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J Natl Cancer Inst. 1978 Dec;61(6):1505-8. Links
Rat differences in mammary tumor induction with estrogen and neutron radiation.
Shellabarger CJ, Stone JP, Holtzman S.
Young adult female rats of either the Sprague-Dawley stock or the ACI strain were each given an implant of a compressed pellet of 5 mg diethylstilbestrol (DES) and 15 mg cholestrol 2 days before irradiation with 0.4, 1.3, or 4.0 rads of 0.43-MeV neutrons. These rats were studied, along with appropriate irradiated and nonirradiated controls, until death or for a maximum of 48 weeks. Response differences between the strain and stock included the following: DES produced both pituitary tumors and mammary adenocarcinomas (MAC) in ACI rats only. Neutron radiation increased mammary fibroadenoma (MFA) formation in Srague-Dawley rats only. No interactions between DES and radiation on MAC formation in Sprague-Dawley rats or MFA formation in ACI rats were demonstrated. However, when DES and neutron radiation were combined, DES appeared to inhibit the MFA response to radiation in Sprague-Dawley rats. In contrast, DES appeared to act synergistically with neutron radiation on MAC formation in ACI rats. These results clearly demonstrate rat differences in mammary gland carcinogenesis in response to estrogen, to radiation, or to a combination of both agents.


Ultrastructure of intermediate lobe of the pituitary and melanocyte-stimulating hormone secretion in oestrogen-induced kidney tumours in male hamsters.
Saluja PG, Hamilton JM, Thody AJ, Ismail AA, Knowles J.
One group of male Syrian hamsters was killed after various periods of diethylstilboestrol (DES) treatment, ranging from 6 to 36 weeks. All developed renal tumours by 24 weeks. DES also induced hyperplastic and neoplastic changes in the pars intermedia of the pituitary with proliferation of MSH-secreting cells and elevated serum MSH concentration. Another group of male Syrian hamsters was given DES for 36 weeks followed by cessation of hormone treatment. The animals were killed at various intervals from 12 to 36 weeks after DES withdrawal. In these animals the DES-induced renal tumours underwent regression whilst the pituitary changes persisted until the termination of the experiment. The findings suggested that the hormone MSH may be implicated in renal carcinogenesis but plays no role in the maintenance of the established tumours.



Arch Toxicol Suppl. 1979;(2):263-74. Links
Physiological mechanisms of diethylstilbestrol organotropic carcinogenesis.
Forsberg JG.
Treatment of pregnant women with diethylstilbestrol (DES) during pregnancy has been demonstrated to be associated with an increased risk in the female offspring for development of an otherwise very rare type of malignancy: clear-cell adenocarcinoma of the vagina and cervix. The present knowledge about this association is reviewed. In experimental animals, many different types of malignancy can be induced by DES administered in large doses and during long periods. For the human situation there are as yet no indications that exposure to DES during fetal life has resulted in any generally increased incidence of malignant tumors. By injecting neonatal mice with DES for the first five days after birth, histologically malignant changes develope in the uterine cervix of the animals when more than one year old. A comparison is made between this animal model and development of tumors in the human female offspring of DES treated mothers. In the female mice, neonatal DES treatment results in a disturbed epithelial differentiation process in the upper part of the vagina and the uterine cervix, a disturbed development of the hypothalamic-pituitary gland control system as well as a disturbance in the normal development of the lymphoid system. The abnormal epithelial differentiation process results in development of adenosis and within these areas the malignant changes later appear. We do no know whether adenosis is a pre-cancerous condition or not, in the meaning that it contains dormant malignant cells. Other factors could act upon adenosis to result in cancer. The reasons for DES being called a "carcinogen" are reviewed. The possibility for factors in the environment acting as potential transplacental carcinogens in the human fetus should not be excluded.


J Ark Med Soc. 1979 May;75(12):451-2. Links
Congenital diethylstilbestrol-associated vaginal/cervical adenosis (DES babies).
Barclay DL.
PIP: An epidemiologic study of clear cell vaginal adenocarcinoma in young women (15-22 years old) showed an apparent association with maternal ingestion of diethylstilbestrol (DES) during 1st trimester pregnancy. In 1971, a Registry of Clear Cell Adenocarcinoma of the Genital Tract in Young Females was established, and shortly thereafter the Food and Drug Administration warned that DES and chemically related nonsteroidal estrogens were contraindicated during pregnancy. DES-exposed females have a 0.14 to 1.4/1000 risk of developing adenocarcinoma of the cervix/vagina by age 24. Diagnoses of these cancers usually are made in girls between the age of 14 and 23 years with peak incidence at age 19; data further shows that DES is an incomplete carcinogen and that additional factors contribute to its carcinogenesis. About 20% of DES-exposed women will have a deformity of the upper vagina/cervix, and approximately 95% will have abnormal columnar epithelium on the cervix/upper vagina. 75% of patients whose mothers were exposed to DES in utero during the 8th week of gestation or earlier will have vaginal adenosis; 7% will have this finding if the mother's exposure occurred after the 17th week. Recent reports also indicate a high incidence of abnormalities in the uterus/oviducts associated with gross changes in the upper vagina/cervix. Asymptomatic girls who had DES exposure in uteru should have a complete annual pelvic examination at menarche or by age 14 years. Younger girls who develop abnormal vaginal bleeding/discharge should also have a periodic thorough examination and Pap smear, as well as palpation of the entire length of the vagina/cervix. So far, cervical/vaginal adenocarcinoma has been diagnosed at initial examination, with the ratio of vaginal to cervical adenocarcinoma being almost 2:1. There is no standard therapy yet for adenocarcinoma of young women. Treatment is on a case to case basis, and prognosis depends on the stage of the disease when diagnosed.


