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

Persisting focal lesions, namely glycogen storage (glycogenotic) foci and mixed cell foci, were induced in liver by treatment of rats with the hepatocarcinogen N-nitrosomorpholine in a concentration of 200 mg/l drinking water for 7 weeks. Four and seven weeks after withdrawal of the carcinogen, the persisting foci were dissected from freeze-dried cryostat sections and their glycogen content and glucose-6-phosphate dehydrogenase activity were analyzed with highly sensitive luminometrical tests. The foci composed exclusively of storage cells contained on an average 100% more glycogen than the surrounding tissue of normal appearance or the liver parenchyma of untreated control animals. The overall glycogen content of the mixed cell foci, which were composed of both glycogenotic and glycogen-poor basophilic cells, was not distinguishable from that of the normal liver tissue. The activity of the G6PDH showed a clear tendency to higher values in the majority of the small glycogen storage foci (up to 100 ng dissected material). However, in larger glycogenotic foci and in particular in the mixed cell foci the activity of this enzyme was significantly higher (by a factor of approximately 3 and 6, respectively) than in the surrounding tissue of normal appearance and in the liver parenchyma of untreated controls. The data support the concept that hepatocarcinogens induce a focal hepatic glycogen storage disease of the liver which appears to elicit adaptive enzymatic changes gradually redirecting the disturbed carbohydrate metabolism towards other metabolic pathways, such as the pentose phosphate pathway.
Carcinogenesis 1984 Feb
PMID:Biochemical microanalysis of glycogen content and glucose-6-phosphate dehydrogenase activity in focal lesions of the rat liver induced by N-nitrosomorpholine. 669 43

Effects of nucleic acids on the formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were studied in a model system. When a mixture of a certain amount of DNA or RNA, creatinine (1 mmol) and phenylalanine (1 mmol) in 10 ml of 50 mM phosphate buffer, pH 7.4, was heated at 60 degrees C for 4 weeks in a screw-capped vial, PhIP was produced, and the yield of PhIP was dependent on the heating time as well as the dose of nucleic acid added to the mixture. However, PhIP was not detectable in the mixtures without the presence of nucleic acids. Both deoxyribonucleotides and ribonucleotides tested induced the formation of PhIP under the presence of phenylalanine and creatinine, although bases of nucleic acids such as adenine and guanine did not induce PhIP formation. Moreover, we confirmed that 2-deoxy-D-ribose as well as D-ribose induced the formation of PhIP in the presence of creatinine and phenylalanine. These results indicate that nucleic acids can induce the formation of PhIP in the presence of creatinine and phenylalanine in the model system. Our data also suggest that pentose in nucleic acids may participate in PhIP forming reactions.
Carcinogenesis 1993 May
PMID:Nucleic acids induce the formation of a carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a model system. 768 55

Mouse renal cell tumors (RCTs) were induced in male CBA mice by 5 subcutaneous injections of 8 mg 1,2-dimethylhydrazine (DMH)/kg body weight once a week. After a lag period of 2 yr kidneys were removed, and serial cryostat sections of the kidneys were histochemically analyzed for the following parameters: glycogen content, basophilia, and the activities of glycogen synthase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH), hexokinase (HK), pyruvate kinase (PK), lactate dehydrogenase (LDH), malic enzyme (ME), succinate dehydrogenase (SDH), alkaline phosphatase (ALPase) and gamma-glutamyltranspeptidase (GGT). RCTs displayed the same histochemical profile irrespective of their size and growth pattern. In comparison with the normal kidney epithelium, the neoplastic cells exhibited elevated activities of enzymes for glycolysis (HK, PK, LDH) and the pentose phosphate pathway (G6PDH), while negative G6Pase and low SDH activity were observed in these cells. The majority of RCTs showed high PHO activity and weak staining for SYN. Activities of ALPase and GGT were negative in most of the RCTs. Markedly enlarged cells with atypical nuclei were detected in some advanced RCTs. Higher activities of glycolytic and mitochondrial enzymes and G6PDH were found in these enlarged cells than in other tumor cells. Tubular preneoplastic lesions were similar to neoplastic lesions in morphological and histochemical characteristics. The present study revealed that a markedly elevated capacity for glycolysis and the pentose phosphate pathway occurred in RCTs in mice. A similar histochemical pattern in the few preneoplastic tubular lesions observed suggests that these metabolic aberrations emerge early during carcinogenesis, but additional studies on early stages of renal carcinogenesis are needed to substantiate this assumption.
 ...
PMID:Enzymic pattern of preneoplastic and neoplastic lesions induced in the kidney of CBA mice by 1,2-dimethylhydrazine. 781 30

