpha-OHE1 were 2.8-fold higher when E1 was generated in situ from E1S than when E1 was added. Kinetic values for E1 metabolism to 16alpha-OHE1 by human liver microsomes and for the expressed CYP3A4 system were Km 154 and 172 microM, respectively, and Vmax 238 pmol/min/nmol total P450 and 1050 pmol/min/nmol CYP3A4, respectively. Thus, formation of the putative carcinogen 16alpha-OHE1 is catalysed by CYP3A4 and 3A5 and stimulated by cytochrome b5. E1S is not a substrate but formation of E1 from E1S in situ stimulates formation of 16alpha-OHE1, possibly because E1S is more water soluble and in situ generation of E1 provides for facilitated exposure of E1 to the P450 substrate binding sites. Blocking of the pathway of E1 to 16alpha-OHE1 could provide a therapeutic approach for diminishing the risk of estrogen dependent breast cancer.
Carcinogenesis 1998 May
PMID:16Alpha-hydroxylation of estrone by human cytochrome P4503A4/5. 963 76

In carcinogen-treated rats, gamma-glutamyl transpeptidase (GGT) is induced in preneoplastic liver lesions and liver tumors. However, in mice, GGT is rarely detected during hepatocarcinogenesis. Data in this study reveal that GGT is not induced in mouse hepatocytes when they are maintained in vitro under the same conditions that induce GGT activity in primary cultures of rat hepatocytes. GGT activity in rat hepatocytes increased 20-fold during the first 7 days in culture, but there was no induction of GGT in primary cultures of mouse hepatocytes. Comparison of intracellular glutathione levels in rat and mouse liver cells showed that the glutathione level was higher in the mouse liver cells than the rat. Blocking glutathione synthesis with buthionine sulfoximine reduced the intracellular glutathione concentration in mouse liver cells but did not trigger an induction of GGT. Analysis of the GGT mRNA in primary cultures of rat hepatocytes showed that only GGT mRNA(III) is induced. This is the same GGT mRNA species present in preneoplastic hepatic lesions and liver tumors in the rat (1-3). Therefore activation of promoter III in the GGT gene is responsible for induction of GGT in both hepatocytes in vitro and liver tumors in vivo. These data show that primary cultures of rat and mouse hepatocytes provide a model system with which to study interspecies differences in the regulation of this enzyme and to better understand the role of GGT in normal and neoplastic processes.
Carcinogenesis 1998 Jul
PMID:Differential induction of gamma-glutamyl transpeptidase in primary cultures of rat and mouse hepatocytes parallels induction during hepatocarcinogenesis. 968 85

The sun is the most important and universal source of non-ionizing radiation shed on human populations. Life evolved on Earth bathed by this radiation. Solar UV damages cells, leading to deleterious conditions such as photoaging and carcinogenesis in human skin. During the process of evolution, the cells selected dark- and light-dependent repair mechanisms as a defence against these hazardous effects. This study describes the induction by non-coherent infrared radiation (700-2000 nm), in the absence of rising temperature, of a strong cellular defense against solar UV cytotoxicity as well as induction of cell mitosis. Blocking mitoses with arabinoside-cytosine or protein synthesis with cycloheximide did not abolish the protection, leading to the conclusion that this protection is independent of cell division and of protein neosynthesis. The protection provided by infrared radiation against solar UV radiation is shown to be a long-lasting (at least 24 h) and cumulatif phenomenon. Infrared radiation does not protect the lipids in cellular membranes against UVA induced peroxidation. The protection is not mediated by heat shock proteins. Living organisms on the Earth's surface are bathed by infrared radiation every day, before being submitted to solar UV. Thus, we propose that this as yet undescribed natural process of cell protection against solar UV, acquired and preserved through evolutional selection, plays an important role in life maintenance. Understanding and controlling this mechanism could provide important keys to the prevention of solar UV damage of human skin.
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PMID:Non-coherent near infrared radiation protects normal human dermal fibroblasts from solar ultraviolet toxicity. 976 44

