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

Endometrial carcinogenesis induced by concurrent oral administration of ethylenethiourea (ETU) and sodium nitrite (NaNO2) was investigated in ICR (Crj:CD-1) female mice. A mixed solution of ETU (100 mg/kg) and NaNO2 (70 mg/kg) was given to animals orally once a week for up to 6 months and all surviving animals were killed at 12 months of study. During the study, estrous cycle was monitored by vaginal smear and five or 10 selected animals were subjected to interim killing at 3 month interval to observe time-related carcinogenic responses of the uterus. Treatment with ETU and NaNO2 resulted in development of endometrial adenocarcinomas in the uterine horn and the incidence reached 42% in the surviving animals at 12 months. Prior to the development of the tumor, atypical hyperplasia of endometrial glands was frequently observed and regarded as the precancerous lesion. Immunohistochemistry for bromodeoxyuridine (BrdU) incorporation revealed higher labeling indices in both hyperplastic and neoplastic endometrial glandular cells, and the index in the adenocarcinoma was more than 20% on average at any stage of the estrous cycle. Overexpression of p53 protein, which is frequently demonstrated in virulent phenotypes of human corpus cancers, was seen in three out of eight (38%) adenocarcinomas, but not in the atypical hyperplasia or normal endometrial glands. There were no treatment-related changes in the estrous cycle on vaginal smears at any interval of the study. The analyses for plasma ovarian hormones at 12 months disclosed a marked depression of progesterone in the treated animals, while the 17 beta-estradiol (E2) level was comparable to the controls. These results suggest that endometrial carcinogenesis by ETU and NaNO2 could be initiated with atypical hyperplasia of the endometrial gland and a decrease in plasma progesterone level may play an important role in the development of endometrial carcinogenesis. In addition, inactivation of the p53 gene may play a significant role in the malignant transformation of endometrial epithelial cells in mice.
Carcinogenesis 1994 Oct
PMID:Endometrial carcinogenesis induced by concurrent oral administration of ethylenethiourea and sodium nitrite in mice. 795 72

Treatment of female CD-1 mice with the synthetic estrogen diethylstilbestrol (DES) on days 1 through 5 after birth results in a 90% incidence of endometrial adenocarcinomas by 18 months of age Three cell lines were established from DES-induced uterine carcinomas and studied for specific chromosomal changes. Each cell line exhibited numerical decreases in chromosomes 9, 11, 13, and X as common abnormalities. Structural alterations involving chromosomes 3, 6, 11, and 19 occurred nonrandomly among the three cell lines. Every cell line showed a rearrangement in the long arm of chromosome 3 (3q+), a translocation between chromosomes 3 and 19 [t(3;19)], isochromosome of chromosome 11 [i(11)], and a marker chromosome (M2) either as common abnormalities or recurrent abnormalities. t(3;19), i(11), and M2 were observed also in the primary colonies from which the cell lines arose. The changes were not observed in a cell line derived from the uterus of one untreated control mouse, suggesting that these chromosomal alterations may have occurred during DES-induced neoplastic transformation. The chromosomal alterations found in the present study may prove useful in investigating the genetic changes involved in DES carcinogenesis.
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PMID:Cytogenetic analysis of murine cell lines from diethylstilbestrol-induced uterine endometrial adenocarcinomas. 801 68

