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)

A mouse mRNA, provisionally designated 5B10, has been cloned based on its inducibility by serum in quiescent murine fibroblasts. Here we report the full-length complementary DNA sequence and a partial characterization. There are about five copies of the gene in the mouse genome. Sequence analysis of the 5B10 coding region reveals 94 and 97% amino acid identity to human and rat calcyclin, respectively. Although the coding region has been highly conserved during evolution of the rodent and human genomes, the untranslated flanking sequences differ significantly. A protein of Mr about 8000 was produced by in vitro translation of the mRNA transcribed in vitro from 5B10 complementary DNA in a riboprobe vector. An antiserum raised against a portion of the predicted human calcyclin protein cross-reacted with this mouse protein. 5B10 mRNA was found in greatest amount in organs containing proliferating cells, e.g., epidermis, skin, stomach, uterus of pregnant mouse, placenta, and decidua. Brain, liver, mature thymus, and skeletal muscle had little or no detectable 5B10 mRNA. 5B10 mRNA levels were higher in cells treated with 7,12-dimethylbenzanthracene and 12-O-tetradecanoylphorbol-13-acetate than in their normal counterparts, suggesting a role in tumorigenesis. In addition, high 5B10 mRNA levels were associated with metastatic ability in a series of ras-transformed cells, in proportion to levels of ras p21 expressed by the cells, implicating 5B10 even more deeply in carcinogenesis.
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PMID:Identification of a serum-inducible messenger RNA (5B10) as the mouse homologue of calcyclin: tissue distribution and expression in metastatic, ras-transformed NIH 3T3 cells. 217 33

Pathology of gynecological malignancies including cancers of the uterus and ovary were described with a particular focus on early stage cancers and borderline lesions. Histological criteria appeared in this paper are mentioned in accordance with The General Rules for Clinical and Pathological Management of Uterine Cervical Cancer and Uterine Body Cancer and WHO Classification of Ovarian Tumours. Carcinogenesis of the uterine and ovarian cancers were also discussed.
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PMID:[Pathological aspects of gynecological malignancies--early stage cancers and borderline lesions]. 221 43

O-Methylation of catecholestrogens catalyzed by catechol-O-methyltransferase provides a major route for the rapid metabolic clearance of these steroids. However, the metabolic clearance rate of 4-hydroxyestradiol (4-OH-E2) is considerably lower than that of 2-hydroxyestradiol, although 2- and 4-hydroxycatecholestrogens (2- and 4-OH-CE) have similar apparent affinities for the enzyme. To determine the reason for this apparent paradox we have examined whether the efficiency of O-methylation of 4-OH-E2 could be affected by other catecholestrogens or their O-methyl ethers. The ratio of 4-methoxyestradiol:4-hydroxyestradiol 3-methyl ether was 2.6 at pH 8.5, the pH optimum for the reaction. The O-methylation of 4-OH-E2 (apparent Km 10 microM) was inhibited by 2-hydroxyestradiol (2-OH-E2) but not by 2- or 4-methyoxyestrogens. The values for Km, Vmax as well as the slope for the methylation of 4-OH-E2 were altered by 2-OH-E2 indicating a mixed inhibition. The inhibition constant for the intercept 1/V'max versus 2-OH-E2 concentrations and the inhibition constant for the slope versus 2-OH-E2 concentrations were 35 and 5.7 microM, respectively. The inhibition of O-methylation of 4-OH-E2 by 2-OH-E2 increased with the pH. In target tissues of the carcinogenic action of estrogens such as the rat pituitary, hamster kidney, or mouse uterus in which 2- and 4-OH-CE are both generated in almost equal amounts, the inactivation of 4-OH-CE by O-methylation may be impeded. Consequently, 4-OH-E2 would remain available as substrate for redox cycling, generation of active radicals and DNA damage.
Carcinogenesis 1990 Mar
PMID:The O-methylation of 4-hydroxyestradiol is inhibited by 2-hydroxyestradiol: implications for estrogen-induced carcinogenesis. 231 Nov 90

