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

A rodent model of hereditary cancer in which a single gene mutation predisposes rats to bilateral multicentric renal cell carcinoma (RCC) is described. This rat hereditary cancer syndrome shares certain similarities with von Hippel-Lindau disease (VHLD). In addition to the early development of renal epithelial tumors with morphologic similarity to human RCC, rats which bear the RCC gene are predisposed to the development of secondary primary cancers later in life. Splenic vascular proliferative lesions, including hemangiosarcoma, were seen in 23% of 14-month-old rats of both sexes that had renal tumors. At fourteen months of age, 62% of female rats with renal cell tumors had sarcomas of the lower reproductive tract of probable smooth muscle origin. Non-carrier siblings of affected animals did not have renal, reproductive, or splenic neoplasia. The finding of a specific constellation of familial neoplasms, including multicentric bilateral renal cell carcinoma, in this autosomal dominant disorder of rats suggests that this syndrome is analogous to human VHLD. In addition to its usefulness for studies of the biochemical and molecular mechanisms of renal carcinogenesis, this animal model will provide a unique tool to investigate how cancer susceptibility genes interact with environmental risk factors such as chemical carcinogens.
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PMID:Hereditary renal cell carcinoma in the Eker rat: a rodent familial cancer syndrome. 143 48

Male and female B6C3F1 mice from 12 National Toxicology Program (NTP) 2-yr carcinogenesis studies were found to be infected with Helicobacter hepaticus. Many of the male mice from 9 of these studies had an associated hepatitis (affected studies). Helicobacter hepaticus has been reported to be associated with an increased incidence of hepatitis and hepatocellular neoplasms in the A/JCr male mouse. We attempted to determine if the data from the Helicobacter-affected NTP B6C3F1 mouse studies were compromised and unsuitable for cancer hazard identification. The incidences of neoplasms of the liver (both hepatocellular and hemangiosarcoma) but not of other organs in control male B6C3F1 mice were increased in affected studies as compared with control males from unaffected studies. The increased incidence of hepatocellular neoplasms was observed in those males exhibiting H. hepaticus-associated hepatitis. Other observations further differentiated control male mice from affected and unaffected studies. H-ras codon 61 CAA to AAA mutations were less common in liver neoplasms from males from affected studies as compared with historical and study controls. In addition, increases in cell proliferation rates and apoptosis were observed in the livers of male mice with H. hepaticus-associated hepatitis. These data support the hypothesis that the increased incidence of liver neoplasms is associated with H. hepaticus and that hepatitis may be important in the pathogenesis. Therefore, interpretation of carcinogenic effects in the liver of B6C3F1 mice may be confounded if there is H. hepaticus-associated hepatitis.
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PMID:Impact of Helicobacter hepaticus infection in B6C3F1 mice from twelve National Toxicology Program two-year carcinogenesis studies. 978 46

We recently reported p53 mutations to be frequent in mouse invasive urinary bladder carcinomas, with and without metastasis. However, the role of p53 dysfunctions during carcinogenesis remains unclear. In the present study, heterozygous and nullizygous p53-deficient mice and their littermates were treated with the urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), at a concentration of 0.01% in the drinking water throughout the experiment. This markedly accelerated urinary bladder carcinogenesis but not development of other tumors in the nullizygous p53-deficient mice. Thus the appearance of neoplastic urothelial lesions in nullizygotes (at day 60 of the experiment) was earlier than in wild-type mice and heterozygotes (at day 125). Moreover, malignant vascular tumors (hemangiosarcomas (HS)) were found in all four nullizygotes killed later than day 108. Mutational inactivation of the wild-type allele was not apparent in either the single transitional cell carcinoma observed in a wild-type mouse and a hemangiosarcoma in a heterozygote. Overall, it can be concluded that the number of normal p53 alleles is a significant determining factor in the susceptibility of urothelial cells to carcinogens. The role of the p53 defect in mouse urinary bladder carcinogenesis may thus be to diminish the threshold for occurrence of additional genetic alterations.
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PMID:Enhancement of urinary bladder carcinogenesis in nullizygous p53-deficient mice by N-butyl-N-(4-hydroxybutyl)nitrosamine. 1009 21

