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)

We earlier demonstrated that simultaneous administration of EHEN and uracil for 3 weeks resulted in enhancement of renal carcinogenesis in F344 female rats. Therefore, to establish a model of renal carcinogenesis in rats that can induce advanced renal carcinoma at a high incidence, differences in the susceptibility to N-ethyl-N-hydroxyethylnitrosamine (EHEN) and uracil of the kidneys in male and female rats of two strains were examined. Group 1 (male Wistar rats), group 2 (female Wistar rats), group 3 (male F344 rats), and group 4 (female F344 rats) received a 3-week simultaneous administration of 0.05% EHEN in the drinking water and 3% uracil in the diet after one week's acclimation. In all the above four groups, the rats were thereafter given a basal diet and water without chemical addition for a 29-week period. Group 5 (male Wistar rats), group 6 (female Wistar rats), group 7 (male F344 rats) and group 8 (female F344 rats) received no chemicals for the entire 33 weeks. At the end of the experiment, renal adenocarcinomas were found in 85, 68, 14 and 0% of the rats in groups 1, 2, 3 and 4, respectively. The incidence of adenomas and adenocarcinomas in Wistar rats were significantly greater than in F344 rats (p < 0.0001). These findings indicate strain and possibly sex differences in kidney carcinogenesis in rats treated with EHEN and uracil, and simultaneous administration of the two agents to male Wistar rats might have an advantage for models to induce advanced renal carcinoma at a high incidence.
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PMID:Strain and sex differences in kidney carcinogenesis in rats treated with N-ethyl-N-hydroxyethylnitrosamine and uracil. 853 74

The Eker rat hereditary renal carcinoma is an excellent example of Mendelian dominant predisposition to a specific cancer in an experimental animal. We recently reported that a germline insertion in the rat homologue of the human tuberous sclerosis gene (TSC2) gives rise to dominantly inherited cancer in the Eker rat model, as well as a tumor suppressor nature for the Tsc2 gene function. We also showed a strong conservation between the rat and human gene products. The molecular function of the Tsc2 gene product (called "tuberin" in the human case) is not yet understood, although it contains a short amino acid sequence homologous to ras family GTPase-activating proteins (Rap1GAP). Here, we describe transcriptional activation domains (AD1 and AD2) in the carboxyl terminus of the Tsc2 product (in exons 30 and 32 and exon 41, respectively). The Eker insertional mutation (intron 30) disrupts their transcriptional activity. Whereas a COOH-terminal truncated Tsc2 protein was localized in the nucleus, the full-length protein is found predominantly in the perinuclear region of cytoplasm. The present demonstration of transcriptional activation domains in the Tsc2 gene provides clues for studying its role in renal carcinogenesis.
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PMID:Presence of potent transcriptional activation domains in the predisposing tuberous sclerosis (Tsc2) gene product of the Eker rat model. 856 46

Ferric nitrilotriacetate (Fe-NTA), an iron chelate, induces necrosis of renal proximal convoluted tubules as a consequence of lipid peroxidation, and a high incidence of renal cell carcinoma (RCC) is also observed in rats and mice. The incidence of RCC and the extent of lipid peroxidation are greater in males than females. In the present study, the effects of castration or ovariectomy, and sex hormone treatment on Fe-NTA-induced renal carcinogenesis in rats were examined. Male and female Wistar rats were each divided into 5 groups. In group 1, rats were sham-operated and treated intraperitoneally (i.p.) with nitrilotriacetate (NTA). In group 2, sham-operated rats were treated with Fe-NTA (5-10 mg iron/kg/day, i.p.). Castrated or ovariectomized rats treated with Fe-NTA served as group 3. Group 4 or 5 was treated in the same way as group 3, but in addition received either testosterone (group 4) or estradiol (group 5). NTA, Fe-NTA or sex hormone treatments were initiated 4 weeks after the operation. NTA or Fe-NTA treatments were conducted for 12 weeks, and sex hormones were administered for 10 months. After 10 months of treatment, all rats were autopsied and both kidneys were examined histopathologically. In NTA-treated groups, there was no pathological change in the kidneys. In Fe-NTA-treated groups (groups 2-5), testosterone treatment or ovariectomy increased the incidence of RCC, and estradiol treatment or castration decreased the incidence of RCC (male: sham operation, castration and testosterone treatment > castration > castration and estradiol treatment, female: ovariectomy and testosterone treatment > ovariectomy > sham operation, ovariectomy and estradiol treatment). These results indicate that sex differences observed in the incidence of RCC induced by Fe-NTA are dependent upon sex hormones.
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PMID:Sex hormone-dependent renal cell carcinogenesis induced by ferric nitrilotriacetate in Wistar rats. 856 98

