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

Chronic administration of tamoxifen to female rats causes hepatocellular carcinomas. We have investigated damage to liver DNA caused by the administration of tamoxifen to female Fischer F344/N rats or C57B1/6 or DBA/2 mice using 32P-postlabelling. Following the administration of tamoxifen for 7 days (45 mg/kg/day) and extraction of hepatic DNA, up to 7 radiolabelled adduct spots could be detected after PEI-cellulose chromatography of the 32P-labelled DNA digests. Tamoxifen caused a time-dependent increase in the level of adduct detected up to a value of at least 1 adduct/10(6) nucleotides after 7 days dosing. A dose response relationship was demonstrated over the range of 5-45 mg/kg/day (0.013-0.12 mmol/kg/day). On cessation of dosing there was a loss of adducts from the liver DNA. These adducts were not detected in DNA from vehicle-dosed controls or in DNA from kidney, lung, spleen, uterus or peripheral lymphocytes. Pyrrolidinotamoxifen caused a similar level of adduct formation as tamoxifen. In contrast, no significant adduct formation could be detected in liver DNA from rats given droloxifene or toremifene. Mice given tamoxifen (45 mg/kg/day for 4 days) showed levels of adducts in the liver which were 30-40% of those present in rats. Exposure of rat hepatocytes to tamoxifen in vitro, resulted in induction of unscheduled DNA synthesis, when preparations from rats which had been pretreated with tamoxifen in vivo were used. No such increase could be detected in hepatocytes from control rats, suggesting tamoxifen may induce enzymes responsible for its own activation. Tamoxifen induced a significant increase in micronucleus formation in a dose dependent manner in cultures of MCL-5 cells, a human cell line that expresses 5 different human cytochrome P450 isoenzymes, as well as epoxide hydrolase.
Carcinogenesis 1992 Dec
PMID:Genotoxic potential of tamoxifen and analogues in female Fischer F344/n rats, DBA/2 and C57BL/6 mice and in human MCL-5 cells. 147 24

N-Nitroso-N-methylurea (NMU) is an effective carcinogen for the induction of mammary carcinoma in the rat. Tamoxifen (TAM), used as a chemopreventive agent to reduce tumor incidence, has been well studied using this model. We have utilized the rat mammary carcinoma model to assess the effect of TAM on preneoplastic changes. Fifty-day-old virgin female Sprague-Dawley rats were randomized by weight and divided into the following five groups: Group 1, normal controls (n = 24); Group 2, TAM (n = 20); Group 3, NMU-short term (n = 24); Group 4, NMU-short term + TAM (n = 26); and Group 5, NMU-long term (n = 23). Seven weeks after the exposure to NMU, rats in Groups 1, 2, 3, and 4 were given injections of [3H]thymidine and sacrificed 4 h later for autoradiographic determination of thymidine labeling index (TLI). The rats from Group 5 were observed for 30 weeks after NMU exposure to confirm mammary tumor development. TLI in both terminal ducts and terminal end buds was modulated by treatment with TAM. Carcinogen administration induced higher TLI relative to the normal controls [18.3 +/- 1.8% (SD) versus 15.5 +/- 2.1%, P less than 0.001] in terminal end buds. The effect of carcinogen on TLI was also apparent in the terminal ducts (15.8 +/- 1.1% versus 9.5 +/- 1.1%, P less than 0.001). TAM administration was able to suppress both constitutive and NMU-induced TLI increases in terminal end buds (15.5 +/- 2.1% versus 2.8 +/- 1.1% and 18.3 +/- 1.8% versus 6.8 +/- 1.4%, respectively, P less than 0.001). Similar effects were observed in terminal ducts. In addition to its antiproliferative effect on nontransformed mammary tissue, TAM was effective in suppressing NMU-induced mammary tumor incidence and frequency. NMU-induced hyperproliferation is an intermediate stage in NMU carcinogenesis in the rat and is suppressed by TAM. Mammary epithelial hyperproliferation may provide a useful quantitative intermediate end point to evaluate chemopreventive efficacy.
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PMID:Effect of tamoxifen on preneoplastic cell proliferation in N-nitroso-N-methylurea-induced mammary carcinogenesis. 154 Sep 55

Triphenylmethane (TPM) was found to inhibit 3-methyl-cholanthrene-induced neoplastic transformation of 10T1/2 cells in a dose-dependent manner (ED50 = 2.8 microM). This activity was independent of any effect on intercellular communication and did not appear to be directly related to the general antioxidant properties of TPM as measured by cellular thiobarbituric acid-reactive substances. Triphenylmethanol (TPMOL) and diphenylmethane also inhibited transformation (ED50 = 6.9 and 90 microM respectively). TPM had no effect on the proliferation of exponentially growing cells. At higher concentrations TPM and its analogues enhanced plating efficiency of cells indicating no significant toxicity for these compounds at levels up to 50 microM. The inhibitory effects of TPM on transformation were reversible when TPM was removed from the medium. While TPM had no effect on the growth of fully transformed cell lines, it was able to inhibit the growth of 1/3 neoplastic foci in the presence (but not absence) of 10T1/2 cells. TPM was found to stimulate protein kinase C (PKC) activity for both crude C3H10T1/2 cytosolic PKC and purified PKC obtained from rat brain. The ability of TPM to stimulate PKC activity appeared to be dependent on [CaCl2] and the order of reagent addition in the assay. Tamoxifen, a structurally related compound to TPM, was also found to enhance PKC activity over the same concentration range but was less potent than TPM. The biological effects of TPM and related compounds indicate that they function in a manner distinct from other highly unsaturated transformation inhibitors such as carotenoids and retinoids. The inability of triphenylene to inhibit transformation suggests that a reactive methyl carbon may be essential for activity.
Carcinogenesis 1992 Jul
PMID:Inhibition of cellular transformation by triphenylmethane: a novel chemopreventive agent. 163 75