We exposed embryos (83 hours postfertilizaton) and fry (3 weeks posthatch) to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) by immersion in aqueous solutions of 0-10 ppm for 1 hour (embryo) or 0-2 ppm for 24 hours (fry). Zebrafish embryos were microinjected with MNNG at levels of 0 or 96 ng/egg. Diets containing 0-2,000 ppm MNNG were fed to juvenile zebrafish for 3 months beginning at 2 months posthatch. Fish were sampled for histopathologic study at 6-12 months after initiation of carcinogen exposure. Embryos and fry were both quite responsive to MNNG; however, juvenile zebrafish were remarkably refractory to MNNG-induced neoplasia. Principal target organs in zebrafish treated as embryos with MNNG were liver and testis, with hepatocellular adenoma the most prevalent hepatic neoplasm. A variety of mesenchymal neoplasms occurred in zebrafish following embryo exposure to MNNG, including chondroma, hemangioma, hemangiosarcoma, leiomyosarcoma, and rhabdomyosarcoma. Testis and blood vessels were primary target organs for MNNG following fry exposure, with seminoma, hemangioma, hemangiosarcoma, and various other epithelial and mesenchymal neoplasms occurring. The zebrafish is a responsive, cost-effective lower vertebrate model system in which to study mechanisms of carcinogenesis.
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PMID:Neoplasia in zebrafish (Danio rerio) treated with N-methyl-N'-nitro-N-nitrosoguanidine by three exposure routes at different developmental stages. 1102 8

