Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Influence of sex steroids on the growth of an azaserine-induced transplantable rat pancreatic carcinoma, DSL-2, was studied. This established transplantable tumor has been maintained in syngeneic rats. Inbred male Lewis rats were pretreated with castration and s.c. implantation of 1.0-mg 17 beta-estradiol (CAS: 50-28-2; estradiol) pellets at 7 weeks of age. Tumor cells were inoculated s.c. on the back of intact male, castrated male, or 17 beta-estradiol-treated castrated male rats. Additional male rats served as non-tumor-bearing controls. There was no difference in the body weight between tumor-bearing and non-tumor-bearing male rats. A distinct difference in the tumor growth was observed in variously conditioned recipients. In castrated male hosts, the serum testosterone levels and the epididymis weights were significantly decreased, and the tumor weights were significantly less as compared to intact control hosts. Additional pretreatment with 17 beta-estradiol caused a markedly slower growth of tumors and increases of the serum 17 beta-estradiol levels and the pituitary weights in castrated male recipients. The remarkable response of tumor growth to castration was also observed in a fast-growing tumor derived from DSL-2. Moreover, close positive relationships between tumor weights and the activities of both serum amylase and lipase were observed. Results showed that the pretreatment with castration alone or in combination with 17 beta-estradiol treatment was able to inhibit the growth of the transplantable tumor. In addition, tumor cells had an ability to produce amylase and lipase, and the amount of enzymic activity was related to the tumor volume. Thus, these data indicate that the transplantable rat pancreatic carcinoma retains physiological function. Our previous study has shown the modulation by sex steroids of azaserine-induced preneoplastic lesions of pancreas in rats. Therefore, androgens and estrogens may play key roles as promoters and inhibitors during the process of pancreatic carcinogenesis.
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PMID:Inhibition of a transplantable pancreatic carcinoma by castration and estradiol administration in rats. 247 69

The synthetic dithiolethione Oltipraz has marked cancer chemopreventive and phase II enzyme inducing activity in various animal carcinogenesis models, but has not been examined in any animal models of ductal pancreatic cancer relevant to the human disease. The chemopreventive potential of Oltipraz on pancreatic tumor incidence and multiplicity was examined in the N-nitrosobis(2-oxopropyl)-amine (BOP)-induced ductal pancreatic adenocarcinoma model in Syrian hamsters. Animals were maintained on control semipurified diets or semipurified diets containing 300 and 600 mg/kg Oltipraz beginning 2 weeks prior to BOP initiation and throughout the 26 week study. Oltipraz at 300 mg/kg had no effect on the incidence or multiplicity of preneoplastic, neoplastic or metastatic lesions, while at 600 mg/kg dietary Oltipraz the incidence of pancreatic adenocarcinomas was reduced significantly (P < or = 0.05) compared to BOP-treated controls. Dietary Oltipraz at both doses had a significant influence on reducing mortality and morbidity in tumor-bearing animals with metastatic disease. At 26 weeks, total hepatic glutathione-S transferase (GST) activity and GST mu activity were elevated significantly in Oltipraz-treated animals, while total pancreatic GST activity was reduced, albeit not significantly. Serum lipase activity, a marker for pancreatic damage, exhibited a progressive decline in BOP-treated animals administered Oltipraz compared to BOP-treated controls at 12 weeks of the study; by week 26, lipase activity was comparable in all groups and reduced compared to activity at week 12. Positive nuclear immunostaining for the p53 tumor suppressor protein, a hallmark of human pancreatic cancer and a transient response to DNA damage, was observed in only a small percentage of BOP-induced pancreatic lesions and was not influenced Oltipraz administration. Further chemoprevention and pharmacologic studies of Oltipraz in relevant animal models of ductal pancreatic cancer could provide a foundation for future studies in human populations at potential risk for pancreatic cancer.
Carcinogenesis 1995 Sep
PMID:Chemopreventive activity of Oltipraz against N-nitrosobis(2-oxopropyl)amine (BOP)-induced ductal pancreatic carcinoma development and effects on survival of Syrian golden hamsters. 755 69

