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

Epidemiological and animal studies have indicated that 17beta-estradiol (E2) is involved in breast cancer; however, the mechanism is unclear. We found that E2 could be activated by epoxidation, resulting in its ability to inhibit nuclear DNA-dependent RNA synthesis, and to bind DNA, forming DNA adducts both in vitro and in vivo. Because epoxidation is required for the activation of many chemical carcinogens, including benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene and aflatoxins, we proposed previously that E2 epoxidation is the underlying mechanism for the initiation of breast cancer. The first part of this review is to present the experimental evidence obtained from this laboratory in support of this hypothesis. Based on these newly discovered insights on E2 epoxidation and its initiation role in breast cancer carcinogenesis, a method to screen chemopreventive agents against breast cancer has been developed. This constitutes the second part of the review. Two examples will be used to illustrate the utility of this screening technique. The effect of fat on breast cancer has been a longstanding but unresolved issue. Epidemiological studies provide conflicting results regarding the association of dietary fat and breast cancer. Because vegetable oils contain various amount of mono- and polyunsaturated fatty acids, they are potential antioxidants. Data are presented to show that commercial vegetable oils, independent of their mono- or polyunsaturated fatty acid content, are all able to prevent the formation of E2 epoxide, as measured by the loss of the ability of E2 to inhibit nuclear RNA synthesis in vitro. Tamoxifen (TAM), an anti-estrogen used for breast cancer treatment, has recently been found to have a strong breast cancer preventive effect. The mechanism for this is unknown. Using the same screening technique, we found that when incubated together with E2 for epoxidation, TAM was able to prevent the formation of E2 epoxide, as evidenced by both the loss of the ability of E2 to inhibit nuclear RNA synthesis and the reduced binding of [3H]-labelled E2 to nuclear DNA in a dose-dependent manner. These experimental results suggest that the breast cancer preventive effect of TAM is to prevent the formation of E2 epoxide through a competitive epoxidation mechanism with E2.
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PMID:17Beta-estradiol epoxidation as the molecular basis for breast cancer initiation and prevention. 1249 35

The cyclin-dependent kinase inhibitor, p27, has been shown to mediate cell growth arrest thereby significantly reducing the percentage of proliferating cells. It seems that p27 expression is essential for the control of normal endometrial proliferation, and reduced or absent p27 expression may be an important step in endometrial carcinogenesis. Our aim was to demonstrate the effects of tamoxifen therapy on the expression of p27 protein in the endometrium of postmenopausal breast cancer patients. Fifty-three pre- and post-tamoxifen treatment endometrium samples were examined immunohistochemically using p27 antibody. Tamoxifen therapy (20 mg/day) for 60 days increased the expression of p27 protein in the endometrium of postmenopausal breast cancer patients. We conclude that tamoxifen therapy does not seem to be directly involved in the carcinogenesis of endometrial carcinoma since the expression of p27 is not decreased.
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PMID:Effects of tamoxifen therapy on the expression of p27 protein in the endometrium of women with primary breast cancer. 1461 25

Carcinogenesis in the breast is a hormonally dependent process. Evidence implicating estrogen as a key breast carcinogen comes from various lines of investigation. Traditional epidemiologic studies demonstrate associations between estrogen exposure, both exogenous and endogenous, and increased breast cancer risk. Ongoing genetic epidemiologic studies also show associations between specific polymorphisms in estrogen-metabolizing genes and risk, albeit inconsistently. The application of these findings to the treatment and, more recently, the prevention of breast cancer has led to the development of agents that either (1) inhibit estrogen action at the estrogen receptor (selective estrogen receptor modulators (SERMs]); or (2) inhibit estrogen-synthesizing enzymes, thereby abrogating synthesis of this hormone (aromatase inhibitors). Large phase III trials have evaluated the ability of such agents to reduce the incidence of breast cancer in women at increased risk of the disease. The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1: Breast Cancer Prevention Trial (BCPT) demonstrated the superiority of the SERM tamoxifen to placebo in reducing breast cancer risk, leading to the Food and Drug Administration approval of tamoxifen for risk reduction. The implementation of tamoxifen for this indication has not become widespread in clinical practice, however, for a variety of reasons that we discuss. Results from the NSABP Study of Tamoxifen and Raloxifene, which compares the risk-reducing efficacy as well as toxicity of these two SERMs in a similar high-risk population, will be available in the near future. Based on promising data involving reduction of contralateral breast cancer risk in adjuvant studies, several aromatase inhibitors, including letrozole, anastrozole, and exemestane, are being incorporated into trials evaluating their efficacy as preventive agents in women at increased risk.
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PMID:Prevention of hormone-related cancers: breast cancer. 1599 63

