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)

The chemopreventive efficacy of dehydroepiandrosterone (DHEA) and indomethacin (IM) alone or in combination was investigated in a rat multiorgan carcinogenesis model. These two chemicals were selected as chemopreventive agents with different functions. Animals were sequentially given five carcinogens with different organ target sites in the first 4-week initiation period. One week after its completion, the rats received 0.3% DHEA in the diet, 20 ppm IM in the drinking water, or 0.3% DHEA + 20 ppm IM until experimental week 28. DHEA enhanced hepatocarcinogenesis, but concurrent treatment with IM suppressed tumor development as compared to the DHEA group. DHEA inhibited tumor development in the thyroid, with a similar tendency observed for the small intestine. In addition, treatment with this hormone decreased occurrences of preneoplasias in the urinary bladder and seminal vesicles. Treatment with IM clearly suppressed development of preneoplasias or neoplasias in the lung and small and large intestines. In the urinary bladder, treatment with IM tended to decrease preneoplastic lesion development. Analysis of multiplicity of total tumors of any category revealed comparable values for DHEA and control groups, while the IM group showed a significant reduction. IM in combination with DHEA caused suppression as compared to DHEA alone. In a separate 8-week experiment, DHEA or IM were administered for 4 weeks after prior carcinogen application, and biochemical responses in the target organs were investigated. DHEA increased glucose-6-phosphate dehydrogenase levels in the liver but caused a decrease in the small intestine. In addition, DHEA decreased serum T4 but not T3. IM decreased prostaglandin E2 content in the small intestine. In conclusion, although DHEA or IM exert significant chemopreventive effects in multiorgans with the exception of the DHEA-treated liver case, treatment in combination did not result in amplification of their beneficial influence. Our results suggest the possible application of IM for chemoprevention in high-risk individuals, but the question of effects of DHEA in the liver must be answered before this hormone can be considered for use in humans.
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PMID:Chemoprevention by dehydroepiandrosterone and indomethacin in a rat multiorgan carcinogenesis model. 758 22

Male Sprague-Dawley rats received the hepatocarcinogen N-nitrosomorpholine (NNM) in the drinking water at low dose levels ranging from 6 mg/l to 60 mg/l for 6 and 12 weeks, respectively. Foci of altered hepatocytes (FAH) were demonstrated histochemically using changes in the activities of glucose-6-phosphate dehydrogenase and glycogen phosphorylase, and in the glycogen content as markers. Proliferating cells were detected by the immunohistochemical reaction for proliferating cell nuclear antigen (PCNA). The number and size of foci of altered hepatocytes increased in a time and dose-related manner. The dose-effect curves were non-linear with a slight positive slope at the low doses and a markedly increased slope at higher doses. The number of PCNA positive hepatocytes showed a dose-dependent increase. In addition to the granular distribution of PCNA in the nuclei, hepatocyte nuclei with homogeneously distributed PCNA occurred in animals exposed to 60 mg/l NNM. It is proposed that these cells are related to the occurrence of hepatocytes with higher ploidy induced by NNM and may be regarded as cells in the G2 phase of the cell cycle. The non-linear shape of the dose-response-curve of the FAH suggests that some mechanisms contribute to carcinogenesis over the whole dose range, whereas other mechanisms enhance carcinogenesis only at higher doses. The relevance of the non-linear dose-effect curve for the risk assessment of carcinogens is discussed.
Carcinogenesis 1995 Jul
PMID:Effects of low doses of N-nitrosomorpholine on the development of early stages of hepatocarcinogenesis. 761 84

In this work comprehensive data of antioxidant enzymes are reviewed and their role in carcinogenesis is discussed. When compared to their normal tissue counterparts, more of the tumor tissues were low in Cu, Zn-SOD and catalase activity and in some cases in Mn-SOD. It is probably characteristic for tumor tissues. Glutathione peroxidase, and glutathione reductase and glucose-6-phosphate dehydrogenase activities are highly variable. The reason why cancerous cells exhibit abnormal levels and activities of antioxidant enzymes is unknown. It was hypothesized, that during formation of the tumor, by certain obscure mechanism, cells with imbalance of antioxidant enzymes profile were selected over normal cells. It is not known whether the changes in antioxidant defence observed in cancerous tissues play a role in carcinogenesis, or are formed as a results of the disease.
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PMID:[Activity of antioxidant enzymes in cancer diseases]. 763 95

