三苯氧胺与脂肪性肝病

三苯氧胺用于雌激素受体阳性乳腺癌患者的内分泌治疗效果肯定，但长期应用可诱发脂肪性肝病。其机制包括药物聚集于肝细胞线粒体、脂肪酸氧化异常、雌激素拮抗作用等。对服用三苯氧胺的乳腺癌患者需定期监测肝功能、血脂、超声及CT等。可选择托瑞米芬、芳香化酶抑制剂替代治疗及应用降脂药物等进行防治。     

三苯氧胺对子宫内膜的致癌作用

三苯氧胺作为乳腺癌等治疗的有效药物,长期服用后其雌激素样作用可使子宫内膜增生及子宫内膜癌发病率增加,应对用三苯氧胺治疗的病人定期检查。     

三苯氧胺子对宫内膜的致癌作用

三苯氧胺作为乳腺癌等治疗的有效药物，长期服用后其雌激素样作用可使子宫内膜增生及子宫内膜癌发病率增加，应对用三苯氧胺治疗的病人定期检查。     

三苯氧胺抗肿瘤的分子生物学机制

三苯氧胺是临床上常用的雌激素受体拮抗剂，临床内分泌治疗一部分雌激素受体阳性乳腺癌能够明显提高肿瘤局部控制率和患者生存率。但是仍有部分乳腺癌患者对三苯氧胺治疗无效或耐受。本文从分子生物学水平就三苯氧胺的抗肿瘤机制及耐受原因进行了综述。     

绝经前女性乳腺癌辅助内分泌治疗选择策略

0 引言 我国女性乳腺癌患者50％以上属于绝经前,因为国人乳腺癌发病年龄高峰在45～49岁.虽然绝经前乳腺癌患者激素受体阳性的比例略低(大约60％),但适合选择内分泌治疗病例的绝对数则多于绝经后患者.绝经前女性乳腺癌患者内分泌治疗的主要手段包括雌激素受体选择性调节剂三苯氧胺( tamoxifen,TAM)、卵巢功能抑制(包括手术、放射或药物去势)及卵巢功能抑制联合三苯氧胺,芳香化酶抑制剂(AI)必须联合卵巢去势.     

三苯氧胺在乳腺癌治疗中的应用

自1966年首次生产出三苯氧胺(tamoxifen)新型抗雌激素药物后,从70年代初开始已越来越多地用于治疗乳腺癌。本文就近年来对三苯氧胺治疗乳腺癌的研究情况综述如下。 一、三苯氧胺的作用机理 三苯氧胺治疗乳腺癌的作用有激素相关和非激素相关两方面的机理。三苯氧胺及其代谢物能通过阻断雌激素与其受体结合而发挥抗雌激素作用。雌激素和靶细胞核的受体蛋白结合后刺激细胞生长,增加细胞自身分泌生长因子(TGF-α)和其它蛋白,     

三苯氧胺对子宫内膜癌的潜在致癌作用机制

三苯氧胺是一种具有抗雌激素作用的非甾体类化合物,已成为各期乳腺癌患者的一线内分泌治疗药物。但最新的临床研究表明,使用三苯氧胺作为辅助治疗的乳腺癌患者并发子宫内膜癌的危险性增加。通常认为,三苯氧胺在乳腺组织中具有抗雌激素作用,但是在子宫内膜细胞中却表现出类雌激素作用。越来越多的临床试验正聚焦于三苯氧胺与子宫内膜癌的关系,三苯氧胺对子宫内膜的潜在致癌作用机制也成为当前研究的一项热点。     

女性乳腺癌患者三苯氧胺治疗后血清雌二醇浓度的变化

三苯氧胺（Ｔａｍｏｘｉｆｅｎ）作为一种非甾类雌激素拮抗剂已广泛应用于乳腺癌的内分泌治疗。但在临床应用中它又表现出类雌激素效应。我们应用放射免疫法监测了５３例女性乳腺癌患者接受三苯氧胺治疗后血清雌二醇（ｅｓｔｒａｄｉｏｌＥ２）浓度变化,报告如下：一般资...     