Our previous studies demonstrated that inhibitors of arachidonate-phospholipid remodeling [i.e. the enzyme CoA-independent transacylase (CoA-IT)] decrease cell proliferation and induce apoptosis in neoplastic cells. The goal of the current study was to elucidate the molecular events associated with arachidonate-phospholipid remodeling that influence cell proliferation and survival. Initial experiments revealed the essential nature of cellular arachidonate to the signaling process by demonstrating that HL-60 cells depleted of arachidonate were more resistant to apoptosis induced by CoA-IT inhibition. In cells treated with CoA-IT inhibitors a marked increase in free arachidonic acid and AA-containing triglycerides were measured. TG enrichment was likely due to acylation of arachidonic acid into diglycerides and triglycerides via de novo glycerolipid biosynthesis. To determine the potential of free fatty acids to affect cell proliferation, HL-60 cells were incubated with varying concentrations of free fatty acids; exogenously provided 20-carbon polyunsaturated fatty acids caused a dose-dependent inhibition of cell proliferation, whereas oleic acid was without effect. Blocking 5-lipoxygenase or cyclooxygenases had no effect on the inhibition of cell proliferation induced by arachidonic acid or CoA-IT inhibitors. An increase in cell-associated ceramides (mainly in the 16:0-ceramide fraction) was measured in cells exposed to free arachidonic acid or to CoA-IT inhibitors. This study, in conjunction with other recent studies, suggests that perturbations in the control of cellular arachidonic acid levels affect cell proliferation and survival.
Carcinogenesis 1999 May
PMID:Perturbations in the control of cellular arachidonic acid levels block cell growth and induce apoptosis in HL-60 cells. 1033 91

In this report, we describe a novel lytic mechanism exploited by antimicrotubule drugs (AMDs) such as Taxol which are frequently used to treat multiple human cancers including breast and ovarian cancers. In cells lacking the G1-arresting capacity due to the defect in retinoblastoma or p53 gene function, AMDs trigger hyperploid progression and death. The hyperploid progression occurs via continued cell-cycle progression without cell division. Blocking hyperploid progression through hydroxyurea or ectopically expressed p27(Kip1), a G1-specific Cdk inhibitor, abrogates AMD cytotoxicity. Thus, AMDs induce lethality in G1-checkpoint-defective cells by triggering hyperploid progression. The phenomenon is reminiscent of that observed previously with bub-1 yeast mutant. The potential significance of this finding lies in that hyperploid progression-mediated death may be exploited to develop a therapy with tumor-specificity at the genetic level. As a large fraction of human cancers are mutated in p53 gene, it may have a wide therapeutic applicability.
Carcinogenesis 1999 Jul
PMID:Taxol, vincristine or nocodazole induces lethality in G1-checkpoint-defective human astrocytoma U373MG cells by triggering hyperploid progression. 1038 85

Mitogen-activated protein kinases (MAPKs) play a major role in the mitogenic signal transduction pathway and are essential components of both growth and differentiation. Constitutive activation of the MAPK cascade is associated with the carcinogenesis and metastasis of human breast and renal cell carcinomas. The gelatinases B (MMP-9) and A (MMP-2) are 2 members of the matrix metalloproteinase (MMPs) family which are expressed in human cancers and thought to play a critical role in tumor cell invasion and metastasis. In a previous study, we have shown that EGF and amphiregulin upregulate MMP-9 in metastatic SKBR-3 cells but have no effect on MMP-2 secretion. We now investigated specific step(s) in EGF-induced signalling associated with regulation of cell proliferation and MMP-9 induction. EGF-induced signalling in SKBR-3 cells was blocked by relatively specific inhibitors either on ras (FPT inhibitor-1) or P13 kinase (Wortmannin) or by reduction in EGF-induced tyrosine kinase activity (RG 13022). Blocking these signalling pathways significantly inhibited of EGF-induced cell proliferation but only partially reduced in EGF-induced MMP-9 secretion. In contrast, when SKBR-3 cells were exposed to MEK inhibitor (PD 98059) or MAPK inhibitors (Apigenin or MAPK antisense phosphorothioate oligodeoxynucleotides), EGF-induced cell proliferation, MMP-9 induction and invasion through reconstituted basement membrane were significantly reduced. Our results suggest that interfering with MAPK activity may provide a novel means of controlling growth and invasiveness of tumors in which the signalling cascade is activated.
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PMID:Mitogen-activated protein kinase (MAPK) regulates the expression of progelatinase B (MMP-9) in breast epithelial cells. 1038 62


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