1,3-Butadiene is produced in large volumes for use in the manufacture of synthetic rubber and of thermoplastic resins. In previous inhalation studies conducted by the NTP (NTP, 1984) there was clear evidence of multiple organ carcinogenicity in male and female mice exposed to 625 or 1,250 ppm 1,3-butadiene for 60 or 61 weeks. To better characterize exposure-response relationships for neoplasms and nonneoplastic lesions, toxicology and carcinogenesis studies were conducted by exposing groups of male and female B6C3F1 mice to air containing 1,3-butadiene (greater than 99% pure) for up to 2 years. An additional study in male B6C3F1 mice, in which exposure to 1,3-butadiene was stopped after limited exposure periods (13, 26, 40, or 52 weeks), was performed to assess the effects of varying concentration and duration of exposure on the incidences of 1,3-butadiene-induced neoplasms. In vitro genetic toxicology studies were conducted in Salmonella typhimurium and mouse lymphoma cells. In vivo genetic effects were assayed in germ cells of male Drosophila melanogaster and in bone marrow and peripheral blood cells of B6C3F1 mice. 2-Year Studies: Groups of 70 male and 70 female mice were exposed to air containing 0, 6.25, 20, 62.5, or 200 ppm 1,3-butadiene for 6 hours per day, 5 days per week for up to 2 years; groups of 90 male and 90 female mice were exposed to 625 ppm 1,3-butadiene on the same schedule. Up to 10 animals from each group were examined after 9 and 15 months of exposure. Survival and Body Weight in the 2-Year Studies: Two-year survival was decreased for males and females exposed to concentrations of 20 ppm or above, primarily due to the development of chemical-related malignant neoplasms. No female mice exposed to 200 or 625 ppm or males exposed to 625 ppm survived to the end of the studies (males: 35/50, 39/50, 24/50, 22/50, 4/50, 0/70; females: 37/50, 33/50, 24/50, 11/50, 0/50, 0/70). Mean body weights of exposed male and female mice were similar to those of the controls. Hematologic Effects in the 2-Year Studies: Hematologic parameters were evaluated after 9 and 15 months of exposure. At 9 months, decreases in erythrocyte counts, hemoglobin concentration, and packed red cell volume were observed in male mice exposed to 62.5 ppm or above and in female mice exposed to 200 or 625 ppm. Mean erythrocyte volume was increased in male mice exposed to 625 ppm and in females exposed to 200 or 625 ppm. At 15 months, decreases in erythrocyte counts, hemoglobin concentration, and packed red cell volume and increases in mean erythrocyte volume were observed in male and female mice exposed to 625 ppm. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: Exposure of mice to 1,3-butadiene induced benign and malignant neoplasms at multiple sites. Statistically significant increases in the incidences of neoplasms at one or more sites were seen at concentrations of 20 ppm and higher in males and 6.25 ppm and higher in females. There was no exposure level in this study at which a significant carcinogenic response was not observed. Statistically significant increases occurred in the incidences of malignant lymphoma; histiocytic sarcoma; cardiac hemangiosarcoma; harderian gland adenoma; hepatocellular adenoma and carcinoma; alveolar/bronchiolar adenoma and carcinoma; mammary gland carcinoma, adenoacanthoma, and malignant mixed tumor (females only); benign and malignant ovarian granulosa cell tumor; and forestomach squamous cell papilloma and carcinoma. Low incidences of uncommon neoplasms also occurred in exposed male and female mice, including intestinal carcinomas in males, renal tubule adenomas in males and females, skin sarcomas (all types combined) in females, and Zymbal's gland adenomas and carcinomas in females. Lymphocytic lymphomas appeared as early as week 23 and were the principal cause of death of male and female mice exposed to 625 ppm 1,3-butadiene. The early and extensive development of lethal lymphocytic lymphomas in mice exposed to 625 ppm resulted in a reduced number of mice at risk for neoplasms developing laterg later at other sites. Exposure-response relationships for 1,3-butadiene-induced neoplasms were more clearly characterized at concentrations below 625 ppm and after adjustment for intercurrent mortality. Increased incidences of nonneoplastic lesions in exposed mice included bone marrow atrophy; testicular atrophy; ovarian atrophy, angiectasis, germinal epithelial hyperplasia, and granulosa cell hyperplasia; uterine atrophy; cardiac endothelial hyperplasia and mineralization; alveolar epithelial hyperplasia; forestomach epithelial hyperplasia; and harderian gland hyperplasia. Stop-Exposure Study: The stop-exposure study consisted of groups of 50 male mice exposed to 1,3-butadiene at concentrations of 200 ppm for 40 weeks, 625 ppm for 13 weeks, 312 ppm for 52 weeks, or 625 ppm for 26 weeks. After the exposures were completed, these groups were placed in control chambers for the remainder of the 2-year study. The total exposure of 1,3-butadiene (concentration times duration of exposure) of the 13- and 40-week stop-exposure groups was approximately 8,000 ppm-weeks, while that of the 26- and 52-week stop-exposure groups was approximately 16,000 ppm-weeks. The survival of all stop-exposure groups was markedly lower than that of the controls. The incidences of lymphocytic lymphoma, histiocytic sarcoma, cardiac hemangiosarcoma, alveolar/bronchiolar adenoma and carcinoma, forestomach squamous cell papilloma and carcinoma, hepatocellular adenoma, harderian gland adenoma and adenocarcinoma, and preputial gland carcinoma were significantly increased. Neoplasms were induced at most of these sites after only 13 weeks of exposure to 1,3-butadiene. Additionally, low numbers of malignant gliomas and neuroblastomas of the brain and Zymbal's gland carcinomas occurred in one or more stop-exposure groups. At similar total exposures, the incidence of lymphocytic lymphoma was greater with exposure to a higher concentration of 1,3-butadiene for a short time compared with exposure to a lower concentration for an extended period (34% at 625 ppm for 13 weeks versus 12% at 200 ppm for 40 weeks; 60% at 625 ppm for 26 weeks versus 8% at 312 ppm for 52 weeks). Genetic Toxicology: 1,3-Butadiene has been tested both in vitro and in vivo for mutagenic activity. In vitro, positive results were obtained in the Salmonella typhimurium gene mutation assay with strain TA1535; mutagenic activity was not observed in other S. typhimurium strains (TA100, TA97, and TA98). 1,3-Butadiene was negative in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells with and without S9. In vivo, 1,3-butadiene did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster; however, it did induce significant increases in chromosomal aberrations and sister chromatid exchanges in bone marrow cells of mice exposed for 2 weeks by inhalation. In addition, significant increases in micronucleated erythrocytes were observed in peripheral blood samples obtained from male and female mice exposed to 1,3-butadiene for 2 or 13 weeks or 15 months by inhalation. Conclusions: The previous inhalation studies of 1,3-butadiene (TR-288) in male and female B6C3F1 mice provided clear evidence of carcinogenicity at exposure concentrations of 625 or 1,250 ppm. The present inhalation studies - 2-year exposures of 6.25, 20, 62.5, 200, or 625 ppm or shorter duration exposures of 200, 312, or 625 ppm - provide a better characterization of the concentration-dependent responses for 1,3-butadiene-induced neoplasms and nonneoplastic lesions. The present studies confirmed the clear evidence of carcinogenicity of 1,3-butadiene in male B6C3F1 mice based on increased incidences of neoplasms in the hematopoietic system, heart, lung, forestomach, liver, harderian gland, preputial gland, brain, and kidney. There was clear evidence of carcinogenicity of 1,3-butadiene in female B6C3F1 mice based on increased incidences of neoplasms in the hematopoietic system, heart, lung, forestomach, liver, harderian gland, ovary, and mammary gland. Low incidences of intestinal carcinomas in male mice, Zymbal's gland carcinomas in male and female mice, and renal tubule adenomas and skin sarcomas in female mice may also have been related to administration of 1,3-butadiene. Synonyms: alpha,gamma-Butadiene; bivinyl; divinyl; erythrene; vinylethylene; biethylene; pyrrolylene
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PMID:NTP Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS No. 106-99-0) in B6C3F1 Mice (Inhalation Studies). 1261 97