Multifocal renal cell carcinomas (RCCs), together with angiomyolipomas (AMLs) and renal cysts, were identified in early adult life in two sisters with tuberous sclerosis (TSC). They were members of a multigenerational tuberous sclerosis family showing strong evidence for a mutant TSC causing gene on chromosome 9 (TSC1). Previous reports of multifocal RCC in young patients with TSC suggest that constitutional mutations at the TSC loci may predispose to RCC. In the rat a germline mutation affecting the TSC2 gene is associated with transmission of multifocal RCC as an autosomal dominant trait. However, the cases reported here are the first to suggest a similar role for the TSC1 gene in renal cell carcinogenesis.
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PMID:Multifocal renal cell carcinoma in sibs from a chromosome 9 linked (TSC1) tuberous sclerosis family. 859 24

The incidence of renal cancer increased during the 1980's in Finland. The influence of environmental factors on carcinogenesis has been discussed in recent years. We determined the concentrations of cadmium and lead in renal tissue in 13 renal cancer patients. The mean concentration of cadmium for women was 9430 micrograms/kg (range 3437-13,962 micrograms/kg) and for male patients 14,702 micrograms/kg (range 3263-21,272 micrograms/kg). The mean concentration of lead for women was 73 micrograms/kg (range 41-105 micrograms/kg) and for male patients 96 micrograms/kg (range 34-106 micrograms/kg). Our results showed that the mean concentrations of cadmium and lead were-low in the renal cortex of renal cell cancer patients.
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PMID:Concentrations of cadmium and lead in renal cell cancer. 860 8

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces acute renal proximal tubular necrosis, a consequence of free radical-mediated oxidative tissue damage, that eventually leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we investigated the free radical-induced oxidative stress response in this carcinogenesis model, focusing on the expression of glutathione S-transferases (GSTs) which catalyze the conjugation of reactive chemicals with glutathione and play an important role in protecting cells. A single intraperitoneal Fe-NTA treatment (15 mg Fe/kg body weight) induced a rapid oxidative stress, which was monitored by the accumulation of lipid peroxidation products and the loss of sulfhydryl contents in the kidneys, resulting in a 30% reduction of GST activity 1 h after an Fe-NTA treatment. The enzyme activity returned to the control level after 16 h. The immunoblot analysis of GST isozymes demonstrated that the level of alpha-class GSTs (GST-Ya and GST-Yc) and pi-class GST (GST-Yp), major GST isozymes constitutively produced in the kidney, decreased immediately within 1 h of the Fe-NTA treatment. The onset of the recovery of GST-Yp protein levels was detected 3 h after the Fe-NTA treatment. The enhanced production of GST-Yp in gene expression was evident in the drastic elevation of mRNA levels and these increases coincided with a substantial rise in the GST activity and protein levels. The alpha-class GSTs were not inducible by treatment with Fe-NTA. The immunohistochemical analysis demonstrated that the expression of GST-Yp was strongly induced in the regenerating proximal tubular cells. A steady accumulation of GST-Yp protein was observed in the subacute toxicity experiments with multiple injections of Fe-NTA. These results suggest that the enhanced expression of GST-Yp is important in mediating cell repairs or increasing the resistance to subsequent injury.
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PMID:Oxidative stress response in iron-induced renal carcinogenesis: acute nephrotoxicity mediates the enhanced expression of glutathione S-transferase Yp isozyme. 861 33

An iron chelate, ferric nitrilotriacetate (Fe-NTA, induces renal proximal tubular damage, a consequence of iron-catalyzed free radical reactions, that finally leads to a high incidence of renal cell carcinoma (RCC) in rodents. Previous studies have identified, within 24 h after administration of Fe-NTA, lipid peroxidation products, aldehyde-modified proteins and a variety of modified DNA bases such as 8-hydroxyguanine that may be mutagenic in vivo. In the present study, pathological features of the RCCs were studied, and, in an effort to correlate them with carcinogen-specific molecular events in Fe-NTA-induced carcinogenesis, the H-, K- and N-ras oncogenes and the p53 tumor suppressor gene were investigated for the presence of mutations. Fe-NTA-induced RCCs showed similarity to human RCCs in that they are often invasive, metastatic and fatal. None (0 of 12) of the tumors had mutation in codons 12, 13 and 61 of the H-, K- and N-ras genes by direct sequencing. Only one (1 of 12) tumor with high grade histology revealed a CGC-to-CTC (Arg to Leu) transversion in codon 246 of the p53 gene by the use of single strand conformation polymorphism (SSCP) analysis and direct sequencing. High expression of mutant p53 protein was confirmed by Western blotting and immunohistochemistry. Study of three peritoneal mesotheliomas induced by Fe-NTA revealed no mutation in ras and p53 genes. These results suggest that the ras and p53 genes are not the major targets of mutation in Fe-NTA-induced carcinogenesis of kidney and mesothelium. Instead, p53 mutation may work for potentiation of malignant character in Fe-NTA-induced renal carcinogenesis.
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PMID:Low incidence of point mutations in H-, K- and N-ras oncogenes and p53 tumor suppressor gene in renal cell carcinoma and peritoneal mesothelioma of Wistar rats induced by ferric nitrilotriacetate. 863 3