Natl Cancer Inst Monogr. 1979 May;(51):77-87. Links
Role of hormone imbalance in transplacental carcinogenesis induced in Syrian golden hamsters by sex hormones.
Rustia M.
Data are presented from studies on Syrian golden hamsters with the ENU precursors, EU, and NaNO2, given transplacentally and in adulthood, and with transplacentally administered DES. Hormone modification by gonadectomy of offspring prenatally exposed to ENU caused a significantly greater incidence and multiplicity of PNS neoplasms and other tumor types in orchidectomized males, compared with intact males, and in ovariectomized and intact females. That PNS tumors in gonadectomized males appeared within a significantly shorter latency period indicated that endogenously generated androgens inhibited neoplastic development. The endocrine imbalance also induced a higher incidence of neoplasia in other tissues and organs, e.g., skin melanomas, thyroid and adrenal cortex tumors, and notably gliomas in the CNS of ovariectomized female siblings. Exposure to single doses of ENU on days 12, 13, 14, and/or 15 caused PNS tumors predominantly in females and with an increased frequency in progeny treated during the final days of gestation. The spectrum of neoplasms was greater and their incidence significant in ENU-treated adult hamsters; the tumor types different from those of transplacentally treated animals (i.e., vascular, vaginal, and ovarian tumors and fore-stomach papillomas were seen). Determining factors in carcinogenesis at the time of carcinogen treatment possibly included stage of ontogenic development, degree of cell differentiation, hormone state of host, age, total dose, and duration of treatment. DES results indicated that the haster may be a useful model for reproducing lesions similar to those observed in children of mothers treated with this drug during pregnancy.


Obstet Gynecol Surv. 1979 Nov;34(11):844. Links
DES-associated clear cell adenocarcinoma of the vagina and cervix.
Herbst AL.
PIP: Epidemiologic, clinical and pathologic data on all cases of clear cell adenocarcinoma of the genital tract in women born in 1940 and later are collected by the Registry for Research on Hormonal Transplacental Carcinogenesis. Other cases of genital cancer are also recorded if there is a history of prenatal hormone exposure. Evidence strongly suggest a mullerian nature for clear cell adenocarcinomas. Of the 333 cases accessioned between 1970 and 1976, about 2/3 of the completely investigated cases had histories of prenatal exposure to stilbestrol (DES) or similar compounds. Estimated risk of clear cell adenocarcinoma ranges from 0.14 to 1.4 per 1000 DES-exposed, with age-incidence peaking at age 19. Cytology and a thorough pelvic examination are important tools for accurate diagnosis. Surgery and radiation are used to treat these tumors, but follow up in most cases has been limited to 5 years. Several cases of small or superficial tumors have been observed to spread to regional pelvic nodes, with recurrences in the lungs or supraclavicular areas. For inquiries, contact the Registry for Research on Hormonal Transplacental Carcinogenesis, 5841 S. Maryland Ave., Chicago, Ill 60637. Analysis of pathologic specimens should be directed to Robert E. Scully, MD, Dept of Pathology, Massachusetts General Hospital, Boston, Mass 02114.


The stilbestrol disorders in historical perspective.
Ulfelder H.
In the late 1960's when a series of adolescent girls with adenocarcinoma of the vagina presented themselves to our hospital, we did not immediately suspect the cause. Previous experience with radical hysterectomy and with vaginal reconstruction had prepared us technically to treat them sucessfully. Then a clue to etiology from one mother's observation regarding DES as a pregnancy supportive medication was quickly and conclusively converted into fact by an investigation with case controls. Rapid expansion of our knowledge came about through information accumulated in a Registry, and untoward effects other than cancer soon came to notice as young asymptomatic women presented themselves for examination because of known fetal exposure. The dominant event is clearly recognizable ss teratogenic, resulting in anomalous development of the vagina and cervix. Although the appearance of clear cell adenocarcinoma in a small fraction of DES-daughters is a consequence, the role of DES in its carcinogenesis is still unproved.


J Natl Cancer Inst. 1980 Jul;65(1):169-75. Links
Synergism of diethylstilbestrol and other carcinogens in concurrent development of hepatic, mammary, and pituitary tumors in castrated male rats.
Sumi C, Yokoro K, Kajitani T, Ito A.
Castrated male WF rats, given implants of pellets containing 5.0 mg diethylstilbestrol (DES), were given N-butyl-N-nitrosourea (NBU) in small amounts, which alone produced no mammary tumors in intact female rats. Treatment resulted in the high yield of hepatic tumors (HT), mammary tumors (MT), and pituitary tumors (PT) concurrently in each rat. If animals were further treated with prolactin, the development of HT and MT was accelerated, whereas that of PT was suppressed. None of the intact or castrated rats receiving NBU and/or prolactin developed tumors in any tissues if DES treatment was omitted. Exposure of male rats, preconditioned similarly to NBU treatment, to 200 rads of 14.1-MeV fast-neutron radiation also elicited HT, MT, and PT with an efficiency comparable to that of NBU-treated rats. These findings indicate that DES played an essential role in the whole carcinogenic process in each tissue and that castrated male rats, if conditioned properly with estrogens, are useful for the study of the carcinogenesis mechanism in these tissues.


Cancer. 1981 Mar 1;47(5 Suppl):1071-80. Links
Drug-induced cancer.
Hoover R, Fraumeni JF Jr.
This report reviews the medicinal agents that have been linked to human cancer, with emphasis on recent evidence implicating estrogenic compounds such as DES, menopausal estrogens, and oral contraceptives. Attention is also given to drugs that have fallen under suspicion and requires further epidemiologic evaluation. The detection of drug-cancer associations not only influences clinical and public health practice, but may also provide insights into mechanisms of carcinogenesis. The clinician contributes to the prevention of drug-induced cancer by being alert to iatrogenic hazards and cooperating in epidemiologic investigations, by weighing risks versus benefits in individual cases, and by discussing with patients the rationale and risks of proposed forms of therapy.


Gann. 1982 Dec;73(6):862-9. Links
Enhancing effect of diethylstilbestrol on urinary bladder carcinogenesis in neonatally castrated male rats.
Ogiso T, Arai Y, Fukushima S, Nishizuka Y, Ito N.
The effects of diethylstilbestrol (DES) on the development of urinary bladder cancer induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in neonatally castrated rats and on metaplastic changes of the coagulating glands and ejaculatory ducts were studied. Pretreatment with DES during infancy increased the incidence of preneoplastic lesions, papillomas, and cancers of the urinary bladder in BBN-treated males. Pretreatment with DES was more effective in castrated males than in uncastrated males. BBN did not induce tumors of the coagulating glands or ejaculatory ducts, in which metaplastic changes were observed in DES-treated rats.