Continuous cell lines have been isolated from islet cell, small cell anaplastic and acinar cell carcinomas arising in the pancreas of transgenic mice, line Tg(Ela-1-SV40E)Bri18. These mice carry the pseudogene construct composed of elastase-1 promoter linked to the SV40 T antigen. Cells derived from islet cell or small cell anaplastic tumors secreted insulin and somatostatin during the early period of culture. Phenotypic alterations occurred during culture, whereby insulin secretion ceased and cells instead secreted somatostatin, indicating a change from beta-cell to delta-cell phenotype. Acinar cell lines did not secrete amylase or lipase.
Carcinogenesis 1994 Jan
PMID:Cell lines derived from pancreatic tumors of Tg(Ela-1-SV40E)Bri18 transgenic mice express somatostatin and T antigen. 790 4

Phospholipase C (PLC) activity and its response to stimulation by bile acids was assayed in cellular extracts from 16 primary human colon tumors of various Duke's stages and paired adjacent normal mucosal samples. In the absence of bile acid, there was negligible degradation of phosphatidylinositol (PI) 1-stearoyl-2-[14C]-arachiodonoyl by tumor or normal tissue, but the addition of deoxycholic acid (DCA) or taurocholic acid (TCA) resulted in concentration-dependent and time-dependent stimulation of diacylglycerol (DAG) formation at optimal concentrations of 2 mM DCA and 4 mM TCA. Triton X-100 (0.125-1.0%) inhibited rather than enhanced the PI-degrading activity of these extracts, indicating that the stimulatory effects of DCA and TCA were not simply due to a detergent effect. Under the same assay conditions there was only a small amount of labeled monoacylglycerol or free arachidonic acid produced by extracts incubated in the absence or presence of DCA or TCA. No major differences in DAG production from PI were seen between paired samples of normal colon mucosa and primary colon tumors, in assays done in the presence of 2 mM TCA. Extracts from tumors in the distal part of the colon had higher activity than those from the proximal colon. This was also true for the extent of release of free arachidonic acid from labeled PI. Under the same conditions, labeled phosphatidylcholine or phosphatidylethanolamine did not serve as substrates for the colon mucosa or tumor extracts. Nor was there significant hydrolysis of the labeled DAG (1-stearoyl-2-14C-arachidonoylglycerol) by normal colon mucosa or tumor extracts, in the absence or presence of DCA or TCA. On the other hand, a low level of DAG lipase activity was detected in the presence of Triton X-100. These findings provide the first evidence that normal human colon mucosa and primary colon tumors contain a PI-specific PLC activity that is markedly stimulated by bile acids. Our results also suggest that bile acids may enhance colon carcinogenesis by acting on this enzyme system, thereby influencing signal transduction pathways in the target cells.
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PMID:The effects of bile acids on phospholipase C activity in extracts of normal human colon mucosa and primary colon tumors. 814 13

8-Oxo-2'-deoxyguanosine (8-oxo-dG) is emerging as a useful marker for oxidative DNA damage. Reported basal levels determined by 32P-postlabeling (PPL) method were 10-fold or more higher than those obtained with HPLC/electrochemical detection (ECD). This discrepancy was investigated. In commercial calf thymus DNA, levels of 4 +/- 1 and 64 +/- 14 8-oxo-dG per 10(6) 2'-deoxynucleosides (dN) were measured by the standard HPLC/ECD and PPL methods, respectively. DNA digestion by micrococcal nuclease/spleen phosphodiesterase and nuclease P1 (as used in the standard PPL method), followed by ECD analysis resulted in a level of 8 +/- 3. In calf thymus DNA spiked with chemically synthesized 8-oxo-dGp to give an increment of 9 8-oxo-dG/10(6) dN, the added standard produced a significant increase with HPLC/ECD but not PPL. After spiking the DNA with 90 8-oxo-dG/10(6) dN, the added 8-oxo-dGp was detectable also with PPL, with a labeling efficiency of 65%. In order to investigate the role of ionizing radiation from 32P for the higher 8-oxo-dG levels in PPL, incubation times and amounts of radioactivity in the phosphorylation reaction with commercial dGp were increased, and external irradiation of commercial dG with 32P was investigated. All modifications resulted in higher values of 8-oxo-dG measured, but the effect was not large enough to fully explain the discrepancy between PPL and HPLC/ECD. Using [gamma-33P]ATP instead of [gamma-32P]ATP or adding [33P]phosphate to a 32P-PPL assay resulted in even higher levels of 8-oxo-dG measured. The increase in 8-oxo-dG levels during the PPL workup is attributed to the presence and oxidation of unmodified dGp in the reaction mixture. For a determination of true basal levels, the PPL method will have to be modified, including the removal of dGp prior to the phosphorylation reaction.
Carcinogenesis 1997 Dec
PMID:Comparative analysis of 8-oxo-2' -deoxyguanosine in DNA by 32P- and 33P-postlabeling and electrochemical detection. 945 Apr 83

