Adenocarcinoma of the Vagina

Herbst, Arthur L.; Ulfelder, Howard; Poskanzer, David C.

doi:10.1056/nejm197104222841604

Cited by 2,262 publications

(186 citation statements)

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“…[12][13][14] Assay of in Vitro Antitumor Activity The assay of in vitro antitumor activity was performed using murine leukemia L1210 cells and human epidermoid carcinoma KB cells. NIH-3T3 cells transformed with oncogenes such as Ha-ras, Ki-ras, sis, abl, and src were obtained from the Virus Department of Kanazawa University.…”

Section: Methodsmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9] Among them, an involvement in carcinogenesis is of particular interest. [10][11][12] Consequently, the environmental effects of a synthetic estrogen, diethylstilbestrol (DES), large amounts of which have been used in stock-farming, have become a serious concern.We have shown that natural and synthetic estrogens and their related compounds have inhibitory activities on the in vitro polymerization of microtubule proteins, which play important roles in the cytoskeleton and cell division in addition to having hormonal activity. [13][14][15][16][17][18] We have also clarified that indenestrol A (IA), which is a metabolite of DES, has the highest antioxidant action among its related compounds.…”

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confidence: 99%

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confidence: 99%

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Cytotoxicity of Synthetic Estrogen and Related Compounds in Various Tumor-Derived Cells.

Oda¹,

Tanaka

Sasaki

2001

Biological & Pharmaceutical Bulletin

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Various activities of estrogen, other than its primary activity as a hormone, have recently been revealed. [1][2][3][4][5][6][7][8][9] Among them, an involvement in carcinogenesis is of particular interest. [10][11][12] Consequently, the environmental effects of a synthetic estrogen, diethylstilbestrol (DES), large amounts of which have been used in stock-farming, have become a serious concern.We have shown that natural and synthetic estrogens and their related compounds have inhibitory activities on the in vitro polymerization of microtubule proteins, which play important roles in the cytoskeleton and cell division in addition to having hormonal activity. [13][14][15][16][17][18] We have also clarified that indenestrol A (IA), which is a metabolite of DES, has the highest antioxidant action among its related compounds. 19) Because the cytotoxicity of IA on colony formation by Chinese hamster V79 cells is similar to the effects of IA on microtubule proteins, the cytotoxicity is considered to be due partially to these effects on microtubule proteins. 16) We have also found that indenestrol B (IB), an isomer of IA, is highly cytotoxic to Chinese hamster V79 cells. 16) Taxol, which has the opposite effect of the well-known microtubule inhibitor colchicine, has drawn attention as a carcinostatic. However, the compounds related to synthetic estrogens mentioned in this study are more promising as carcinostatics, because their inhibitory activity against microtubule proteins is weaker than that of colchicine. In this study, cell growth inhibition by DES and its related compounds was examined by the MTT method using L1210, KB, and NIH-3T3 cells transformed with oncogenes, which are commonly used as screening systems for carcinostatics. MATERIALS AND METHODSMaterials DES and EE-dienestrol were obtained from Sigma Chemical Co. Other test compounds were synthesized as described previously. [12][13][14] Assay of in Vitro Antitumor Activity The assay of in vitro antitumor activity was performed using murine leukemia L1210 cells and human epidermoid carcinoma KB cells. NIH-3T3 cells transformed with oncogenes such as Ha-ras, Ki-ras, sis, abl, and src were obtained from the Virus Department of Kanazawa University. Roswell Park Memorial Institute medium 1640 supplemented with 10% heat-inactivated fetal bovine serum and kanamycin 50 mg/ml was used as the cell culture medium. The test compounds were dissolved in DMSO and added to the culture plates at 1% as the final volume. The DMSO concentration had no effect on the cytotoxicity. Tumor cells (2ϫ10 3 cells/ml) were cultured in 1 ml of the medium containing various concentrations of test compounds in a CO 2 gas incubator at 37°C for 72 h. Their viability, estimated by a modification of the colorimetric (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) MTT assay, 20) was compared to that of control cells incubated in the same medium without the test compounds. The antitumor activity was evaluated as the IC 50 (the concentration [mM] of the compounds required for 50% ...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Cytotoxicity of Synthetic Estrogen and Related Compounds in Various Tumor-Derived Cells.