Cancer Res. 1983 Oct;43(10):4879-84. Links
Transplacental action of diethylstilbestrol on mammary carcinogenesis in female rats given one or two doses of 7,12-dimethylbenz(a)anthracene.
Boylan ES, Calhoon RE.
Aspects of the development, morphology, and estrogen binding capacity of mammary tumors in rats exposed prenatally to the synthetic estrogen, diethylstilbestrol (DES), and treated postnatally with 7,12-dimethylbenz(a)anthracene (DMBA) were analyzed as part of a project aimed at understanding the effects of transplacental exposure to DES on estrogen-sensitive tissues. Pregnant Sprague-Dawley rats were given injections of DES (total dose, 1.2 micrograms) or vehicle alone on Days 15 and 18 of gestation. All female offspring were given gastric intubations of DMBA, either a single 10-mg dose on Day 50 or two doses (10 mg each) on Days 50 and 57. Among rats treated postnatally with 10 mg of DMBA, the DES-exposed group had a significantly greater incidence of palpable mammary tumors than did the vehicle-exposed controls. In addition, there was an earlier time of appearance of palpable tumors in the DES-exposed group. When the data from rats treated postnatally with two 10-mg doses of DMBA were analyzed, there were no significant differences in palpable mammary tumor incidence or tumor latency between the DES-exposed and vehicle-exposed groups. When the pathology of the mammary tumors produced in rats treated with 10 mg of DMBA was analyzed, the DES-exposed group had a significantly higher proportion of benign tumors (fibroadenoma, adenoma, lobular hyperplasia) than adenocarcinomata compared to vehicle-exposed controls. Both exposure groups had similar numbers of nonpalpable mammary lesions discovered at necropsy. Estrogen binding capacities of representative adenocarcinomata did not differ significantly between the two prenatal exposure groups treated postnatally with 10 mg of DMBA. These results demonstrate the importance of the dose of the challenge carcinogen in revealing the effects of transplacental drug exposure and may have special significance for women who were exposed to DES in utero.


1: Pathol Res Pract. 1984 Mar;178(4):339-44. Links
A histological study of the promotive effect of diethylstilbestrol on diethylnitrosamine initiated carcinogenesis of liver in rat.
Ding L, Zou DY, Chen JY, Wang JT, Wang YB, Pan SR, Wand SH.

A single dose (80 mg/kg) of diethylnitrosamine (DEN) was given orally to castrated female Wistar rats. One week after that one half of the animals were treated with diethylstilbestrol (DES) 3 mg/kg/once a week subcutaneously. The other half of the animals received no any hormone or hormone derivatives. The change of the liver cells in animals treated with DEN alone failed to progress beyond the stage of hepatocellular alterations in foci or neoplastic nodules within 8 months, while most of those animals which received DES treatment after DEN initiation developed hepatocellular carcinomas after 6 months. This result denotes that the DES exerts a definite promotive effect on DEN initiated liver cell carcinogenesis.


Food Addit Contam. 1984 Apr-Jun;1(2):95-100. Links
[Carcinogenic potential of estrogens used in breeding]
[Article in French]
Rico AG.

The oestrogens that are used in husbandry are oestradiol (natural compound), zeranol (non-steroid drug) and stilbenes such as diethylstilboestrol (D.E.S.). Oestrogens present carcinogenic activity especially on target organs (cervix uteri, corpus uteri, breast). Oestrogens, except perhaps D.E.S., do not initiate cancer directly, but may influence carcinogenesis by their hormonal properties. In these conditions it is possible to define rules of use which can protect the health of consumers. It is necessary to take into account the no-hormonal effect level, and the metabolism after oral administration. Oestradiol and zeranol, when used in good husbandry practice are not toxic, but D.E.S. must be banned and controlled.


Carcinogenesis. 1985 Jul;6(7):1067-9. Links
Target organ-specific covalent DNA damage preceding diethylstilbestrol-induced carcinogenesis.
Liehr JG, Randerath K, Randerath E.
The synthetic estrogen diethylstilbestrol (DES), a known human carcinogen, induces renal carcinoma in male Syrian hamsters within 6 months after s.c. implantation. Tumor formation could be evoked by its hormonal properties or by a reactive genotoxic metabolite binding to DNA, but previous attempts to detect adducts have failed. In the present study, kidney DNA of male Syrian hamsters, treated with s.c. DES implants to induce renal carcinoma, was analyzed for the presence of DES-induced adducts using 32P-postlabeling assay. Covalently-modified DNA nucleotides were detected in the kidneys after chronic DES treatment, but not in kidneys of untreated hamsters, or in liver or tumor tissue of DES-treated animals. This report demonstrates for the first time the ability of an estrogen to give rise to covalent DNA modification in vivo specifically in the target organ of carcinogenesis. DES-induced covalent DNA adducts are taken as evidence for tumor initiation by DES via damage to cellular macromolecules, in addition to tumor-promotional effects described previously.


Biochem Pharmacol. 1985 Sep 15;34(18):3251-7. Links
DNA clastogenic activity of diethylstilbestrol.
Birnboim HC.
Incubation of human leukocytes with the synthetic estrogen and known human carcinogen, diethylstilbestrol (DES), for 40 min caused extensive DNA strand breakage (clastogenesis), as measured by a fluorometric assay. The level of DNA clastogenesis was dose dependent above an apparent threshold of 10 microM. Clastogenesis was increased by addition of cysteamine, a reducing agent and hydroxyl radical scavenger, and was blocked by low concentrations of plasma. DES epoxide, a weakly estrogenic derivative, was about one-tenth as potent as a DNA clastogen. Unexpected and paradoxical findings were observed when cells were treated with DES in the presence of a hydrogen peroxide-generating system plus a peroxidase. At the subthreshold concentration of 10 microM DES, the oxidizing system increased DNA clastogenicity, yet at 30 microM DES the oxidizing system decreased clastogenicity. The addition of superoxide dismutase to the oxidizing system increased clastogenicity at both concentrations of DES. DNA damage was largely blocked by arsenite, N-ethylmaleimide, iodoacetamide and bromophenacyl bromide. These experiments provide further indication of the complex nature of reactions involving DES which can lead to DNA damage and which may be relevant to DES-induced carcinogenesis.