Tamoxifen is a well-tolerated palliative and adjuvant treatment for human breast cancer and requires continuous, long-term administration for optimal therapeutic effectiveness. A two-stage model of experimental hepatocarcinogenesis, based upon the natural history of cancer development, has been employed to assess the carcinogenic potential of tamoxifen. In this study, the effectiveness of tamoxifen both as an initiator and a promoter in hepatocarcinogenesis was assessed in female F-344 rats. Tamoxifen was tested as an initiator at a single intragastric dose of 40 mg/kg, followed by promotion with 0.05% phenobarbital. The number and size of the resulting altered hepatic lesions were quantified, and tamoxifen was found to lack initiating action at the dose tested. Other groups of animals were initiated with a nonnecrogenic, subcarcinogenic dose of diethylnitrosamine (10 mg/kg) and were fed tamoxifen at either 250 or 500 mg/kg in the AIN-76A purified diet for 6 months. The livers of these animals showed an increase in the size and number of altered hepatic lesions compared with those animals that were initiated but not exposed to tamoxifen; this indicates that tamoxifen acts as a tumor promoter in the rat liver. The promotion index of tamoxifen, a measure of relative potency, was less than one-tenth that of ethinyl estradiol and more than four times that of phenobarbital, an agent commonly employed as a representative promoting agent in experimental carcinogenesis. Since tamoxifen lacked initiating activity in the rat liver at the dose tested, the mechanism of tumor induction in long-term feeding studies by tamoxifen may be due to its promotion of spontaneously initiated hepatocytes. The chronic therapeutic use of tamoxifen should therefore be limited by the potential carcinogenic risk of this agent as an effective tumor promoter.
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PMID:Tumor promotion as a target for estrogen/antiestrogen effects in rat hepatocarcinogenesis. 167 62

In a previous study we showed that endometrial carcinoma (EC) patients have a T cell deficiency manifested in a reduced ability to be stimulated in vitro by PHA and to produce IL-2. In an attempt to understand the mechanism responsible for this alteration we present in this paper a study on T cells characterized by the ability to form rosettes, with human erythrocytes, following Con-A activation (designated auto-rosette forming cells--ARFC). These cells are also known to manifest suppressive activity. We show that the frequency of ARFC in con-A activated peripheral blood leukocytes (PBMC) of EC patients is significantly (2-5 fold) higher than that of healthy age-matched controls or that of patients with stage--I colon or vaginal cancer. Endometrial carcinoma is known to be associated with long term exposure to estrogens unopposed by progestins. Examining the possible role of estrogens in increasing the frequency of ARFC from EC patients, we found that in vitro addition of estradiol to Con-A stimulated PBMC from healthy donors increased the frequency of ARFC to levels found in EC patients. Tamoxifen, an anti estrogen drug, reduced the frequency of the estrogen stimulated ARFC to the original low level. Our results suggest a dual role for estrogen in carcinogenesis as well as in immunomodulation.
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PMID:Frequency and activity of autorosette forming cells in Con-A activated PBL from women with hyperplasia or carcinoma of the endometrium--possible role of estrogens. 196 3

The pharmacology of the antiestrogen tamoxifen is reviewed. The drug is currently used extensively in the treatment of all stages of breast cancer and is being considered as a preventive agent for women at high risk for breast cancer. Extensive laboratory studies demonstrate that tamoxifen is a tumoristatic agent in models of mammary carcinogenesis. Any clinical applications must therefore consider long-term (5-10 years) treatment strategies. Tamoxifen prevents rat mammary carcinogenesis. However, the timing of the carcinogenic insult is unknown among women. Tamoxifen must be considered to be a chemosuppressive agent to prevent the appearance of the primary tumor rather than to prevent the initial carcinogenic insult.
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PMID:Chemosuppression of breast cancer with long-term tamoxifen therapy. 200 27