We showed earlier that 5-bromodeoxyuridine (BrdUrd), which can substitute for thymidine during DNA synthesis, inducing transition mutations, is incorporated into DNA of various tissues when administered to newborn rats and is not subjected to repair processes. The main purpose of the present experiment is to verify if a direct perturbation of DNA would be sufficient to initiate carcinogenesis. Rats aged 1, 3, 7, and 21 days were given BrdUrd s.c. at a dose of 3.2 mg/animal. At 2 months some of the females were subjected to treatment known to induce persistent estrus; at 1 month a group of males underwent removal of one kidney, and groups of males and females were exposed to a single total-body X-irradiation at a dose of 1.5 Gy (150 rads) per rat. In females, treatment with BrdUrd induced tumors of the ovaries, polyps in the uterus, and tumors of the soft tissues, nervous system, forestomach, glandular stomach, and salivary gland; no such tumor occurred in control females. Induction of persistent estrus increased the incidences of ovarian tumors and of malignant tumors of the uterus. Treatment with BrdUrd also increased the carcinogenic effect of X-rays on the mammary gland. In males, BrdUrd induced tumors of the testis (seminomas) and adenomas of the thyroid gland; solitary tumors of the kidney, nervous system, soft tissues, and bladder were also found. Unilateral nephrectomy reduced the incidences of tumors in the testis and pituitary gland, whereas subsequent treatment with X-rays did not alter the incidences of tumors induced by BrdUrd. These studies demonstrated for the first time that a nucleoside analogue, BrdUrd, has carcinogenic potential. Possible molecular mechanisms for its carcinogenicity and for the effects of the promoting factors are discussed.
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PMID:5-Bromodeoxyuridine-induced carcinogenesis and its modification by persistent estrus syndrome, unilateral nephrectomy, and X-irradiation in rats. 264 37

Diethylstilbestrol-4',4"-quinone (DES Q) has previously been postulated to be a reactive intermediate in diethylstilbestrol (DES) metabolism. DES is oxidized to DES Q in vitro, but the occurrence of the quinone metabolite in vivo has not yet been demonstrated due to its instability and chemical reactivity. In this report, the characteristics of in vitro formation of DES Q and the isolation of 3H-labeled DES Q from tissue extracts of hamsters injected with radiolabeled DES is described. In vitro, the time-dependent formation of DES Q as a function of microsomal protein, cofactor or substrate concentrations was demonstrated. The microsome-mediated oxidation of DES to quinone was inhibited by various compounds that also effectively inhibit the peroxidatic activity of cytochrome P-450. In vivo, the formation of DES Q occurred in all tissues investigated, livers and kidneys of male and female adult hamsters, neonates and fetuses, and in uterus and placenta. Concentrations of quinone metabolite in liver and kidney of adult hamsters after injection of 75 mumol/kg DES were 76 and 20 pmol/g tissue respectively. In neonates and fetus, concentrations of DES Q after the same dose of DES were markedly less than those in adults (0.026 and 0.047% of adult levels in neonatal liver and kidney and 0.013 and 0.016% of adult levels in fetal liver and kidney respectively). Since DES Q was also formed by fetal liver homogenate in vitro, fetal oxidizing enzymes appear to be the source of the quinone metabolite in this tissue. DES Q concentrations were also examined after injection of DES into hamsters pretreated with vitamin C or alpha-naphthoflavone, substances known to inhibit DES-induced renal carcinogenesis. Quinone metabolite levels were cut in half in response to vitamin C in correlation with the approximately 50% decrease in DES-induced renal tumors reported previously. alpha-Naphthoflavone pretreatment decreased renal and hepatic DES Q concentrations by 70 and 17% respectively, also in correlation with the known prevention of kidney tumors by this flavone. These data support a role of DES Q in DES-induced carcinogenesis. Since there is no correlation between DES Q concentrations and target site specificity of DES induced tumors, the oxidation of DES to DES Q and the genotoxicity of this metabolite may be a necessary but not sufficient event in tumor development. Hormone-dependent growth of initiated cells may also be necessary for the occurrence of cancers.
Carcinogenesis 1989 Jul
PMID:Metabolic oxidation of diethylstilbestrol to diethylstilbestrol-4',4"-quinone in Syrian hamsters. 273 17