Carcinogenesis. 1986 Aug;7(8):1329-34. Links
Possible role of oxygen radicals in cell transformation by diethylstilbestrol and related compounds.
Epe B, Schiffmann D, Metzler M.
Diethylstilbestrol (DES) and four derivatives, viz. tetrafluoro-DES, 3'-hydroxy-DES, Z,Z-dienestrol and hexestrol, were examined for their abilities to form superoxide radicals and to induce DNA strand breaks in the presence of horseradish peroxidase/hydrogen peroxide metabolism in a cell-free system. Furthermore, the induction of strand breaks by these compounds was tested in Syrian hamster embryo (SHE) cells in vitro. Formation of superoxide radicals could be demonstrated by reduction of nitro blue tetrazolium for DES but not for its derivatives. With isolated superhelical DNA, induction of strand breaks in the presence of Fe3+ was observed for DES, tetrafluoro-DES and 3'-hydroxy-DES, while hexestrol and Z,Z-dienestrol were ineffective. In SHE cells, alkaline elution technique showed that DNA strand breaks were induced by DES and all derivatives tested, although only at cytotoxic concentrations. It is concluded that DES, under conditions of peroxidative metabolism, can give rise to superoxide generation and DNA strand breaks, and that these events may play a role in the process of DES-induced cell transformation.


Carcinogenesis. 1986 Sep;7(9):1415-8. Links
Alteration in diethylstilbestrol-induced mutagenicity and cell transformation by exogenous metabolic activation.
Tsutsui T, Suzuki N, Maizumi H, McLachlan JA, Barrett JC.
It was shown previously that diethylstilbestrol (DES) can induce morphological and neoplastic transformation of Syrian hamster embryo cells in culture in the absence of detectable gene mutations or DNA damage. However, in the presence of exogenous metabolic activation with rat liver post-mitochondrial supernatant, DES can induce unscheduled DNA synthesis. In this report we have examined whether with exogenous metabolic activation DES can also induce biological effects possibly related to its carcinogenicity, i.e. specific locus mutations in Syrian hamster embryo cells and cell transformation. We observed that DES was mutagenic only in the presence of exogenous metabolic activation. DES induced morphological transformation both in the absence and presence of exogenous metabolic activation. Enhanced cell transformation was observed in the presence of exogenous metabolic activation. These results indicate that two pathways may exist for the induction of cell transformation by DES. One does not apparently involve direct DNA damage, and the other, which requires rat liver post-mitochondrial supernatant-mediated exogenous metabolic activation, is associated with DNA damage and mutagenicity. These results may provide an experimental model to elucidate the biological properties of DES metabolites.


Cancer Lett. 1987 Jul;36(1):19-27. Links
Induction of DNA fragmentation and DNA repair synthesis in human and rat hepatocytes by diethylstilbestrol.
Martelli A, Robbiano L, Bartoli FG, Ghia M, Loche A, Brambilla G.
The synthetic estrogen diethylstilbestrol (DES), a known human carcinogen, was examined for cytotoxicity, and the induction of DNA damage and repair in primary cultures of human and rat hepatocytes. In both species concentrations of DES ranging from 5.6 to 18 micrograms/ml constantly produced reduction of cell viability and DNA fragmentation in dose-related amounts. However, large individual quantitative differences in the sensitivity to the cytotoxic and DNA-damaging activities of DES were observed among cultures derived from the 5 human donors. DES capability of eliciting DNA-excision repair was weak but statistically significant in both human and rat hepatocytes. Taken as a whole these results contribute to support the hypothesis of a genotoxic mechanism in DES-induced carcinogenesis.


Carcinogenesis. 1989 May;10(5):957-9. Links
Autoradiographic evidence of estrogen binding sites in nuclei of diethylstilbesterol induced hamster renal carcinomas.
Tse J, Goldfarb S, Pugh TD.
Department of Pathology, University of Wisconsin, Medical School, Madison 53706.
Estrogen binding sites were demonstrated by autoradiography in one transplantable and five primary diethylstilbesterol induced renal carcinomas in three hamsters. Radiolabelling, following the in vivo injection of 3H-17 beta estradiol, was increased only over the nuclei of tumor cells; stereologic analysis revealed a 4.5- to 6.7-times higher concentration of reduced silver grains over nuclei than cytoplasm of these cells. Despite rapid tubular excretion of estradiol which peaked in less than 1 h, the normal cells did not appear to bind the ligand. This is the first published report documenting the preferential in vivo binding of estrogen to nuclei of cells in estrogen induced hamster renal carcinomas.


J Biol Chem. 1989 Oct 5;264(28):16847-52. Links
Mechanism of genotoxicity of diethylstilbestrol in vivo.
<AuthorList>Gladek A, Liehr JG.
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77550-2774.
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.


Environ Health Perspect. 1990 Aug;88:117-21. Links
Role of metabolic activation in the carcinogenicity of estrogens: studies in an animal liver tumor model.
<AuthorList>Metzler M, Blaich G, Tritscher AM.
Institute of Pharmacology and Toxicology, University of Würzburg, Federal Republic of Germany.
Male Syrian golden hamsters chronically exposed to certain synthetic estrogens such as diethylstilbestrol (DES) or 17 alpha-ethinylestradiol (EE2) and fed a diet containing 7,8-benzoflavone (BF) develop a high incidence of liver tumors. No such tumors are found in animals treated with estrogen or BF alone. To clarify the role of metabolic activation of the estrogen and BF in the mechanism of hepatocarcinogenesis in this animal model, the effects of pretreatment with DES and EE2 alone and in combination with BF on the metabolism of DES, EE2, and BF in hepatic microsomes, isolated hepatocytes, and hamster bile were studied. Hamsters were pretreated for up to 32 weeks. The results clearly show that DES metabolism was not significantly modified under any pretreatment regimen. EE2 metabolism exhibited a slight increase in 2-hydroxylation after pretreatment with BF and with BF plus EE2. The most pronounced effect was observed in BF metabolism after pretreatment with BF, with BF plus DES, and with BF plus EE2: the metabolic rate was increased and several new metabolites that were not found in untreated or estrogen-pretreated animals were formed. These metabolites were tentatively identified as BF-dihydrodiol and dihydroxy-BFs. The formation of these new BF metabolites was accompanied by a change in the activities of certain cytochrome P-450 isoenzymes in hamster liver microsomes. The results of this study imply that metabolic activation of BF rather than of the estrogens plays an important role in the mechanism of carcinogenesis in this animal liver tumor model.