Malondialdehyde (MDA) is a product of lipid peroxidation and prostaglandin biosynthesis. It is mutagenic and carcinogenic and the major adduct formed by reaction with DNA, a highly fluorescent pyrimidopurinone (M1-dG), has been detected in healthy human liver and leukocyte DNA. Analytical methods used so far for the detection of M1-dG have not been applied to a large number of individuals or variety of samples. Often, only a few microg of DNA from human tissues are available for analysis and a very sensitive assay is needed in order to detect background levels of M1-dG in very small amounts of DNA. In this paper, the development of an immunoslot blot (ISB) assay for the measurement of MI-dG in 1 microg of DNA is described. The limit of detection of the assay is 2.5 adducts per 10(8) bases. A series of human samples were analysed and levels of 5.6-9.5 (n = 8) and 3.1-64.3 (n = 42) of M1-dG per 10(8) normal bases were detected in white blood cell and gastric biopsy DNA, respectively. Results on four human samples were compared with those obtained using an HPLC/32P-post-labelling (HPLC/PPL) method previously developed and indicated a high correlation between M1-dG levels measured by the two assays. The advantages of ISB over other assays including HPLC/PPL, such as the possibility of analysing 1 microg DNA/sample and the fact that it is less time-consuming and laborious, means that it can be more easily used for routine analysis of a large number of samples in biomonitoring studies.
Carcinogenesis 1998 Nov
PMID:Determination of malondialdehyde-induced DNA damage in human tissues using an immunoslot blot assay. 985 3

Conjugated fatty acids have attracted much attention as a novel type of biologically beneficial functional lipid. Some isomers of conjugated linoleic acid (CLA) reduce carcinogenesis, atherosclerosis, and body fat. Considering the use of CLA for medicinal and nutraceutical purposes, a safe isomer-selective process is required. The introduction of biological reactions for CLA production could be an answer. We screened microbial reactions useful for CLA production, and found several unique reactions in lactic acid bacteria. Lactic acid bacteria produced CLA from linoleic acid. The produced CLA comprised a mixture of cis-9,trans-11-octadecadienoic acid (18:2) and trans-9,trans-11-18:2. Lactobacillus plantarum AKU 1009a was selected as a potential CLA producer. Using washed cells of L. plantarum AKU 1009a as a catalyst, CLA production from linoleic acid reached 40 mg/ml under the optimized conditions. The CLA-producing reaction was found to consist of two successive reactions, i.e., hydration of linoleic acid to 10-hydroxy-12-octadecenoic acid and dehydrating isomerization of the hydroxy fatty acid to CLA. On the basis of these results, the transformation of hydroxy fatty acids by lactic acid bacteria was investigated. Lactic acid bacteria transformed ricinoleic acid (12-hydroxy-cis-9-octadecenoic acid) to CLA (a mixture of cis-9,trans-11-18:2 and trans-9,trans-11-18:2). Castor oil, which is rich in the triacylglycerol form of ricinoleic acid, was also found to act as a substrate for CLA production by lactic acid bacteria with the aid of lipase-catalyzed triacylglycerol hydrolysis. L. plantarum AKU 1009a produced conjugated trienoic fatty acids from alpha- and gamma-linolenic acid. The trienoic fatty acids produced from alpha-linolenic acid were identified as cis-9,trans-11,cis-15-octadecatrienoic acid (18:3) and trans-9,trans-11,cis-15-18:3. Those produced from gamma-linolenic were cis-6,cis-9,trans-11-18:3 and cis-6,trans-9,trans-11-18:3. The conjugated trienoic fatty acids produced from alpha- and gamma-linolenic acid were further saturated by L. plantarum AKU 1009a to trans-10,cis-15-18:2 and cis-6,trans-10-18:2, respectively.
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PMID:Production of conjugated fatty acids by lactic acid bacteria. 1631 Jul 24