Diethylstilbestrol (DES) is a carcinogen in humans and rodents which has eluded mechanistic clarification of its carcinogenic action. In vitro and in vivo, binding of DES to DNA has been found previously, but covalent DNA adducts could not be identified. In this study, the nature of binding was investigated by 32P-postlabeling, a rapid and highly sensitive assay for covalent DNA damage, to distinguish between a genotoxic or epigenetic mechanism of carcinogenesis by DES. A unique and distinct DNA adduct pattern was observed in kidney, liver, uterus (or testes) of female (or male, respectively) Syrian hamsters treated with a single injection of DES (200 mg/kg body weight). This set of DNA adducts closely matched patterns generated in vitro by reaction of diethylstilbestrol-4',4''-quinone with DNA or 2'-deoxyguanosine 3'-monophosphate. The major and several minor DES-DNA adducts in vivo had identical chromatographic mobilities in 11 different solvent systems with corresponding adducts obtained in vitro. The major adduct spot, generated in vitro by reaction of diethylstilbestrol-4',4''-quinone and DNA, was chemically unstable (half-life at 37 degrees C: 4-5 days). The persistence in vivo of these DNA modifications was low (biological half-life: 14 h) presumably because of chemical instability in concert with DNA repair. After injection of identical dosages of DES, adduct concentrations were 4-6-fold higher in females than in males. These results demonstrate that DES is capable of covalently modifying DNA. Moreover, diethylstilbestrol-4',4"-quinone is the major reactive metabolic intermediate responsible for the genotoxic activity of DES. Tumors are expected to arise only in rapidly dividing cells due to the short biological lifetimes of DES-DNA adducts.
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PMID:Mechanism of genotoxicity of diethylstilbestrol in vivo. 277 10

In an attempt to understand the mechanism by which estrogens stimulate cell proliferation and mammary carcinogenesis, metastatic human breast cancer cell lines (MCF7, ZR75-1) were found to secrete a 52,000 dalton (52K) protein under estrogen stimulation. Following its purification to homogeneity, the 52K protein was identified as a secreted procathepsin-D-like aspartyl protease bearing mannose-6-phosphate signals. This precursor displays an in vitro autocrine mitogenic activity on estrogen-deprived MCF7 cells and is able to degrade basement membrane and proteoglycans following its autoactivation. The total protease (52K + 48K and 34K) was detected and assayed by monoclonal antibodies and was found to be highly concentrated in proliferative and cystic mastopathies. In breast cancer, its cytosolic concentration appears to be correlated more to tumor invasiveness than to hormone responsiveness. The mRNA of the 52K protease accumulates rapidly following estradiol treatment, as was shown by Northern blot analysis with cloned cDNA. The 52K cathepsin-D-like protease is the first example of a lysosomal protease induced by estrogens in cancer cells. Results obtained using different approaches suggest that two cysteinyl cathepsins are also related to cell transformation and invasiveness. It has been proposed that cathepsin-B is involved in breast cancer and metastatic melanoma, and its regulation by estrogen has been shown in the rat uterus. Cathepsin-L corresponds to the major excreted protein (MEP) whose synthesis and secretion are markedly increased by transformation of NIH 3T3 cells with Ki ras and are regulated by several growth factors. In addition to secreted autocrine growth factors and to other proteases (plasminogen activator, collagenase), lysosomal cathepsins may therefore play an important role in the process of tumor growth and invasion as long as their precursor is secreted abundantly.
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PMID:Estrogen-induced lysosomal proteases secreted by breast cancer cells: a role in carcinogenesis? 331 45