Cancer Res. 1991 Aug 1;51(15):3882-5. Links
Elevated 8-hydroxydeoxyguanosine levels in DNA of diethylstilbestrol-treated Syrian hamsters: covalent DNA damage by free radicals generated by redox cycling of diethylstilbestrol.
<AuthorList>Roy D, Floyd RA, Liehr JG.
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77550-2782.
The generation of free radicals by microsome-mediated redox cycling between catechol estrogens or diethylstilbestrol and their corresponding quinones has previously been demonstrated in vitro. However, the reaction of free radicals with DNA has not yet been detected in animals treated with estrogen and is the subject of this investigation. The reaction of guanine bases of DNA with hydroxyl radicals to form 8-hydroxydeoxyguanosine has been used as a monitor of free radical generation in kidney and liver of Syrian hamsters, a species prone to estrogen-induced carcinogenesis. Prior to in vivo measurements, the in vitro hydroxylation of guanine bases of DNA under conditions of redox cycling of estrogen was investigated. In incubations of DNA or deoxyguanosine with hamster kidney microsomes, NADPH, and diethylstilbestrol 4',4"-quinone, the hydroxylation of guanine bases of free deoxyguanosine or of DNA was 50 to 100% higher than in controls. When incubations were carried out in the presence of iron(III) chloride, the hydroxylation of guanine bases was 2.5- or 10-fold higher than control values. There was a 65% increase from control values in levels of 8-hydroxydeoxyguanosine in liver DNA of hamsters treated with 20 mg/kg/day diethylstilbestrol for 3 days and 100 mg/kg on the 4th day. In hamsters treated chronically with diethylstilbestrol implants for 15 days, 8-hydroxydeoxyguanosine levels more than doubled from control values in kidney but not liver DNA. Treatment of hamsters with estradiol for various time periods did not induce any changes in levels of hydroxylated guanine in either kidney or liver. It was concluded that in vitro and in vivo redox cycling of diethylstilbestrol hydroxylated guanine bases in DNA.


Res Commun Chem Pathol Pharmacol. 1992 Dec;78(3):341-58. Links
Morphometric analysis of renal cortex changes induced by diethylstilbestrol (DES) in Syrian hamsters.
<AuthorList>Chang CJ, Lin YC, Brueggemeier RW, Rikihisa Y.
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Ohio State University, Columbus 43210-1092.
Estrogen-induced renal adenocarcinoma usually can be readily detected in castrated hamsters after 9 to 12 months of DES treatment. In the present study, we examined the morphological characteristics of the renal cortices of castrated hamsters that had received 3 months of DES treatment in order to describe early histological evidence of carcinogenesis induction. Twelve Syrian Golden hamsters, 8 to 9 weeks of age, were first castrated and then subjected to either subpannicular implantation of a 20 mg DES pellet (experiment group), or sham operation (controls). Morphological and 2-D morphometric evaluations were conducted sequentially on kidney histological sections. Numbers (N's) or area fractions (AF's) of renal components in the juxta-medullary junction of each kidney section were processed for morphometric evaluation. The DES treatment caused a 15% increase in kidney weight, but not body weight. Dysplastic foci associated with hyperplastic tubules were present in 67% of the left kidneys or 17% of the right kidneys of hamsters in the test group, but were absent in kidneys of controls. DES treatment decreased glomeruli N by 33% and increased the vasculature AF by 169% per examination field. DES also increased AF's of glomeruli, proximal tubules, distal tubules, and vasculature by 17, 81, 53 and 346% per nephron, respectively. Our results showed that, after the first three months of DES-treatment, hamster kidneys developed dysplastic foci and their masses were greater than controls. Increased renal components in the juxta-medullary junction region included glomeruli, tubules, and vasculature. The dysplastic foci may be sites of subsequent malignancies, whereas the increased renal mass might be a result of functional adaptation/expression to exogenous estrogen which might contribute to the carcinogenic process.


Epidemiol Rev. 1993;15(1):108-9. Links
Diethylstilbestrol (DES) and breast cancer.
<AuthorList>Malone KE.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98104-2092.
PIP: It is estimated that 2 million US women used diethylstilbestrol (DES), a nonsteroidal estrogen, to reduce the risk of fetal loss from the late 1940s through the early 1960s. The results of clinical trials of the effectiveness of DES in the early 1950s precipitated the eventual decline of DES prescription by the 1960s. Concern about the breast cancer risk associated with the high dose of stilbestrol used led to 2 follow-up studies of these clinical trial participants, as well as 2 other retrospective cohort studies to examine the subsequent risk of breast cancer in DES-exposed women. 3 of the 4 studies reported positive results, with an overall 50% increase in risk for ever using DES during pregnancy and an apparent latency period of more than 20 years. These studies have or more limitations, including the absence of information on dosage taken and duration of use, confusion about the identify of the exposed group and the inability to distinguish between the effect of DES and the effect of indications for using DES. Nevertheless, the findings supported a possible association between DES and breast cancer risk. The 4 studies were published between 1980 and 1984 and included many women who had only recently entered the age period when breast cancer incidence is high. It is possible that the incidence of breast cancer associated with DES may increase with additional follow-up time. Prenatal influences on carcinogenesis have recently become of interest in the etiology of adult cancer, and, in particular, it has been proposed that increased estrogen levels during pregnancy might increase the probability of breast cancer in daughters. It has been demonstrated that DES use during pregnancy can influence the subsequent risk of clear cell adenocarcinoma in offspring, although the issue of whether DES might also influence the subsequent risk of breast cancer in daughters remains to be investigated.


Induction of chromosome aberrations in Syrian hamster renal cortical cells by various estrogens.
<AuthorList>Banerjee SK, Banerjee S, Li SA, Li JJ.
University of Kansas Cancer Center, Department of Pharmacology, Kansas City.
Estrogens, both natural and synthetic, have been implicated in carcinogenesis at different organ sites in a variety of animals, including man, for more than six decades. However, the molecular mechanism(s) involved in the carcinogenic action of estrogens still remains both controversial and elusive. Cytogenetic damage in the hamster kidney has been studied after in vivo treatment with either potent or weak estrogens for varying periods. Compared to age-matched untreated control, diethylstilbestrol (DES) treatment resulted in significant increases in the number of chromatid gaps and breaks, chromosome breaks, and endoreduplicated cells in hamster renal cortical cells. These chromosomal aberrations (CA) were cumulative with continued hormone exposure from 1.0 to 5.0 months. However, chromosome exchanges as a result of the breaks were not elevated. After 5.0 months of hormone treatment, potent estrogens such as 17 beta-estradiol and Moxestrol exhibited similar frequencies of CA in the hamster kidney to that found for DES, whereas weak estrogens such as 17 alpha-estradiol and beta-dienestrol exhibited CA frequencies that were not significantly different from untreated levels. Ethinylestradiol treatment for a similar period resulted in significant increases in chromatid gaps, although these did not evolve into increases in either chromatid or chromosome breaks, and in a rise in endoreduplicated cells. These results raise the possibility that the CA generated after estrogen treatment may be involved in renal tumorigenic processes.