The effects of dehydroepiandrosterone (DHEA) with/without ribonucleoside (RNs) supplementation on butylated hydroxyanisole (BHA) bladder-tumor promotion and forestomach carcinogenesis were investigated. Male F344 rats were given N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks and then received basal diet or diet containing BHA, DHEA, a mixture of RNs, BHA + DHEA or BHA + DHEA + RNs for 32 weeks. The occurrences of papillomas and carcinomas in the urinary bladder were increased in the groups given BHA or BHA + DHEA + RNs, as compared with control group values. In comparison with the BHA group, the BHA + DHEA group incidences and numbers of these tumors were decreased. However, the incidence and multiplicity of papillomas in the group given BHA + DHEA + RNs were again elevated. DNA synthesis levels in normal-appearing bladder epithelium, but not tumor cells, were closely correlated with the observed level of promotion in most groups. The case of DHEA alone proved exceptional in that DNA synthesis was markedly decreased without any significant influence on lesion development. In the forestomach, DHEA, which itself was associated with slight although non-significant hyperplasia, enhanced BHA-induced epithelial lesions, characterized by marked basal-cell proliferation and keratin-cyst formation, independently of additional RNs administration. Our results suggest that the anti-promoting effects of DHEA in the bladder depend on a deficiency in the pentose phosphates necessary for production of nucleosides. Organ-specific modulation is indicated by the enhancing effects of DHEA on BHA-induced forestomach hyperplasia.
 ...
PMID:Inhibition by dehydroepiandrosterone of butylated hydroxyanisole (BHA) promotion of rat-bladder carcinogenesis and enhancement of BHA-induced forestomach hyperplasia. 844 7

Mouse renal cell tumors (RCT) were induced in male CBA male mice by 5 subcutaneous injections of 8 mg 1,2-dimethylhydrazine (DMH) per kg body weight once a week. After a lag period of two years the kidneys were removed, and serial cryostat sections of the kidneys were histochemically analyzed for the following parameters: Glycogen content, basophilia, and activities of glycogen synthase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH), hexokinase (HK), pyruvate kinase (PK), lactate dehydrogenase (LDH), malic enzyme (ME), succinate dehydrogenase (SDH), alkaline phosphatase (ALPase) and glutamyl-transpeptidase (GGT). RCT displayed the same histochemical profile irrespective of their size and growth pattern. In comparison with normal kidney epithelium, the neoplastic cells exhibited elevated activities of enzymes for glycolysis (HK, PK LDH) and the pentose phosphate pathway (G6PDH) while negative G6Pase and low SDH activity were observed in these cells. The majority of RCT showed high PHO activity and weak staining for SYN. Activities of ALPase and GGT were negative in most of the RCT. Giant cells were detected in some large RCT. Higher activities of glycolytic and mitochondrial enzymes and G6PDH were found in giant cells compared with other tumor cells. Tubular preneoplastic lesions were similar to neoplastic lesions in morphological and histochemical characteristics. The present study revealed that a markedly elevated capacity for glycolysis and the pentose phosphate pathway occurred in renal cell tumors in mice. A similar histochemical pattern in the few preneoplastic tubular lesions observed suggests that these metabolic aberrations emerge early in carcinogenesis, but studies on earlier stages of renal carcinogenesis are needed to substantiate this assumption.
 ...
PMID:[Enzymic spectrum of preneoplastic and neoplastic changes induced by 1,2-dimethylhydrazine in mouse kidneys]. 874 89

We review here some recent data about glucose-6-phosphate dehydrogenase (G6PD), the first and key regulatory enzyme of the pentose phosphate pathway. New evidence has been presented to suggest that malaria is a selective agent for G6PD deficiency, which is the most common enzymopathy in man, and that G6PD deficiency, generally considered to be a mild and benign condition, is significantly disadvantageous in certain environmental conditions. At the molecular level, the enzyme structure has recently been elucidated and mechanisms regulating G6PD gene expression have been determined. A G6PD knock-out mutation introduced in mouse cells makes them exquisitely sensitive to oxidative stress, indicating that this ubiquitous metabolic enzyme has a major role in the defence against oxidative stress, even in eukaryotic nucleated cells, which have several alternative routes for providing the same protection. Because of the high prevalence of G6PD deficiency in many populations, it is expected that these findings will prompt further studies to ascertain the putative role of G6PD deficiency in conditions such as carcinogenesis and ageing.
 ...
PMID:A new lease of life for an old enzyme. 876 Mar 36

Transgenic mice with both alleles of the p53 tumor suppressor gene product 'knocked out' by gene targeting are susceptible to early development of tumors, chiefly lymphomas and sarcomas. Compared with the control group, administration of dehydroepiandrosterone (DHEA) at 0.3% of the diet to male p53-deficient mice extended their lifespan by delaying death due to neoplasms (from 105 to 166 days on study, P = 0.002), primarily by suppressing lymphoblastic lymphoma (from 45 to 6% of neoplastic deaths, P = 0.010). Treatment with a synthetic DHEA analog, 16alpha-fluoro-5-androsten-17-one (compound 8354), at 0.15% of the diet also increased lifespan, to 140 days for mice that developed tumors (P = 0.037). The effects of these steroids on lifespan and tumor development did not appear to be strongly related to inhibition of food consumption and weight gain, in that a group pair-fed with control diet to the reduced food consumption of the DHEA-treated group developed and died of the same types of neoplasms at the same rate as the controls fed ad libitum. The chemopreventive effect of these steroids has been proposed to be due to suppression of DNA synthesis by inhibition of glucose 6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway. Although DHEA and its analog are strong non-competitive inhibitors of this enzyme in vitro, treatment with DHEA did not deplete cellular nucleotide pools in the liver, as would have been predicted. The chemopreventive effect of DHEA in this model may be due to steroid-induced thymic atrophy and suppression of T cell lymphoma, permitting these mice to survive long enough to develop tumors with longer latency.
Carcinogenesis 1997 May
PMID:Chemoprevention of spontaneous tumorigenesis in nullizygous p53-deficient mice by dehydroepiandrosterone and its analog 16alpha-fluoro-5-androsten-17-one. 916 85