The preventive and therapeutic potential of selenium (Se), a micronutrient, against cancer has been well documented in several test systems, but the mechanism of its action is not known. The possibility that Se might function in a manner similar to steroid hormones and retinoids through mediation of cellular receptors was examined. A specific 2S cellular binding protein (SeBP) for Na2[75Se]O3 was detected in rat tissue extracts. Liver and intestine exhibited highest levels of SeBP, and heart, uterus and spleen had the lowest levels. Oral administration of Na2[75Se]O3 to rats resulted in its uptake by the tissues with concomitant appearance of [75Se]SeBP complex. The protein binds sodium selenite with moderately high affinity; the apparent dissociation constant was determined by Scatchard analysis to be 1.1 X 10(-7) M. SeBP focused at pH 5.3 upon isoelectric focusing in ampholines of pH 3-10. Competitive binding affinity studies with unlabeled test compounds revealed that selenium dioxide and selenocystine showed high binding affinity (90-95%) for the selenite-binding site on SeBP. Sodium selenate, elemental Se powder, and selenomethionine, however, showed poor competition with sodium selenite. Biological activity of the above selenocompounds, as expressed by others, correlate with their binding affinities for SeBP. Sodium sulfite showed 35% inhibition of Na2[75Se]O3 binding, but sulfate showed none. Two ultimate carcinogens, N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine, and two retinoids, retinol and retinoic acid, showed less than 10% inhibition of binding. Interaction of Se with SeBP is completely blocked by thiol inhibitors. Plasma transport of Na2[75Se]O3 is mediated by a protein with a mol. wt of 68,000, which is presently identified, by immunoprecipitation studies as well as by Affi-Gel Blue column chromatographic experiments, as serum albumin. The results suggest that the plasma transport of Se is facilitated by albumin, and that the intracellular transport of Se for its biological functions is accomplished by SeBP.
Carcinogenesis 1988 Feb
PMID:Specific binding proteins for selenium in rat tissues. 333 11

N-Nitrosotriethylurea (NTEU) was administered once into the stomach or intravenously to outbred female rats. The rats given NTEU by oral administration developed malignant tumours of the mammary gland, uterus and liver. The rats exposed to NTEU by i.v. administration developed tumours of the mammary gland and ovaries. NTEU accelerated the appearance of tumours which are normally characteristic of the rat stock used (tumours of the pituitary, thyroid, adrenal cortex, fibroadenoma of the mammary gland, endometrial polyps.
Carcinogenesis 1988 Apr
PMID:Carcinogenic effect of N-nitrosotriethylurea in single administration to female rats. 335 65

Mice were X-irradiated on day 15 of gestation with 0.2, 0.4, 0.8 or 1.6 Gy. Offspring were reared by their mothers and divided into two subgroups at an age of 21 days, one subgroup receiving a single dose (45 mg/kg) of ethylnitrosourea (ENU). All animals were kept ultimately until 22 months to register the long-term tumour pattern. The carcinogenic effects of ENU alone were also studied in two separate experiments. Prenatal X-irradiation with 1.6 Gy mostly abolished the carcinogenic late effects of ENU, with the exception of an almost constant leucosis incidence and an unchanged lung tumour frequency. Lowering the prenatal X-ray dose to 0.8 Gy resulted in a significantly increased rate of liver tumours and ovary tumours. Synergistic effects on various tissues were observed after both 0.4- and 0.2-Gy foetal X-irradiation treatment in combination with postnatal application of ENU. These effects mainly involved a significant increase in the frequency of leucosis and of tumours of the liver, intestine, uterus and ovaries. The greater-than-additive effect in the case of these tumours suggests that low-level prenatal X-irradiation leads to a lasting sensitivity of some tissues towards a subsequent carcinogenic stimulus.
Carcinogenesis 1988 Aug
PMID:Synergistic induction of tumours in NMRI mice by combined foetal X-irradiation with low doses and ethylnitrosourea administered to juvenile offspring. 340 46


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