We tested whether a concentration of unleaded gasoline (UG) vapor that was selectively hepatocarcinogenic in female mice in a chronic bioassay is antiestrogenic and whether liver tumor promotion by UG is secondary to antiestrogenicity. Twelve-day-old female C57BL/6 x C3H F1 mice (hereafter called B6C3F1) received i.p. injections of N-nitrosodiethylamine (5 mg/kg) or vehicle. Beginning at 5-7 weeks of age, mice were exposed to 0, 292, or 2056 ppm of PS-6 blend UG vapor for 6 h/day, 5 days/week for 16 weeks, 1 ppm ethinyl estradiol (EE2) in the diet, or 2056 ppm UG vapor and 1 ppm EE2 in the diet. Treatment with 2026 ppm UG but not 292 ppm UG increased relative liver weight, the number of macroscopic hepatic neoplasms, and the size and volume fraction of altered hepatic foci in N-nitrosodiethylamine-initiated mice. Treatment with 2056 ppm UG reduced relative uterus, ovary, and pituitary weights but did not change serum 17 beta-estradiol levels, uterine peroxidase activity, or uterine cytosolic estrogen receptor levels. EE2 treatment reduced the number and size of altered hepatic foci in N-nitrosodiethylamine-initiated mice, caused weight loss, anestrus, vaginal keratinization, decreased uterine peroxidase activity, and decreased uterine cytosolic estrogen receptor levels. UG/EE2 co-treatment attenuated the weight loss, anestrus, and vaginal keratinization caused by EE2 treatment alone but dramatically increased the number of macroscopic hepatic neoplasms and the size and volume fraction of altered hepatic foci as compared to UG treatment alone. Thus, in this two-stage model of carcinogenesis (a) 2056 ppm UG had antiestrogenic effects, particularly with respect to pharmacological actions of EE2; (b) 2056 ppm UG but not 292 ppm UG acted as a liver tumor promoter; (c) EE2 inhibited liver tumor promotion; and (d) EE2 strongly potentiated liver tumor promotion by UG. These data demonstrate significant individual and interactive effects of UG vapor and estrogens in liver tumor promotion in female mice.
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PMID:Interactive effects of unleaded gasoline and estrogen on liver tumor promotion in female B6C3F1 mice. 811 6

Copper is a ubiquitous metal in the environment, it is a component of dental casting gold alloys and dental amalgams, and it is a main component in some intrauterine contraceptive devices (IUDs). Since copper materials implanted in the human body corrode and release ions into the surrounding tissue, the potential toxicity caused by contact of this metal with bodily fluids needs to be evaluated. We implanted male Wistar rats with osmotic mini pumps that continuously administered saline, CuCl2, or a copper chelate, cupric nitrilotriacetate (Cu-NTA), at a rate of 4 mg copper/kg body wt/day. This experimental design maintained serum copper concentrations at a level 30-70% (CuCl2) or 100-120% (Cu-NTA) higher than in untreated controls. At different times postimplantation, we measured the levels of 8-hydroxydeoxyguanosine (8-OHdG) in DNA of kidney, liver, and tissue surrounding the pump implant, since production of 8-OHdG has been associated with mutagenesis and carcinogenesis. Hepatic and renal levels of 8-OHdG in CuCl2- or Cu-NTA-treated animals were significantly higher than in control animals. In contrast, histopathologic changes in kidneys and livers of rats exposed to CuCl2 and Cu-NTA were limited to mild changes involving hepatic focal necrosis and slightly increased mitotic activity in the renal proximal tubules. These observations suggest that levels of 8-OHdG could be an early marker of copper toxicity. It is unlikely that the high levels of copper at which we observed DNA modification will be encountered after occupational or environmental exposure. A different situation could be found around medical devices that include copper, particularly IUDs, where the amount of copper administered in our experiments could be released in the uterus of women after a few months of continued IUD use.
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PMID:Increased 8-hydroxydeoxyguanosine in kidney and liver of rats continuously exposed to copper. 818 38

The anticarcinogenic effects of bioginseng and two germanium-selective drugs produced by cultivating cells of ginseng radix (Panax ginseng C. A. Mey) in a conventional medium or in media containing organogermanium compounds were studied. Squamous-cell carcinomas of the uterus cervix and vagina were induced by intravaginal applications of 7,12-dimethylbenz(a)anthracene in mice. The drugs of ginseng were used orally or intravaginally during a long period of time of the postinitiation stage of carcinogenesis. All the drugs used locally effectively inhibited the development of induced carcinomas of the uterus cervix and vagina. When orally used, the drugs of ginseng exhibited only an insignificant tendency to inhibit the carcinogenesis of uterus cervix and vagina. The anticarcinogenic effects of the compared drugs were similar.
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PMID:[The inhibition of the development of experimental tumors of the cervix uteri and vagina by using tinctures of the cultured-cell biomass of the ginseng root and its germanium-selective stocks]. 831 54