These investigations of riddelliine analyzed potential carcinogenesis and the utility of the female-rat/male-mouse design in bioassays and dose-response. Groups of 50 Fischer rats and B6C3F1 mice were gavage-administered riddelliine 5 days per week for 105 weeks. The dose levels for male rats were 0 or 1.0 mg/kg body weight; female rats 0, 0.01, 0.033, 0.1, 0.33, or 1.0 mg/kg; male mice 0, 0.1, 0.3, or 1.0, 3.0 mg/kg; and female mice 0 or 3.0 mg/kg. The dose groups were purposely designed to evaluate the dose-response relationship only in female rats and male mice. In rats, liver hemangiosarcoma, hepatocellular adenoma, and mononuclear cell leukemia were significantly increased in the 1.0 mg/kg male and female dose groups. Non-neoplastic lesions occurred in the liver and kidney of male and female rats. In mice, hemangiosarcomas increased significantly in the liver of males in the 3.0 mg/kg dose group. Alveolar/bronchiolar neoplasms in the 3.0 mg/kg dose group of female mice were significantly increased. Hepatocellular neoplasms were significantly decreased in the 1.0 mg/kg dose group of male and 3.0 mg/kg dose groups of male and female mice. Non-neoplastic lesions occurred in the liver and kidney of male and female, and lung and arteries of female mice. These studies demonstrate toxicity and carcinogenicity of riddelliine in rats and mice, and a dose-response relationship in female rats and male mice under the experimental conditions employed.
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PMID:Toxicity and carcinogenicity of riddelliine in rats and mice. 1292 48

The von Hippel-Lindau (VHL) tumor suppressor gene plays a prominent role in the development of renal cell carcinoma (RCC) in humans. VHL functions as a ubiquitin E3 ligase, controlling the stability of hypoxia inducible factor (HIF) and tumor angiogenesis. Alterations in this tumor suppressor gene are rarely observed in spontaneous or chemically induced RCC that arise in conventional strains of rodents and Vhl knockout mice (Vhl+/-) do not develop spontaneous RCC. We tested whether Vhl knockout mice exhibited increased susceptibility to renal carcinogenesis using the well-characterized renal carcinogen streptozotocin. No differences were observed between wild-type and Vhl+/- animals in the frequency or type of renal lesions induced by 50-200 mg/kg streptozotocin. Carcinogen-induced RCC that developed in Vhl heterozygotes and wild-type mice did not contain mutations in the wild-type Vhl, as determined by direct sequencing of the primary tumors. While Vhl+/- mice exhibited no increase in renal lesions in response to streptozotocin, heterozygous animals did develop vascular proliferative lesions of the liver, uterus, ovary, spleen and heart. These lesions, ranging from angiectasis to hemangiosarcoma, were most prominent in the livers of Vhl+/- mice, where they were found in high incidence and high multiplicity. Wild-type mice developed a low-frequency of liver angiectasis (7-15%) only at the highest doses of carcinogen used (150 and 200 mg/kg, respectively) while Vhl+/- mice exhibited angiectasis, hemangioma and hemangiosarcomas with a frequency ranging from 19 to 46% at 50-200 mg/kg streptozotocin. Untreated Vhl+/- mice had a spontaneous incidence of hepatic vascular lesions of 21%. Furthermore, vascular lesions of the uterus, ovary, spleen and heart were observed only in Vhl+/- mice, with an incidence of (5-28%). Taken together, the data indicate that heterozygosity at the Vhl locus predisposes mice to a vascular phenotype ranging from angiectasis to hemangiosarcoma, consistent with the ability of this tumor suppressor gene to control the stability of HIF and regulate key proteins that participate in angiogenesis.
Carcinogenesis 2004 Mar
PMID:Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in Vhl knockout mice. 1460 87