Oda¹,

Tanaka

Sasaki

2001

Biological & Pharmaceutical Bulletin

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“…From the 1940s to the 1970s, the xenoestogen diethylstilbestrol (DES) was extensively prescribed to pregnant women at risk for miscarriage. Women who had been exposed to DES in utero during critical periods of reproductive-tract development developed several types of reproductive-tract abnormalities as well as an increased incidence of cervical-vaginal cancer later in life (12). Animal studies that simulate the human DES experience have since shown that exposure of the developing reproductive tracts of CD-1 mice to DES imparts a permanent estrogen imprint that alters reproductive-tract morphology, induces persistent expression of the lactoferrin and c-fos genes, and induces a high incidence of uterine adenocarcinoma (13)(14)(15).…”

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confidence: 99%

Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

Cook

Davis

Cai

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

102

101

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Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumorsuppressor-gene defect in the adult. Using rats carrying a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor-suppressor gene predisposed to uterine leiomyomas, we show that an earlylife exposure to diethylstilbestrol during development of the uterus increased tumor-suppressor-gene penetrance from 65% to >90% and tumor multiplicity and size in genetically predisposed animals, but it failed to induce tumors in wild-type rats. This exposure was shown to impart a hormonal imprint on the developing uterine myometrium, causing an increase in expression of estrogen-responsive genes before the onset of tumors. Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor-suppressor-gene penetrance in genetically susceptible individuals.developmental programming ͉ gene-environment interaction ͉ Eker rat ͉ uterine leiomyoma ͉ Tsc-2 I nheritance of a defect in a tumor-suppressor gene confers a high risk for developing cancer. However, defects in these genes are rarely 100% penetrant, and, even in families harboring the same genetic mutation, the penetrance of the tumor-suppressor-gene defect can vary significantly (1-4). The importance of geneenvironment interactions in contributing to individual differences in tumor-suppressor-gene penetrance was recently highlighted in the New York Breast Cancer Study, which evaluated the breast and ovarian cancer risk in female relatives harboring mutations in the BRCA1 and BRCA2 tumor-suppressor genes. The magnitude of increase in breast cancer risk in the birth cohort born after 1940 was substantially greater than in those born before 1940 (5). These data suggest that additional factors, such as diet, exercise, hormonal milieu, and environmental exposures, can significantly modify cancer risk in the presence of an inherited cancer-susceptibility gene.Traditionally, gene-environment interactions that influence cancer risk are thought to occur over an individual's lifetime by facilitating or inhibiting acquisition of the multiple somatic mutations required for tumorigenesis (6). However, for some diseases, such as cardiovascular disease and adult-onset diabetes, a developmental programming hypothesis is proposed as an alternative mechanism for modulating adult disease. This hypo...

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“…The evidence for possible viral transplacental carcinogenesis in human beings is also conflicting. Fedrick & Alberman (1972) Herbst & Scully (1970) (Herbst et al 1971). The correlation was subsequently confirmed in a larger series of cases (Greenwald et al 1971, Herbst et al 1972 Ivankovic & Druckrey (1968), who demonstrated the remarkably specific transplacental carcinogenic action of N-ethylnitrosourea in the rat.…”

Section: Hamartomasmentioning

confidence: 99%

Transplacental Carcinogenesis

SpringerReference

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Adenocarcinoma of the Vagina

Cited by 2,262 publications

References 7 publications

Cytotoxicity of Synthetic Estrogen and Related Compounds in Various Tumor-Derived Cells.

Cytotoxicity of Synthetic Estrogen and Related Compounds in Various Tumor-Derived Cells.

Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

Transplacental Carcinogenesis

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