Catechol estrogens have been postulated to mediate estrogen-induced carcinogenesis. As part of our examination of this hypothesis, we studied the catechol-O-methyltransferase-catalyzed O-methylation of 2- and 4-hydroxyestradiol and the inhibition of this reaction by catecholamines. Epinephrine, norepinephrine, or dopamine (2 microM) inhibited the methylation of 2- and 4-hydroxyestradiol (20 mM) catalyzed by porcine liver catechol-O-methyltransferase by approximately 28-46% and 37-57%, respectively. One millimolar concentrations of catecholamines also inhibited the methylation of 5 microM 2- and 4-hydroxyestradiol by hamster kidney cytosol catechol-O-methyltransferase by approximately 27-31% and 19-33%, respectively. At a 15 microM 4-hydroxyestradiol concentration, the IC50 values for epinephrine and for dopamine were approximately 1200 and 3000 microM, respectively. Kinetic analyses of the methylation of 4-hydroxyestradiol in the presence of epinephrine, norepinephrine, or dopamine all revealed a competitive mechanism of inhibition. In contrast, the methylation of 160 microM 2-hydroxyestradiol was enhanced by approximately 75% in the presence of 1600 microM epinephrine or 2400 microM norepinephrine, likely due to a strong positive allosteric effect. An analysis of the substrate concentration dependence of O-methylation of 2-hydroxyestradiol revealed that at low concentrations (< 15 microM) this reaction was inhibited by epinephrine or norepinephrine, whereas it was significantly increased by approximately 50-100% at high substrate concentrations (50-200 microM). In contrast, dopamine competitively inhibited the methylation of all concentrations of 2-hydroxyestradiol (5-160 microM) tested. High levels of catecholamines were measured in hamster kidney or mouse uterus (1041 +/- 204 or 882 +/- 214 ng norepinephrine/g wet tissue, respectively) and in Fisher 344 rat pituitary (9.4 +/- 1.6 ng dopamine/mg protein), target organs of estrogen-induced carcinogenesis. Values were much lower in other organs of the same animals or in kidney, uterus, or pituitary of other rodent strains or species, which do not develop tumors under these conditions. High levels of catecholamines in target organs of hormonal cancer, the inhibition of O-methylation of 4-hydroxyestradiol, and the differential regulation of O-methylation of 2-hydroxyestradiol by catecholamines all support a role of 4-hydroxyestrogen metabolites in estrogen-induced carcinogenesis.
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PMID:Inhibition of the catechol-O-methyltransferase-catalyzed O-methylation of 2- and 4-hydroxyestradiol by catecholamine: implications for the mechanism of estrogen-induced carcinogenesis. 832 88

The effects of X-irradiation on N-methyl-N-nitrosourea (MNU)-induced multi-organ carcinogenesis were examined in both sexes of ACI/N rats. At 6 weeks of age, rats in groups 1 (25 males, 25 females) and 3 (24 males, 23 females) received a single i.p. injection of MNU (25 mg/kg body weight), while those in groups 2 (25 males, 26 females) and 4 (25 males, 25 females) were administered the carcinogen at a dose of 50 mg/kg body weight. At 10 weeks of age, groups 3 and 4 were X-irradiated at a dose of 3 Gy. Group 5 (24 males, 24 females) received X-irradiation alone. Group 6 (21 males, 21 females) served as an untreated control. As a result, neoplasms developed mainly in the digestive tract, kidney, uterus, and hematopoietic organ in groups 1-5. The incidences of adenocarcinoma in small and large intestines of male rats of group 4 (50 mg/kg MNU and X-irradiation) (small intestine: 48%, large intestine: 32%) were significantly higher than those of group 2 (50 mg/kg MNU) (small intestine: 17%, P < 0.05; large intestine: 8%, P < 0.05), and also the frequency of adenocarcinoma in the large intestine of males of group 3 (25 mg/kg MNU and X-irradiation) (22%) was significantly greater than that of group 1 (25 mg/kg MNU) (0%, P < 0.05). These results indicated that X-irradiation enhanced the development of intestinal neoplasms induced by MNU in male ACI/N rats.
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PMID:Effects of X-irradiation on N-methyl-N-nitrosourea-induced multi-organ carcinogenesis in rats. 844 23