In two-stage skin chemical carcinogenesis, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) acts as a promoter essential for clonal expansion of the initiated cells carrying the activated ras oncogenes. Although protein kinase C (PKC) isozymes are the main targets of TPA, their role in tumor promotion remains controversial. We previously reported that mice lacking a Ras/Rap effector phospholipase C epsilon (PLC epsilon(-/-) mice) exhibited marked resistance to tumor formation in the two-stage skin carcinogenesis. PLC epsilon(-/-) mice also failed to exhibit basal layer cell proliferation and epidermal hyperplasia induced by TPA, suggesting a role of PLC epsilon in tumor promotion. Here, we show that PLC epsilon(-/-) mice exhibit resistance to TPA-induced skin inflammation as assessed by reduction in edema, granulocyte infiltration, and expression of a proinflammatory cytokine, interleukin-1 alpha (IL-1 alpha). On the other hand, the proliferative potentials of keratinocytes or dermal fibroblasts in culture remain unaffected by the PLC epsilon background, suggesting that the PLC epsilon's role in tumor promotion may be ascribed to augmentation of inflammatory responses. In dermal fibroblast primary culture, TPA can induce activation of the PLC epsilon lipase activity, which leads to the induction of IL-1 alpha expression. Experiments using small interfering RNA-mediated knockdown indicate that this activation is mediated by Rap1, which is activated by a TPA-responsive guanine nucleotide exchange factor RasGRP3. Moreover, TPA-induced activation of Rap1 and PLC epsilon is inhibited by a PKC inhibitor GF109203X, indicating a crucial role of PKC in signaling from TPA to PLC epsilon. These results imply that two TPA targets, RasGRP3 and PKC, are involved in TPA-induced inflammation through PLC epsilon activation, leading to tumor promotion.
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PMID:Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. 1817 97

Di(2-ethylhexyl)phthalate (DEHP) is a widely used plasticizer and a potentially nongenotoxic carcinogen. Its mechanism had been earlier proposed based on peroxisome proliferator-activated receptor alpha (PPARalpha) because metabolites of DEHP are agonists. However, recent evidence also suggests the involvement of non-PPARalpha multiple pathway in DEHP-induced carcinogenesis. Since there are differences in the function and constitutive expression of PPARalpha among rodents and humans, species differences are also thought to exist in the carcinogenesis. However, species differences were also seen in the lipase activity involved in the first step of the DEHP metabolism, which should be considered in DEHP-induced carcinogenesis. Taken together, it is very difficult to extrapolate the results from rodents to humans in the case of DEHP carcinogenicity. However, PPARalpha-null mice or mice with human PPARalpha gene have been developed, which may lend support to make such a difficult extrapolation. Overall, further mechanical study on DEHP-induced carcinogenicity is warranted using these mice.
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PMID:PPARalpha- and DEHP-Induced Cancers. 1876 59

Intracellular free Ca(2+)concentration ([Ca(2+)](i)) plays a critical role in regulating many diverse cellular functions including cell proliferation and programmed cell death (apoptosis) (1). An elevation in [Ca(2+)](i) activates enzymes (phospholipase A(2), phospho- lipase D and some isoforms of protein kinase C) associated with the liberation of bioactive lipids such as arachidonic acid (AA) and lysophosphatidic acid (LPA) (1,2). AA and its metabolites have been implicated in multiple steps of carcinogenesis (3,4). LPA as well as several other bioactive lipids stimulate release of Ca(2+)from intracellular stores and regulate proliferation of ovarian cancer cells I5-7).
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PMID:Calcium mobilization in ovarian cancer cells in response to lysophospholipids. 2134 Aug 21


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