Carcinogenesis. 1995 Apr;16(4):891-5. Links
Mitochondrial enzyme-catalyzed oxidation and reduction reactions of stilbene estrogen.
<AuthorList>Thomas RD, Roy D.
Department of Environmental Health Sciences, University of Alabama, Birmingham 35294, USA.
We have demonstrated for the first time that mitoplasts (i.e. mitochondria without outer membrane) were able to convert stilbene estrogen (diethylstilbestrol, DES) to reactive metabolites, which covalently bind to mitochondrial (mt)DNA. Depending on the cofactor used, mitochondrial enzymes catalyzed the oxidation and/or reduction of DES. DES was oxidized to DES quinone by peroxide-supported mitochondrial enzyme. A Lineweaver-Burk plot of rate of formation of DES quinone at various substrate concentrations yielded a Km of 33 microM and Vmax of 39 nmol/mg protein/min. The oxidation of DES to DES quinone by mitochondria was drastically decreased by known inhibitors of cytochrome P450. DES quinone was reduced to DES by mitoplasts in the presence of NADH. The Km and Vmax for the DES quinone reduction in the absence of mitoplasts and NADH were 3.2 microM and 5.6 nmol respectively. The reduction of DES quinone to DES by mitoplasts was significantly inhibited by inhibitors of cytochrome b5 reductase and diaphorase. DES quinone was also reduced to DES by pure diaphorase, a mitochondrial reducing enzyme, in the presence of NADH. The Km and Vmax for the DES quinone reduction by diaphorase were 9.0 microM and 4.3 nmol respectively. Under reaction conditions similar to oxidation of DES to DES quinone by mitoplasts, it was observed that mitochondrial metabolic products of DES were able to covalently bind to mtDNA. These data provide direct evidence of mitochondrial enzyme-catalyzed oxidation and reduction reactions of DES. In the cell, activation of DES in the mitochondria (the organelle in which mtDNA synthesis, mtDNA repair and transcription systems are localized) is of utmost importance, because an analogous in vivo mitochondrial metabolism of DES through covalent modifications in mitochondrial genome may produce instability in the mitochondrial genome of the cells. These modifications may in turn play a role in the development of DES-induced hepatocarcinogenicity.


Activation of phosphorylation of plasma membrane insulin-like growth factor-I receptors in the kidney of Syrian hamsters by diethylstilbestrol.
<AuthorList>Chen CW, Roy D.
Department of Environmental Health Sciences, University of Alabama, Birmingham 35294-0008, USA.
In the present work we have investigated activation of phosphorylation of plasma membrane insulin-like growth factor-I receptors (IGF-IR) by diethylstilbestrol (DES). Insulin-like growth factor-I (IGF-I) stimulated the activity of membrane protein tyrosine kinase(s) (PTK) in both normal and DES-treated hamster kidneys. The level of IGF-I-stimulated PTK(s) almost doubled after 15 days of DES treatment. Autophosphorylation experiments revealed that phosphorylation of a 95 kDa band (presumably the beta subunit of IGF-IR) was 2-fold higher in the membranes of kidney from DES-treated animals compared with controls. To understand the mechanism of activation of IGF-I-dependent PTK by DES, we investigated the relationship between the binding capacity of IGF-I to membrane proteins and the level of IGF-IR. The binding of [125I]IGF-I to membranes from the DES-treated group was 30% higher than that of age-matched normal kidney (P < 0.001). Scatchard analysis of the binding data for both normal and DES-treated hamster kidney revealed a single class binding site for IGF-I with a dissociation constant (Kd) of 4.1 and 4.6 nM and a maximum binding capacity (Bmax) of 1786 and 2086 fmol/200 micrograms protein respectively. Therefore, the difference observed in [125I]IGF-I binding between DES-treated and normal kidney membranes may be partially due to an increase in the number of IGF-I binding sites, with no change in the affinity of the receptors for IGF-I. An enhanced level of IGF-IRs in membranes from DES-treated animals was visualized by autoradiography following affinity labeling of membrane proteins subjected to SDS-PAGE. Under reducing conditions a molecular band of 132 kDa was evident. The 132 kDa band represents the alpha-subunit of IGF-IRs. Northern blot analyses revealed that DES treatment increased the level of IGF-IR mRNA 2-fold compared with that of controls. These findings suggest that an enhanced level of IGF-IR coupled with qualitative changes may be responsible for the activation of IGF-I-dependent PTK on DES exposure. Whether the stimulation of IGF-IR phosphorylation by exposure to a carcinogenic dose of DES may be a factor in the induction of renal cancer in Syrian hamsters is not clear.


Carcinogenesis. 1996 Aug;17(8):1615-22. Links
Involvement of transforming growth factor-alpha and its receptor in a model of DES-induced renal carcinogenesis in the Syrian hamster.
<AuthorList>Wattiez R, Nonclercq D, Journé F, Toubeau G, Zanen J, Falmagne P, Heuson-Stiennon JA.
Department of Biological Chemistry, School of Sciences, University of Mons-Hainaut, Belgium.
This study explores the role played by TGF alpha in estrogen-induced renal tumors. Tumors were induced in male Syrian hamster by chronic administration of diethylstilbestrol (DES). Six experimental groups (n = 5-9) were chronically exposed to DES and sacrificed after 1, 2, 4, 6, 9 and 11 months, respectively. In the course of treatment, the nephrons were the site of an important increase of cell turnover, which was characterized by a process of hyperplasia/dysplasia in proximal tubules preceding the neoplastic transformation. In treated animals and in controls, the analysis of renal tissue by Western blot revealed the presence of a 6 kDa polypeptide crossreacting with anti-TGF alpha antibody. In controls, TGF alpha immunoreactivity was localized in proximal and in distal tubules. Before tumor development (1-4 months), TGF alpha RIA showed an increase of TGF alpha concentration in renal tissue, in parallel with the increased cell proliferation observed in proximal tubules. In addition, Western blot analysis also demonstrated in kidney tissue the presence of a 165 kDa protein displaying the immunoreactivity of EGF/TGF alpha receptor. The receptor immunoreactivity was localized in proximal tubular cells suggesting an involvement of TGF alpha in tubular epithelial growth through autocrine or paracrine pathways. In large neoplasms, immunocytochemistry revealed only clusters of transformed cells intensely stained by the anti-TGF alpha antibody. These cells displayed the appearance of stellate or polyhedric cells infiltrating adjacent neoplastic tissues. Antisera raised against intra- or extracytoplasmic domains of the EGF/TGF alpha receptor were assayed to localize this receptor in the tumors. In contrast with tubular structures, immunoreactivity to EGF/TGF alpha receptor was never detected in tumoral tissue. The apparent absence of EGF/ TGF alpha receptor immunoreactivity in malignant cells seems to exclude an involvement of this growth factor in the tumorigenic process, although it could be involved in tumor neovascularization.