Hepatocellular carcinoma (HCC) is one of the most common malignancies world wide. Several experimental treatments have been tested against HCC. Those are chemotherapy, high dose proton beam radiotherapy, external beam radiotherapy, cyberknife, antibody-directed therapy and immunotherapy. Neither single nor combination therapy have demonstrated any clear reproducible benefit in terms of overall survival. Tamoxifen and antiandrogen therapy were not effective in prolonging survival when tested in randomized controlled trial. The modern radiation therapy concept such as intensity-modulated, image-guided, and stereotactic body radiation therapy may show promising effects on HCC. The increasing promise of targeted drug therapy in cancer needs to be particularly pursued in the treatment of HCC, in which cytotoxic agents are not usually effective. Other approaches include hormonal manipulation, immunotherapy, and specific inhibition of angiogenesis or growth factors. These issues stress the need for basic research in carcinogenesis in general and HCC in particular.
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PMID:[Experimental treatment of hepatocellular carcinoma]. 1584 52

Clear links have been established between occupational or therapeutic radiation exposure and breast cancer. Tamoxifen chemoprevention following radiation exposure may be able to reduce the risk of developing breast cancer later in life. In order to model carcinogenesis in this setting, an in vivo model of tamoxifen chemoprevention and tamoxifen failure in a radiation-induced rat mammary carcinoma model was characterized. Two hundred and twenty-seven 60-day-old female rats received whole body or sham exposure to ionizing radiation. Thirty days later long-term, continuous, tamoxifen chemoprevention was initiated in half the population and all animals were monitored over three and a half years for the development of mammary tumors. Mammary tumors were surgically removed and carcinomas were histologically identified and characterized. Results showed that tamoxifen chemoprevention decreased the incidence and prolonged the latency of radiation-induced mammary carcinomas. However, many individuals receiving tamoxifen chemoprevention developed their first carcinoma very late in life. These carcinomas shared morphological features distinct from the majority of carcinomas that developed in the absence of tamoxifen chemoprevention. Analyses of cell lines established from these carcinomas and immunohistochemistry of tumor sections revealed that the highest levels of Her2/neu expression were associated with in vivo tamoxifen exposure. Treatment of rat mammary carcinoma cells with an anti-rat Her2/neu monoclonal antibody (MAb 7.16.4) inhibited cell growth and this effect was more pronounced in the presence of tamoxifen. These studies suggest that carcinoma growth driven by the Her2/neu pathway may be associated with tamoxifen chemoprevention failure in the rat mammary carcinoma model. Additionally, strategies combining targeted Her2/neu antibodies, vaccines or drugs with estrogen pathway modification may be more effective in reducing breast cancer chemoprevention failures.
Carcinogenesis 2005 Sep
PMID:Tamoxifen resistance and Her2/neu expression in an aged, irradiated rat breast carcinoma model. 1586 May 8

Tamoxifen, a breast cancer drug, has recently been approved for the chemoprevention of this disease. However, tamoxifen causes hepatic carcinomas in rats through a genotoxic mechanism and increases the risk of endometrial tumors in women. DNA adducts have been detected at low levels in human endometrium, and there is much interest in determining whether DNA damage plays a role in tamoxifen-induced endometrial carcinogenesis. This study investigates the mutagenicity of tamoxifen DNA adducts formed by alpha-acetoxytamoxifen, a reactive ester producing the major DNA adduct formed in livers of tamoxifen-treated rats. pSP189 plasmid DNA containing the supF gene was treated with alpha-acetoxytamoxifen and adduct levels (0.5-8.0 adducts per plasmid) determined by (32)P-postlabeling. Adducted plasmids were transfected into nucleotide excision repair proficient (GM00637) or deficient (GM04429, XPA) human fibroblasts. After replication, plasmids were recovered and screened in indicator bacteria. Relative mutation frequencies increased with the adduct level, with 1.3-3.6-fold higher numbers of mutations in the XP cells compared to the GM00637 cells, indicating that NER plays a significant role in the removal of these particular tamoxifen DNA adducts. The majority of sequence alterations (91-96%) occurred at GC base pairs, as did mutation hotspots, although the type and position of mutations was cell-specific. In both cell lines, as the adduct level increased, the proportion of GC --> AT transitions decreased and GC --> TA transversions, mutations known to arise from the major tamoxifen adducts, increased. Given the high mutagenicity of dG-N(2)-tamoxifen adducts, if not excised, they may potentially contribute to the initiation of endometrial cancer in women.
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PMID:Mutation spectra induced by alpha-acetoxytamoxifen-DNA adducts in human DNA repair proficient and deficient (xeroderma pigmentosum complementation group A) cells. 1592 39

Tamoxifen citrate is an anti-estrogenic drug used for the treatment of breast cancer. It showed a degree of hepatic carcinogenesis, when it used for long term as it can decrease the hexose monophosphate shunt and thereby increasing the incidence of oxidative stress in liver rat cells leading to liver injury. In this study, a model of liver injury in female rats was done by intraperitoneal injection of tamoxifen in a dose of 45 mg/kg body weight for 7 successive days. This model produced a state of oxidative stress accompanied with liver injury as noticed by significant declines in the antioxidant enzymes (glutathione-S-transferase, glutathione peroxidase and catalase) and reduced glutathione concomitant with significant elevations in TBARS (thiobarbituric acid reactive substance) and liver transaminases; sGPT (serum glutamate pyruvate transaminase) and sGOT (serum glutamate oxaloacetate transaminase) levels. The oral administration of dimethyl dimethoxy biphenyl dicarboxylate (DDB) in a dose of 200 mg/kg body weight daily for 10 successive days, resulted in alleviation of the oxidative stress status of tamoxifen-intoxicated liver injury in rats as observed by significant increments in the antioxidant enzymes (glutathione-S-transferase, glutathione peroxidase and catalase) and reduced glutathione concomitant with significant decrements in TBARS and liver transaminases; sGPT and sGOT levels. The administration of DDB before tamoxifen intoxication (as protection) is more little effective than its curative effect against tamoxifen-induced liver injury. The data obtained from this study speculated that DDB can mediate its biochemical effects through the enhancement of the antioxidant enzyme activities and reduced glutathione level as well as decreasing lipid peroxides.
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PMID:The effect of dimethyl dimethoxy biphenyl dicarboxylate (DDB) against tamoxifen-induced liver injury in rats: DDB use is curative or protective. 1594 5