Loss of heterozygosity (LOH) studies have emerged as a valuable indicator for tumor suppressor genes involved in the formation or progression of carcinomas. We here present data indicating that human chromosome 15 harbours a novel putative tumor suppressor gene which appears to play a role during later stages of carcinogenesis and which may be associated with metastasis in breast cancer. In this study, 153 primary and metastatic carcinomas from 101 patients have been analysed for LOH with 13 polymorphic microsatellite markers on chromosome 15. The tumors included carcinoma of the lung in 49 patients, breast carcinoma in 29, colorectal carcinoma in nine, renal carcinoma in five, pancreatic carcinoma in five, urinary bladder carcinoma in two and prostate carcinoma and ovarial carcinoma in one patient each. LOH15 was seen in 42/99 (42%) informative patients. In metastatic tumors, LOH15 was observed in 37/68 (54%). High incidences of allelic losses were detected in metastases from lung (56%), breast (70%) and colorectal (67%) carcinomas. In carcinomas of the breast, there was a significant difference (P<0.01) in LOH15 frequencies between non-metastatic tumors (11%) and brain metastases (70%). Such a difference was not observed on the chromosomal arm 17p which yielded high proportions of LOH in both non metastatic breast tumor (73%) and breast carcinoma metastases (90%). In 16 patients, interstitial deletions could be detected. The common region of overlap extended from D15S231 to D15S641, thus mapping this putative tumor suppressor gene to chromosome 15q14. Our data indicate that a gene on chromosome 15 contributes to the pathogenesis of metastatic carcinoma.
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PMID:Evidence for a novel tumor suppressor gene on chromosome 15 associated with progression to a metastatic stage in breast cancer. 864 14

In addition to the commonly used pathologic staging systems such as the TNM classification, the grading and demographic features have been reported to affect survival following surgical extirpation of renal cell carcinoma (RCC). These features, especially the pathologic stage, are well established as prognostic factors. However, several cellular and molecular variables, although potentially important in the ultimate outcome, are not taken into consideration by these criteria. Thus patients with different prognoses may be classified as belonging to the same stages. Attempts are now made to use cytogenetic and molecular findings to predict long-term survival of RCC patients. Chromosome 16 q and 14 q aberrations may play an important role in the future by identifying the high-risk groups of patients with papillary and nonpapillary RCC, resp. In nonpapillary RCC, mutations of the von Hippel-Lindau gene have been implicated as the initial step of carcinogenesis. However, the subsequent steps remain to be elucidated and the search for genetic markers associated with tumor progression is under way. The distinction between patients with high and low risk of progression will become increasingly important as more effective adjuvant therapies are available.
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PMID:[Traditional and future criteria for progression in renal cell carcinoma. Molecular biology and clinical aspects]. 871 34

Systemic administration of copper, an essential trace metal in the human body, has never been reported to be carcinogenic in animals. We investigated the induction of tumors by the cupric complex of nitrilotriacetic acid (Cu-NTA) in male Wistar rats. Thirty-two animals received ip injections of Cu-NTA, 3 to 5 mg of copper/kg body weight 5 days a week for 12 weeks, and were kept under close observation. For comparison, 31 animals received ip injections of ferric nitrilotriacetate (Fe-NTA), 5 to 10 mg of iron/kg body weight, and 16 animals received nitrilotriacetic acid (NTA) alone at the molar dose equivalent to Cu-NTA for the same period of time. Sixteen animals were left untreated as controls. Fourteen animals in the Cu-NTA group died of hepatic failure during the treatment period, and renal cell carcinoma (RCC) was induced in eight animals (25%). Of these, four animals died of either pulmonary metastasis or intraperitoneal hemorrhage. A total of 12 RCC were obtained, of which six tumors were > or = 5 mm. The Cu-NTA group yielded fewer RCC and required a longer latent period for their incubation than the Fe-NTA group. Furthermore, the Cu-NTA group showed one hepatocellular carcinoma and one high-grade sarcoma of hepatic origin. No renal or hepatic tumor was observed in the NTA or control groups. The nontumorous part of the kidney treated with Cu-NTA presented hemosiderosis caused by copper-induced hemolytic anemia. This is the first report that systemic administration of copper compounds can induce malignant tumors in animals. Not only copper but also iron may play a role in the Cu-NTA-induced renal carcinogenesis model.
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PMID:Induction of renal cell carcinoma in male Wistar rats treated with cupric nitrilotriacetate. 876 24


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