乳癌术后长期服用三苯氧胺发生子宫内膜癌

三苯氧胺常作为乳癌术后辅助内分泌治疗药物之一,亦用于子宫内膜癌治疗。但Fornander等报告,乳癌术后单独采用三苯氧胺,子宫内膜癌发生率增加。因此,对闭经后乳癌术后患者单独应用三苯氧胺时,应常规作子宫内膜细胞学诊断,以确认三苯氧胺是否具有雌激素样作用。作者首先报告4例乳癌术后长期服用三苯氧胺患者(服用时间2～8年)而发生子宫内膜癌,推测三苯氧胺长期服用引起雌激素     

乳腺癌的内分泌治疗

乳腺癌是对内分泌治疗很敏感的为数不多的人类肿瘤之一,治疗的反应率与雌激素受体及孕激素受体状况有关.乳腺癌内分泌治疗多用于晚期病人的治疗,亦用于具有高复发危险的早期病人的辅助治疗,局部晚期患者的新辅助治疗及激素药物预防.可采用摘除内分泌器官的方法,如卵巢切除,肾上腺切除,垂体切除;然而,具有同样效果的药物治疗应用越来越多.肾上腺切除,垂体切除已被放弃,抗雌激素三苯氧胺为最常使用,且一直作为内分泌治疗的一线药物,但最近新的无雌激素样作用的抗雌激素制剂,新的选择性芳香化酶抑制剂,促性腺激素释放激素类似物正在取代三苯氧胺作为一线治疗的地位.     

The role of tamoxifen in the treatment and prevention of breast cancer.

Tamoxifen is a nonsteroidal antiestrogen that has found successful applications for each stage of breast cancer in the treatment of selected patients. Tamoxifen was originally introduced for the treatment of advanced disease in postmenopausal women; however, the drug is now also available for the palliative treatment of premenopausal women with estrogen receptor (ER) positive disease. The proven efficacy of tamoxifen and the low incidence of side effects made the drug an ideal agent to test as an adjuvant therapy for women with node-positive breast cancer. Laboratory studies indicate that long-term treatment schedules may provide maximal benefit in preventing recurrence, and recent analysis of clinical trials demonstrates that between 2 and 5 years of adjuvant tamoxifen therapy provides a survival advantage for postmenopausal women with node-positive disease. Similarly, adjuvant studies in node-negative breast cancer have demonstrated an increase in the disease-free survival of both pre- and postmenopausal patients with ER-positive tumors. However, the extended use of tamoxifen has raised questions about the long-term safety of antiestrogen therapy. Of special concern is the impact of tamoxifen on ovarian function in premenopausal women and the potential risks to the fetus if pregnancy occurs. Fortunately, there are no reports about the teratogenicity of tamoxifen in the human, but it is important that physicians counsel women about the risk of pregnancy. Tamoxifen should not be used if a patient is pregnant. Initial concerns that the long-term administration of an antiestrogen would increase bone loss and increase the risks of coronary heart disease appear to be unwarranted. Tamoxifen has some estrogen-like activities in postmenopausal women and causes a preservation of bone in the lumbar spine and a decrease in circulating cholesterol. Indeed, a reduction in fatal myocardial infarction (MI) has been noted during 5 years of tamoxifen therapy, possibly the direct result of a prolonged reduction in circulating cholesterol. However, the estrogen-like qualities of tamoxifen that could be valuable as a hormone replacement therapy for all postmenopausal women following a diagnosis of breast cancer may also increase the risk for developing endometrial carcinoma. To date, there are only a few reports of endometrial carcinoma being diagnosed during adjuvant therapy with tamoxifen; however, any instances of uterine bleeding or spotting should be followed up with an endometrial biopsy. There are some concerns about large doses of tamoxifen promoting liver cancer in rats. These results are of particular concern if tamoxifen is to be used as a preventive in normal women.(ABSTRACT TRUNCATED AT 400 WORDS)     