U.S. EPA's integrated risk information system (IRIS) assessment of 2-butoxyethanol (EGBE) indicates that the human carcinogenic potential of EGBE cannot be determined at this time, but that "suggestive evidence" for cancer exists from laboratory animal studies (hemangiosarcoma of the liver in male mice and forestomach squamous cell papilloma or carcinoma in female mice [National Toxicology Program (NTP), 2000a. Toxicology and carcinogenesis studies of 2-butoxyethanol (CAS no. 111-76-2) in F344/N rats and B6C3F1 mice (inhalation studies). National Toxicology Program Technical Report Series No. 484. U.S. Department of Health and Human Services, National Institutes of Health, Washington, DC]). Since the last EGBE IRIS assessment, a number of studies have provided evidence that the carcinogenic effects observed in mice are nonlinear in their mode of action and may be dependent on threshold events such as EGBE-induced hemolytic effects. EPA is in the process of considering several questions relating to this issue. First, can a plausible mode of action be determined for the two types of tumors observed in mice? Second, are the mechanisms involved applicable to humans? If so, should the mode of action be considered to result in a linear or nonlinear dose-response? These questions will be addressed within the context of the agency's new cancer guidelines and with regard to how the answers might affect a revised IRIS assessment for EGBE.
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PMID:U.S. EPA's IRIS assessment of 2-butoxyethanol: the relationship of noncancer to cancer effects. 1570 94

The prophylactic use of zidovudine (3'-azido-3'-deoxythymidine, AZT) during pregnancy greatly reduces transmission of HIV-1 from infected mothers to their infants; however, the affinity of host cell DNA polymerases for AZT also allows for its incorporation into host cell DNA, predisposing to cancer development. To expand upon previous transplacental carcinogenesis assays performed in CD-1 mice, the transplacental carcinogenicity of AZT was evaluated in a second mouse strain and a second rodent species. Date-mated female mice and rats were gavaged daily with 0, 80, 240, or 480 mg AZT/kg bw during the last 7 days of gestation. At 2 years postpartum, male and female B6C3F1 mouse and F344 rat offspring (n = 44-46 of each sex and species/treatment group) were necropsied for gross and microscopic tissue examinations. Under the conditions of these two-year studies, there was clear evidence of carcinogenic activity based upon significant dose-related trends and increases in the incidences of hemangiosarcoma in male mice and mononuclear cell leukemia in female rats. There was some evidence of carcinogenic activity in the livers of male mice based upon a positive trend and an increased incidence of hepatic carcinoma in the high-dose AZT group. The incidence of gliomas in female rats exceeded the historical background rates for gliomas in F344 rats. P53 overexpression was detected in some AZT-treated mouse neoplasms. These and other cancer-related findings confirm and extend those of previous transplacental carcinogenicity studies of AZT in mice, support the need for long-term follow-up of nucleoside reverse transcriptase inhibitor (NRTI)-exposed children, and indicate the necessity for effective protective strategies against NRTI-induced side effects.
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PMID:Transplacental carcinogenicity of 3'-azido-3'-deoxythymidine in B6C3F1 mice and F344 rats. 1735 26

Dehydropyrrolizidine alkaloids (DHPA) are a large, structurally diverse group of plant-derived protoxins that are potentially carcinogenic. With worldwide significance, these alkaloids can contaminate or be naturally present in the human food supply. To develop a small animal model that may be used to compare the carcinogenic potential of the various DHPAs, male heterozygous p53 knockout mice were administered a short-term treatment of riddelliine 5, 15 or 45 mg kg(-1) bodyweight day(-1) by oral gavage for 14 days, or dosed a long-term treatment of riddelliine 1 mg kg(-1) bodyweight day(-1) in pelleted feed for 12 months. Exposure to riddelliine increased the odds of tumor development in a dose-responsive manner (odds ratio 2.05 and Wald 95% confidence limits between 1.2 and 3.4). The most common neoplastic process was hepatic hemangiosarcoma, which is consistent with published lifetime rodent riddelliine carcinogenesis studies. Angiectasis (peliosis hepatis) and other previously unreported lesions were also identified. The results of this research demonstrate the utility of the heterozygous p53 knockout mouse model for further investigation of comparative carcinogenesis of structurally and toxicologically different DHPAs and their N-oxides.
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PMID:Heterozygous p53 knockout mouse model for dehydropyrrolizidine alkaloid-induced carcinogenesis. 2569 Jun 69


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