Single copies of two closely related acetyltransferase genes were detected in Sprague-Dawley derived rat DNA by Southern blot analysis using gene-specific hybridization probes for the 3' end of the acetyltransferase coding regions. Sequence analysis of the two acetyltransferase genes showed that both had intronless, 870 bp coding regions and coded for 290 amino acid protein sequences that were approximately 85% homologous to one another. The calculated molecular weights were 33.4 and 33.9 kDa and the calculated isoelectric points 4.98 and 5.21 for AT1 and AT2, respectively. The inferred amino acid sequence of both the genes and cDNAs indicated that both rat acetyltransferases have cysteines at positions 44, 68 and 223 which have been conserved in all known vertebrate acetyltransferases. Transcripts for both AT1 and AT2 were detected in brain, colon, esophagus, heart, kidney, liver, lung, mammary gland, dorsal prostate, ventral prostate, salivary gland, seminal vesicles, small intestine, spleen, stomach, testes, urinary bladder and uterus of Sprague-Dawley rats by both Northern blot and RT-PCR analysis. A third gene with >80% sequence homology to codons 118-158 of acetyltransferase was also detected.
Carcinogenesis 1996 May
PMID:Genetic analysis of two rat acetyltransferases. 864 Sep 22

The synthetic progestin cyproterone acetate (CPA) has been shown to be a hepatocarcinogen in the rat, but little is known of its effects in mice. A 52 week CPA study in the mouse strain C57Bl/10J has been reported not to produce liver tumours, although CPA induced significant liver enlargement and induction of the mixed function oxidase CYP3A. The present study is a further investigation of the effects of CPA in mice of the C57Bl/10J strain dosed for 104 weeks. A group of 40 mice/sex were fed 800 p.p.m. CPA in the diet for 104 weeks with a control group of eight/sex. Mortality was high in females after 40 weeks due to hormonal effects in the uterus; no female and only four CPA-dosed males survived to 104 weeks. Liver cell hypertrophy with increased fat and glycogen and single cell or small multifocal areas of hepatocellular necrosis were universal. Proliferating cell nuclear antigen demonstrated an increase in proliferating cells within tumours and within the non-tumour bearing liver of CPA-dosed mice compared with normal livers of control mice. Hepatocellular tumours developed in 44% of males and 22% of females dosed with CPA, compared with none in the controls (the strain has a low, <10%, incidence of spontaneous liver tumours compared with other mouse strains). In addition, over 85% of both sexes dosed with CPA developed adenomatous polyps of the pyloric antrum and pancreatic islet cell hyperplasia, shown by immunostaining to be chiefly of insulin-secreting cells. Adrenocortical atrophy was also observed with other widespread effects in the endocrine system. The results suggest that the liver tumours, as in the rat, are likely to be related to effects on liver growth and mitogenesis. It is suggested that the tumours of the stomach and the pancreatic islet cell hyperplasia are manifestations of the effects of CPA in the endocrine system.
Carcinogenesis 1996 Jul
PMID:Carcinogenicity of cyproterone acetate in the mouse. 870 51

Rats administered tamoxifen for 3 months and then returned to a basal diet developed an increase in uterine weight for up to 9 months after tamoxifen exposure. Stereological analysis of the tamoxifen exposed rat uteri showed that there was a significant increase in the amount of uterine myometrium, for a further 9 months, subsequent to the discontinuation of tamoxifen. A low incidence of myometrial proliferations (deciduomas) and uterine tumours was found at the conclusion of the study (20 months). In contrast, continuous administration of tamoxifen to mice for 24 months produced hyperplasia of the uterine endometrial epithelium and atrophy of the myometrium for the first 3 months, followed by atrophy of both the endometrium and myometrium for the remaining 21 months of the study. No uterine tumours were found in mice treated with tamoxifen for 2 years. The use of stereological analysis on interim sacrifice rodent uteri indicated that sustained uterine tissue compartment effects can occur, with either the continuous administration of tamoxifen, or after its discontinuation. Tamoxifen can have an agonist and antagonist like effect on oestrogen activity in different tissue compartments of the mouse uterus, over the same time period. The particular relevance of the finding of uterine proliferation and atrophy in the rodent studies with tamoxifen is discussed with regard to women taking this drug.
Carcinogenesis 1996 Aug
PMID:Tamoxifen associated uterine pathology in rodents: relevance to women. 876 12


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