Eur J Morphol. 1998 Apr;36(2):83-96. Links
Sublethal alterations and sustained cell proliferation associated with the diethylstilbestrol-induced renal carcinogenesis in male Syrian golden hamsters.
<AuthorList>Nonclercq D, Toubeau G, Wattiez R, Laurent G, Bernard A, Journé F, Falmagne P, Heuson-Stiennon JA.
Service d'Histologie, Faculté de Médecine et de Pharmacie, Université de Mons-Hainaut, Belgium.
The current study was initiated to explore the sublethal alterations and the tissue damage occurring in the hamster kidney during diethylstilbestrol-induced renal carcinogenesis. A total of 49 male Syrian golden hamsters (35 treated and 13 control animals) was utilized in the experimental procedure. Chronic exposure to diethylstilbestrol was achieved by s.c. insertion of implants containing 25 mg diethylstilbestrol. For long-term observation, adequate blood level of diethylstilbestrol was insured by renewing the implant every 2 months. Experimental groups (n = 4 to 9) were terminated 1, 2, 4, 6, 9 and 11 months after initial implantation for morphological examination of the kidney. Diethylstilbestrol carcinogenicity in this experimental model was confirmed by the observation that most animals undergoing drug exposure for 6 months or more exhibited renal neoplasms. The most striking nonneoplastic morphological abnormality disclosed by histological and cytological examination consisted in the accumulation of granular inclusions in proximal tubule cells. In renal tissue, the extent of cell proliferation determined by PCNA labeling progressively increased along with the duration of diethylstilbestrol exposure and suggested a sustained proliferative response in altered proximal tubules. The present data suggest that an impairment of functional tubular regeneration could promote, as well as the estrogen genotoxic effect, the tumorigenicity of diethylstilbestrol in the kidney of male hamsters.


Chemosphere. 2000 Jul;41(1-2):187-90. Links
Promotive effect of diethylstilbestrol on urethan-induced mouse lung tumorigenesis.
<AuthorList>Jiang YG, Chen JK, Wu ZL.
Institute for Chemical Carcinogenesis, Guangzhou Medical College, People's Republic of China.
The effect of diethylstilbestrol (DES) on urethan-induced mouse lung tumorigenesis was assessed by a single intraperitoneal injecting of urethan (50 mg/kg) or/and multi intramuscular injecting of DES (5 or 50 mg/kg). All mice were sacrificed 18 weeks after administration, and the lung tumors were examined histopathologically. DES did not produce an elevated lung tumor response when administered alone, but it produced a statistically significant enhancement of incidence of tumors, average number of tumors, incidence of cancers and constituent ratio of malignant tumors when given in conjunction with urethan. The results indicated that DES may be a promoter in lung tumor formation.


Mol Carcinog. 2003 Oct;38(2):78-84. Links
Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus.
<AuthorList>Li S, Hansman R, Newbold R, Davis B, McLachlan JA, Barrett JC.
Laboratory of Biosystems and Cancer, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Perinatal exposure to diethylstilbestrol (DES) induces reproductive tract cancers later in life in both humans and animals. Because there is no clear evidence that perinatal DES exposure induces gene mutation, we proposed that perinatal DES exposure causes epigenetic methylation changes that result in persistent alterations in gene expression, leading to tumorigenesis. The proto-oncogene c-fos is one of the immediately induced genes in uterine epithelium after estrogen simulation and a key player in uterine carcinogenesis. Here, we investigated c-fos expression in mice neonatally exposed to DES (2 microg/pup/day on postnatal days 1-5). The mRNA levels of c-fos in uteri of neonatal DES-treated mice were persistently 1.4-1.9-fold higher than that in the control mice from day 5 to day 60. Overall, the uterine c-fos expression level in the neonatal DES-exposed group was significantly higher than that in the control group. After examination of the methylation status of the c-fos gene, we found that the CpGs in promoter and intron-1 regions were completely unmethylated. In exon-4, from day 17 to day 60, the percentage of unmethylated CpGs was higher in neonatal DES-exposed mice uteri than that in control (42%, 51%, 47%, and 42% in DES-exposed mice vs 33%, 34%, 33%, and 21% in control mice at day 17, 21, 30, and 60, respectively). These results suggest that perinatal DES exposure may permanently alter gene expression and methylation, and the methylation modification may occur in either the promoter regions or other regulatory sites in the gene. Published 2003 Wiley-Liss, Inc.


Mutagenesis. 2004 Jan;19(1):67-73. Links
Age, sex and co-exposure to N-ethyl-N-nitrosourea influence mutations in the Alu repeat sequences in diethylstilbestrol-induced kidney tumors in Syrian hamsters.
<AuthorList>Singh KP, Lopez-Guerrero JA, Llombart-Bosch A, Roy D.
Department of Environmental Health Sciences, University of Alabama at Birmingham, 1665 University Boulevard, 530 Ryals Building, Birmingham, AL 35294-0022, USA.
We report, for the first time, mutations in the Alu repeat regions in the genome of kidney tumors induced by diethylstilbestrol in Syrian hamsters. Among the 66 loci amplified by 11 random primers, 28 loci exhibited insertions, deletions or losses or gains in intensity in the genome of kidney tumor tissues compared with normal kidney tissues from age-matched hamsters. Higher numbers of mutated Alu loci were observed in the tumors of old hamsters compared with young hamsters. In N-ethyl-N-nitrosourea- and diethylstilbestrol-treated hamsters deletion of a 0.59 kb locus amplified with primer OPC03 was observed in most of the female hamsters, but not in male hamsters. An insertion mutation of a 0.498 kb locus amplified with primer OPC03 was observed in 12 of 36 diethylstilbestrol-induced kidney tumors. The cloning and sequencing of the 0.498 kb locus amplified with primer OPC03 revealed that it had significant sequence similarity to the mouse RIKEN cDNA clone. These findings indicate that age, sex and co-exposure to N-ethyl-N-nitrosourea influence mutations in the Alu repeat sequences in the genome of diethylstilbestrol-induced kidney tumors in Syrian hamsters. Structural alterations in Alu repeats in critical target genes may be involved in diethylstilbestrol-induced carcinogenesis.