Tamoxifen in liver disease: Potential exacerbation of hepatic dysfunction

Tamoxifen, a non-steroidal anti-estrogen, has been used successfully for a decade as post-operative adjuvant therapy for breast cancer. Tamoxifen is generally well tolerated with few side effects, especially at the typical dose of 10 mg twice daily. However, hepatic effects have been reported after tamoxifen administration and are usually found to be cholestatic in nature. Although previous reports concentrate on tamoxifen as a probable cause of drug-induced hepatotoxicity, very little attention has been focused on the use of tamoxifen in patients with pre-existing liver dysfunction and the possible need for dose adjustment. We present the case of a 48-year-old woman with an acute exacerbation of her pre-existing liver dysfunction and subsequent elevations of tamoxifen blood levels after approximately one year of tamoxifen therapy for adjuvant treatment of breast cancer. Tamoxifen dosing was adjusted based on serum levels.     

Long-term adjuvant tamoxifen therapy for breast cancer

Tamoxifen (ICI46,474) is a competitive inhibitor of estrogen action which has found ubiquitous application in the treatment of breast cancer. The drug is the front line endocrine therapy for breast cancer and is the proven treatment of choice for the adjuvant therapy of postmenopausal women with node-positive disease. Tamoxifen is available for the treatment of premenopausal patients with advanced disease, and is being evaluated in clinical trials as an adjuvant therapy for premenopausal patients with either node-positive or node-negative disease. Laboratory studies demonstrate that tamoxifen is a tumoristatic agent and long-term treatment strategies (chemosuppression) should be considered to apply the antiestrogen to its maximal therapeutic advantage. Optimal therapy with tamoxifen may also be achieved by treatment strategies to lower circulating estrogen levels in the premenopausal patient.Tamoxifen is a well tolerated drug, and long-term therapy does not appear to induce metabolic tolerance. Concerns about premature osteoporosis or cardiovascular disease appear to be unfounded because tamoxifen has an appropriate level of target site-directed estrogenic activity. Isolated reports about the growth or appearance of endometrial carcinoma during long-term adjuvant tamoxifen therapy must be balanced against the risks of withholding treatment to patients with a fatal disease.     

A prospective,randomized study on hepatotoxicity of anastrozole compared with tamoxifen in women with breast cancer

Tamoxifen and anastrozole are widely used as adjuvant treatment for early stage breast cancer, but their hepatotoxicity is not fully defined. We aimed to compare hepatotoxicity of anastrozole with tamoxifen in the adjuvant setting in postmenopausal breast cancer patients. Three hundred and fifty‐three Chinese postmenopausal women with hormone receptor‐positive early breast cancer were randomized to anastrozole or tamoxifen after optimal primary therapy. The primary end‐point was fatty liver disease, defined as a liver–spleen ratio <0.9 as determined using a computed tomography scan. The secondary end‐points included abnormal liver function and treatment failure during the 3‐year follow up. The cumulative incidence of fatty liver disease after 3 years was lower in the anastrozole arm than that of tamoxifen (14.6% vs 41.1%, P < 0.0001; relative risk, 0.30; 95% CI, 0.21–0.45). However, there was no difference in the cumulative incidence of abnormal liver function (24.6% vs 24.7%, P = 0.61). Interestingly, a higher treatment failure rate was observed in the tamoxifen arm compared with anastrozole and median times to treatment failure were 15.1 months and 37.1 months, respectively (P < 0.0001; HR, 0.27; 95% CI, 0.20–0.37). The most commonly reported adverse events were ‘reproductive system disorders’ in the tamoxifen group (17.1%), and ‘musculoskeletal disorders’ in the anastrozole group (14.6%). Postmenopausal women with hormone receptor‐positive breast cancer receiving adjuvant anastrozole displayed less fatty liver disease, suggesting that this drug had a more favorable hepatic safety profile than tamoxifen and may be preferred for patients with potential hepatic dysfunction.     