Targeted therapies have demonstrated clinical benefit with limited impact on long-term disease specific survival in the treatment of renal cell cancer (RCC). New opportunities for the treatment of tumors that are resistant or have relapsed, are needed. Increased anaerobic glucose fermentation to lactate (aerobic glycolysis), leading to oxygen- and mitochondria-independent ATP generation is a hallmark of aggressive cancer growth. This metabolic shift results in increased lactate production via cycling through the pentose phosphate pathway (PPP), and plays an important role in tumor immune escape, progression and resistance to immune-, radiation- and chemo-therapy. This study explored the activity and impact of the oxidative and nonoxidative branches of the PPP on RCC to evaluate new therapeutic options. Activity was determined in the oxidative branch by glucose-6-phosphate-dehydrogenase (G6PD) activity, and in the nonoxidative branch by the total transketolase activity and the specific expression of the transketolase-like-1 (TKTL1) protein. Transketolase and G6PD activity were intensely elevated in tumor tissues. Transketolase, but not G6PD activity, was more elevated in metastasizing tumors and TKTL1 protein was significantly overexpressed in progressing tumors (p = 0.03). Lethal tumors, where surrogate parameters such as grading and staging had failed to predict progression, showed intensive TKTL1 protein expression. RCC was found to have activated oxidative and nonoxidative glucose metabolism through the PPP, displaying a bioenergetic shift toward nonoxidative glucose fermentation in progressing tumors. The coexistence of cancer cells with differentially regulated energy supplies provides new insights in carcinogenesis and novel anticancer targets.
 ...
PMID:Metastasis is promoted by a bioenergetic switch: new targets for progressive renal cell cancer. 1830 54

Transketolase (TK), a thiamine diphosphate (ThDP)-dependent enzyme, catalyzes several key reactions of non-oxidative branch of pentose phosphate pathway. TK is a homodimer with two active sites that locate at the interface between the contacting monomers. Both ThDP and bivalent cations are strictly needed for TK activation, just like that for all ThDP-dependent enzymes. TK exists in all organisms that have been investigated. Up to now, one TK gene (TKT) and two transketolase-like genes (TKTL1 and TKTL2) have been identified in human genome. TKTL1 is reported to play a pivotal role in carcinogenesis and may have important implications in the nutrition and future treatment of patients with cancer. Researchers have found TK variants and reduced activities of TK enzyme in patients with neurodegenerative diseases, diabetes, and cancer. Recent studies indicated TK as a novel role in the prevention and therapy of these diseases.
 ...
PMID:A review on research progress of transketolase. 1929 28

Angiogenesis is a fundamental process to normal and abnormal tissue growth and repair, which consists of recruiting endothelial cells toward an angiogenic stimulus. The cells subsequently proliferate and differentiate to form endothelial tubes and capillary-like structures. Little is known about the metabolic adaptation of endothelial cells through such a transformation. We studied the metabolic changes of endothelial cell activation by growth factors using human umbilical vein endothelial cells (HUVECs), [1,2-(13)C(2)]-glucose and mass isotopomer distribution analysis. The metabolism of [1,2-(13)C(2)]-glucose by HUVEC allows us to trace many of the main glucose metabolic pathways, including glycogen synthesis, the pentose cycle and the glycolytic pathways. So we established that these pathways were crucial to endothelial cell proliferation under vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) stimulation. A specific VEGF receptor-2 inhibitor demonstrated the importance of glycogen metabolism and pentose cycle pathway. Furthermore, we showed that glycogen was depleted in a low glucose medium, but conserved under hypoxic conditions. Finally, we demonstrated that direct inhibition of key enzymes to glycogen metabolism and pentose phosphate pathways reduced HUVEC viability and migration. In this regard, inhibitors of these pathways have been shown to be effective antitumoral agents. To sum up, our data suggest that the inhibition of metabolic pathways offers a novel and powerful therapeutic approach, which simultaneously inhibits tumor cell proliferation and tumor-induced angiogenesis.
Carcinogenesis 2009 Jun
PMID:Characterization of the metabolic changes underlying growth factor angiogenic activation: identification of new potential therapeutic targets. 1936 82


<< Previous 1 2 3 4 Next >>