The incidence of spontaneous and induced neoplasms of the exocrine pancreas in rats is higher in males than in females. Castration, ovariectomy, and hormone replacement with estradiol and testosterone have been shown to influence the growth of carcinogen-induced preneoplastic foci in the azaserine-rat model of pancreatic carcinogenesis. Similar hormonal treatments have also influenced the growth of an azaserine-induced poorly differentiated acinar cell carcinoma that can be transplanted syngeneically in Lewis rats. The effect on growth of preneoplastic lesions and carcinomas is similar. The preneoplastic lesions and transplanted tumors grow faster in intact male rats than in castrated rats, and the growth of the lesions and tumors is inhibited by estrogen treatment. It appears that testosterone supports the growth of preneoplastic foci and carcinomas, whereas estrogen inhibits such growth. The mechanism is unknown and may be direct, or an indirect effect may be mediated through a peptide hormone. Tamoxifen treatment did not significantly influence the growth of the transplanted carcinomas in the rat model.
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PMID:Effects of sex steroid hormones on pancreatic cancer in the rat. 208 21

The effect of combined treatment with D,L-2-difluoromethylornithine (DFMO) and tamoxifen on the growth status, ornithine decarboxylase (ODC) activity and polyamine content of established 1-methyl-1-nitrosourea (MNU)-induced mammary tumors was investigated. DFMO treatment, a 0.125% solution provided as drinking water, inhibited the rate of tumor occurrence and reduced the number of mammary tumors induced by a high dose of MNU (50 mg/kg body weight) during the first 120 days post-carcinogen treatment. Tamoxifen was administered daily via s.c. injection (25 micrograms/100 g body weight) to tumor-bearing rats in both treatment groups, i.e. control and DFMO-treated, for a 30-day period beginning 120 days after carcinogen. Tamoxifen treatment induced tumor regression but the percentage of regressing, static or growing tumors was no different in the presence or absence of DFMO. Whereas the mammary tumors of DFMO-treated rats had reduced ODC activity and lower polyamine concentrations in comparison to the tumors of untreated animals, tamoxifen had no effect on these parameters independent of its effect on tumor growth status. DFMO did not increase the efficacy of tamoxifen in inducing tumor regression.
Carcinogenesis 1986 May
PMID:Effect of tamoxifen and D,L-2-difluoromethylornithine on the growth, ornithine decarboxylase activity and polyamine content of mammary carcinomas induced by 1-methyl-1-nitrosourea. 308 21

It is generally believed that estrogen may act either as an initiator or as a promoter in carcinogenesis of human breast cancer. This estrogenic action is generally dependent on the estrogen receptor. In the human estrogen receptor, cDNA has a homology to V-erb-A oncogene. Experiments using MCF-7 human breast cancer cells were carried out to study the regulatory effect of estrogen and antiestrogen on RNA activities of oncogenes, estrogen receptor gene, and epidermal growth factor (EGF) receptor gene. The effect of estradiol on activation of estrogen and EGF receptor genes and myc, ras, and fos oncogenes was positive in relation to the concentrations of supplemented estradiol. In addition, the effects of antiestrogen (tamoxifen) were investigated. Tamoxifen suppressed MCF-7 cell growth, and spot hybridization of the RNA of MCF-7 cells revealed that RNA activities of estrogen and EGF receptor genes and myc, ras, and fos oncogenes were suppressed by tamoxifen. These results suggest that the three oncogenes and two receptor genes are partly regulated by estrogen and antiestrogen (tamoxifen) in MCF-7 human breast cancer cells. This regulatory system may have a role in carcinogenesis and in the treatment of human breast cancer.
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PMID:Regulation of human estrogen receptor gene, epidermal growth factor receptor gene, and oncogenes by estrogen and antiestrogen in MCF-7 breast cancer cells. 324 19

Estrogens have previously been shown to induce covalent DNA modifications specifically in the hamster kidney, the target organ of estrogen-inducible and -dependent renal carcinoma. The DNA adducts, formed by yet unknown mechanisms, have been postulated to mediate hormonal carcinogenesis in this animal model. In an attempt to study a possible involvement of estrogen receptor mechanisms in the formation of DNA adducts, 17 beta-estradiol and the antihormone tamoxifen were concomitantly administered as s.c. implants to male Syrian hamsters. 17 beta-Estradiol-treated and tamoxifen-treated animals served as positive and negative controls, respectively. The tumor incidence decreased from 100% in 17 beta-estradiol-treated controls to 25% in the group receiving tamoxifen in addition to hormone. Tamoxifen-treated animals did not develop kidney tumors and did not show any detectable DNA damage. DNA adduct levels were comparable in hamsters treated with 17 beta-estradiol and 17 beta-estradiol plus tamoxifen for 5 or 7 months. In hamsters inoculated with H-301 cells, which are derived from the estrogen-induced hamster renal carcinoma and are estrogen dependent for growth, tamoxifen decreased estrogen-dependent H-301 tumor growth. However, in cell culture, neither 17 beta-estradiol nor tamoxifen influenced H-301 cell division. It was concluded that tamoxifen inhibited the growth of estrogen-induced renal carcinoma but did not interfere with tumor initiation since it did not inhibit the formation of DNA adducts. Moreover, receptor mechanisms were most probably not involved in the induction of DNA modifications by estrogens.
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PMID:Inhibition of estrogen-induced renal carcinogenesis in male Syrian hamsters by tamoxifen without decrease in DNA adduct levels. 333 75


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