J Carcinog. 2004 Mar 5;3(1):4. Links
Somatic mutations in stilbene estrogen-induced Syrian hamster kidney tumors identified by DNA fingerprinting.
<AuthorList>Singh KP, Roy D.
Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-0022, USA. royd@uab.edu
Kidney tumors from stilbene estrogen (diethylstilbestrol)-treated Syrian hamsters were screened for somatic genetic alterations by Random Amplified Polymorphic DNA-polymerase chain-reaction (RAPD-PCR) fingerprinting. Fingerprints from tumor tissue were generated by single arbitrary primers and compared with fingerprints for normal tissue from the same animal, as well as normal and tumor tissues from different animals. Sixty one of the arbitrary primers amplified 365 loci that contain approximately 476 kbp of the hamster genome. Among these amplified DNA fragments, 44 loci exhibited either qualitative or quantitative differences between the tumor tissues and normal kidney tissues. RAPD-PCR loci showing decreased and increased intensities in tumor tissue DNA relative to control DNA indicate that loci have undergone allelic losses and gains, respectively, in the stilbene estrogen-induced tumor cell genome. The presence or absence of the amplified DNA fragments indicate homozygous insertions or deletions in the kidney tumor DNA compared to the age-matched normal kidney tissue DNA. Seven of 44 mutated loci also were present in the kidney tissues adjacent to tumors (free of macroscopic tumors). The presence of mutated loci in uninvolved (non-tumor) surrounding tissue adjacent to tumors from stilbene estrogen-treated hamsters suggests that these mutations occurred in the early stages of carcinogenesis. The cloning and sequencing of RAPD amplified loci revealed that one mutated locus had significant sequence similarity with the hamster Cyp1A1 gene. The results show the ability of RAPD-PCR to detect and isolate, in a single step, DNA sequences representing genetic alterations in stilbene estrogen-induced cancer cells, including losses of heterozygosity, and homozygous deletion and insertion mutations. RAPD-PCR provides an alternative molecular approach for studying cancer cytogenetics in stilbene estrogen-induced tumors in humans and experimental models. Although the exact functional importance of mutated loci is unknown, this study indicates that these altered loci may participate during tumor progression in the kidney.


Allelic loss and mutations in a new ETRG-1 gene are early events in diethylstilbestrol-induced renal carcinogenesis in Syrian hamsters.
<AuthorList>Singh KP, Roy D.
Department of Biology, Texas Southern University, Houston, TX 77004, USA.
Diethylstilbestrol (DES) is a synthetic estrogen and well known human carcinogen, but the mechanism by which DES causes cancer is not clear. In this study, using AP-PCR method we have identified a genetic alteration that was common in DES-induced kidney tumors as well as in its surrounding non-tumor tissue. Further characterization of this genetically altered region revealed that it represents an uncharacterized novel gene. We have named this gene as Estrogen Target Rodent Gene-1 (ETRG-1). Southern blot analysis revealed about 50% reduction in the ETRG-1 gene-specific hybridization signal, indicating genomic loss of one allele of ETRG-1 in DES-induced tumors as compared to its age-matched control. Sequence analysis of the remaining allele of ETRG-1 from tumor revealed point mutations and an insertion of 37 bp as compared to its normal allele from the age-matched control kidney tissue. The expression of ETRG-1 at transcript level was found to be extremely reduced or undetectable in DES-induced kidney tumors as compared to its age-matched control kidney tissue. Thus, the findings of this study suggest that (a) DES-induced allelic loss and mutations may be involved in DES-induced kidney carcinogenesis, (b) Constitutive expression of ETRG-1 in normal kidney tissue and decreased or undetectable expression in tumors, presumably as a result of allelic loss and mutational inactivation, suggest that it may be a tumor suppressor gene, and finally, (c) The identification of the allelic loss and mutations that were common in DES-exposed non-tumor kidney tissue, and in frank kidney tumors indicate that these genetic aberrations are early events in DES-induced kidney carcinogenesis and it may serve as biomarker for early detection of DES-induced cancer.


Последний раз редактировалось Рысь 31 янв 2010, 13:48, всего редактировалось 1 раз.


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Очень полезная подборка :)


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Очень полезная подборка

Вопрос только, для кого. Кто принимает синьку и советует другим, боюсь даже по русски читать не станет, а уж столько текста на английском тем более не будет.


  
 
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Очень полезная подборка

Вопрос только, для кого. Кто принимает синьку и советует другим, боюсь даже по русски читать не станет, а уж столько текста на английском тем более не будет.

Зато те, кому советуют ее принимать, возможно будут читать :)


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Зато те, кому советуют ее принимать, возможно будут читать

Ага. Типа мы тебя предупреждали, а то что ты с английским не в ладах, то сам дурак...


  
 
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Подборку можно перевести на русский, и это даже несложно сделать :)


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Подборку можно перевести на русский, и это даже несложно сделать

Было бы замечательно :)


  
 
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Подборку можно перевести на русский, и это даже несложно сделать

Ну если кто-то возьмется... На мне и так четыре перевода висят. :o

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Вопрос только, для кого. Кто принимает синьку и советует другим, боюсь даже по русски читать не станет, а уж столько текста на английском тем более не будет.

Естественный отбор в действии :idea:



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Теперь будет куда посылать любителей синэстрола.



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По последним агентурным данным эта подборка имеет мало отношения к раку, вызываемом синэстролом, тем более у людей. Пока ждем обновлений ;)



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агентурным данным

Источники в студию!


  
 
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Источники в студию!
Чуть-чуть попозже, имейте терпение. А то, что это не относится к людям и синестролу, можно увидеть и так, внимательно почитав сам текст.



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реальные примеры закомых ,друзей которые реально подхватили рак от синестрола есть или только статьи и выдержки ..?))простите за прямоту..


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реальные примеры закомых ,друзей которые реально подхватили рак от синестрола есть или только статьи и выдержки ..?))простите за прямоту..

Насколько я знаю, нет.


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ну вот и я об этом,я непоклонница синестрола,но ничего плохого сказать о нем немогу тоже..))


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