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.
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PMID:Enzymic pattern of preneoplastic and neoplastic lesions induced in the kidney of CBA mice by 1,2-dimethylhydrazine. 781 30

The activities of several enzymes involved in the antioxidant system of the cell were studied in parallel to cytogenetic alterations at various times after SV40 infection and transformation of human fibroblasts. At early passages after SV40 infection, glutathione reductase (GSR), glutathione peroxidase (GPX), glutathione transferase (GST) and glucose-6-phosphate dehydrogenase (G6PD) activities were decreased. This, associated with the low superoxide dismutase (SOD) and catalase activities previously noticed in these cells, suggested that they are in a highly pro-oxidant status. Although chromosomes carrying the genes encoding these enzymes are frequently underrepresented, there is no direct relationship between the number of chromosomes and enzyme activities. Except for GPX, all the activities tend to increase in established cell lines reaching levels comparable to those of non-transformed fibroblasts. The late increase of G6PD activity may correlate with the frequent duplication of the early replicating X. GSR seems to correlate with G6PD activity and GPX to SOD total activity. The most striking alterations affect mitochondrial and peroxisomal enzymes activities: SOD, GPX and catalase.
Carcinogenesis 1993 Jan
PMID:Alterations of the glutathione cycle enzymes during and after SV40-transformation of human fibroblasts. 838 Oct 54

The biochemical basis for the cancer chemopreventive and anti-cancer activities of glucarate, retinoids (13-cis-retinoic acid, hydroxyphenyl retinamide) and their synergistic combination, has been evaluated. Neither alone nor in combination did these agents affect the level in the rat, of enzymes which are (a) known to correlate with reduced risk of carcinogenesis (detoxification enzyme, catalase, glutathione reductase) nor (b) enzymes which correlate with increased risk of carcinogenesis (beta-glucuronidase, xanthine oxidase, glucose-6-phosphate dehydrogenase). Retinoids, but neither glucarate nor its lactone inhibited free radical-induced lipid peroxidation. Both agents alone and synergistically in combination, raise cellular cAMP levels, repress protein kinase C and more generally inhibited DNA synthesis.
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PMID:Basis for the anti-tumor and chemopreventive activities of glucarate and the glucarate:retinoid combination. 851 53

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.
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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.
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PMID:A new lease of life for an old enzyme. 876 Mar 36

Two different types of focal preneoplastic lesions, tentatively named Type I and II lesions, were recognized in the liver of rats chronically treated with clofibrate for 104 weeks. Type I lesions were characterized by mostly negative glucose-6-phosphate dehydrogenase (G6PD) activity (6 out of 10, 60%) and positive expression of succinate dehydrogenase (10 out of 10, 100%), in addition to the previously documented complete lack of expression of glutathione S-transferase, placental form (GST-P) and gamma-glutamyl transpeptidase (GGT). Furthermore, most importantly, Type I lesions exhibited a clear decrease in immunohistochemically demonstrated connexin32 (Cx32) spot counts on their hepatocyte membranes, similarly to nitrosamine-induced lesions. In contrast, Type II lesions, mostly small in size and positively expressing GST-P and/or GGT and G6PD, similarly to their previously reported nitrosamine-induced counterparts, did not exhibit a significant decrease in Cx32 count. In addition, spontaneously occurring lesions, again sharing the same enzyme phenotype, did not show a decrease in Cx32. The results indicate that: (i) a clear distinction between the two lesions, with Type I being involved in clofibrate-induced tumors and Type II being more likely to be spontaneous in nature; (ii) a decrease in Cx32 is closely linked to lesion development and possibly stage of progression, irrespective of the enzyme phenotype and the applied carcinogen; (iii) the unaltered condition of Cx32 may suggest a slow growing or non-progressive nature.
Carcinogenesis 1996 Nov
PMID:Decreased connexin32 and a characteristic enzyme phenotype in clofibrate-induced preneoplastic lesions not shared with spontaneously occurring lesions in the rat liver. 896 61

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


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