An increasing amount of experimental and epidemiological evidence implicates the involvement of oxygen derived radicals in the pathogenesis of cancer development. It is well known that chemical carcinogenesis is multistage process. Free radicals arefound to be involved in both initiation and promotion of multistage carcinogenesis. Tamoxifen (TAM) is a potent antioxidant and a non-steroidal antiestrogen drug most used in the chemotherapy and chemoprevention of breast cancer. Besides its anticarcinogenic potential, it also produces some adverse toxic side effects, while taken for a long time. In order to minimise the side effects and to improve the antioxidant efficacy of tamoxifen, coenzyme Q10 (CoQ10) was added. Hence the present study was designed to investigate the combined efficacy of TAM along with CoQ10 in 7, 12 dimethyl benz(a)anthracene (DMBA) induced peroxidative damage in rat mammary carcinoma. The experimental setup comprised of one control and five experimental groups and it was carried out in adult female Sprague-Dawley rats. Mammary carcinoma was induced by oral administration of DMBA (25 mg kg(-1) body wt) and the treatment was started by the oral administration of TAM (10 mg kg(-1) body wt day(-1)) and CoQ10 (40 mg kg(-1) body wt day(-1)) dissolved in olive oil and continued for 28 days. Rats induced with DMBA showed a decline in the thiol capacity of the cell accompanied by high malondialdehyde content levels along with lowered activities of antioxidant status (superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione). In contrast, glutathione metabolising enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase) were increased significantly in chemically induced carcinoma bearing rats. Administration of TAM along with CoQ10 restored the activities to a significant level thereby preventing cancer cell proliferation. This study highlights the increased antioxidant enzyme activities in relation to the susceptibility of cells to carcinogenic agents and the response of tumour cells to the chemotherapeutic agents.
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PMID:Combined efficacy of tamoxifen and coenzyme Q10 on the status of lipid peroxidation and antioxidants in DMBA induced breast cancer. 1601 50

Tamoxifen citrate (TAM), is widely used for treatment of breast cancer. It showed a degree of hepatic carcinogenesis. The purpose of this study was to elucidate the antioxidant capacity of green tea (Camellia sinensis) extract (GTE) against TAM-induced liver injury. A model of liver injury in female rats was done by intraperitoneal injection of TAM in a dose of 45mg Kg(-1) day(-1), i.p. for 7 successive days. GTE in the concentration of 1.5 %, was orally administered 4 days prior and 14 days after TAM-intoxication as a sole source of drinking water. The antioxidant flavonoid; epicatechin (a component of green tea) was not detectable in liver and blood of rats in either normal control or TAM-intoxicated group, however, TAM intoxication resulted in a significant decrease of its level in liver homogenate of tamoxifenintoxicated rats. The model of TAM-intoxication elicited significant declines in the antioxidant enzymes (glutathione-S-transferase,glutathione peroxidase, superoxide dismutase and catalase) and reduced glutathione concomitant with significant elevations in TBARS (thiobarbituric acid reactive substance) and liver transaminases; sGPT (serum glutamate pyruvate transaminase) and sGOT (serum glutamate oxaloacetate transaminase) levels. The oral administration of 1.5 % GTE to TAM-intoxicated rats, produced significant increments in the antioxidant enzymes and reduced glutathione concomitant with significant decrements in TBARS and liver transaminases levels. The data obtained from this study speculated that 1.5 % GTE has the capacity to scavenge free radical and can protect against oxidative stress induced by TAM intoxication. Supplementation of GTE could be useful in alleviating tamoxifen-induced liver injury in rats.
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PMID:Hepatoprotective effect of green tea (Camellia sinensis) extract against tamoxifen-induced liver injury in rats. 1620 36

Tamoxifen, a selective oestrogen receptor modulator, has been used in the treatment of all stages of hormone-responsive breast cancer. However, tamoxifen shows partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial cancer. The molecular explanation for these observations is not known. Here we show that tamoxifen and oestrogen have distinct but overlapping target gene profiles. Among the overlapping target genes, we identify a paired-box gene, PAX2, that is crucially involved in cell proliferation and carcinogenesis in the endometrium. Our experiments show that PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and that this activation is associated with cancer-linked hypomethylation of the PAX2 promoter.
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PMID:Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. 1635 16


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