Tamoxifen-induced severe hypertriglyceridemia--report of 3 cases

Tamoxifen, an anti-estrogen, has been used for a long time as an adjuvant therapy in cases of estrogen receptor positive breast cancer. Tamoxifen also demonstrates some weak estrogenic activity. A small increase in serum triglycerides is commonly found after tamoxifen administration. Herein we report 3 cases of sever hypertriglyceridemia due to tamoxifen. Case 1 recovered with tamoxifen withdrawal. Tamoxifen was replaced with toremifene in case 2. The level of triglyceride decreased significantly after the change of agent. Tamoxifen was discontinued and anastrozole administration was started in the third patient. Her triglyceride levels improved. Tamoxifen-induced severe hypertriglyceridemia seen in these patients was an effect of its estrogen action. Anastrozole has been used to treat postmenopausal metastatic breast cancer, and several clinical trials in the adjuvant setting are ongoing. Anastrozole does not affect lipid metabolism. Therefore, anstrozole might be safe for patiens with abnormal triglyceride profiles during tamoxifen treatment. We recommended that a periodic serum triglyceride check is needed for patients treated with tamoxifen.     

托瑞米芬和他莫昔芬对血脂影响的对比研究

目的　探讨托瑞米芬 (TOR)在乳腺癌术后辅助治疗中对血脂的影响程度。方法　 10 3例乳腺癌患者分为治疗组和对照组。治疗组包括TOR组和TAM组 ,TOR组口服TOR 60mg/天 ,TAM组口服TAM 2 0mg/天。在内分泌治疗前 ,治疗 3、6、9和 12个月后 ,分别晨取患者空腹静脉血进行血脂检测。结果　TOR治疗组血总胆固醇平均水平下降 11.0 % ,S LDL平均水平下降 11.1% ,血甘油三酯平均水平下降 10 .7% ;TAM治疗组血总胆固醇平均水平下降 9.0 % ,S LDL平均水平下降 17.4% ,而血甘油三酯水平无明显变化 (P =0 .491)。结论　TOR对血脂的影响程度与TAM相近 ,2组血总胆固醇和S LDL平均水平均较治疗前下降。不同的是 ,TOR治疗组血甘油三酯水平下降 ,而TAM治疗组无明显变化。提示TOR可影响与冠心病发病相关的血脂水平。     

Eicosapentaenoic acid restores tamoxifen sensitivity in breast cancer cells with high Akt activity.

BACKGROUND: Tamoxifen resistance is the underlying cause of treatment failure in a significant number of patients with breast cancer. Activation of Akt, a downstream mediator in the phosphatidylinositol 3-kinase (PI3K) signaling pathway has been implicated as one of the mechanisms involved in tamoxifen resistance. Breast cancers with heightened Akt activity are frequently associated with an aggressive disease and resistance to chemo- and hormone-therapy-induced apoptosis. Inhibition of PI3K restores apoptotic response to tamoxifen in hyperactive Akt cells. Therefore, agents that demonstrate Akt inhibitory properties are attractive therapeutic agents for the treatment of hormone-resistant breast cancer. n-3 fatty acids have proven to be potent and efficacious broad-spectrum protein kinase inhibitors. MATERIALS AND METHODS: In this study we demonstrate that the n-3 fatty acid, eicosapentaenoic acid (EPA), inhibits the kinase activity of Akt. Co-treatment with EPA renders breast cancer cells that overexpress a constitutively active Akt more responsive to the growth inhibitory effects of tamoxifen by approximately 35%. CONCLUSIONS: These findings suggest that EPA may be useful for the treatment of tamoxifen-resistant breast cancer cells with high levels of activated Akt and provide the rationale to test this hypothesis in the clinic.     

Salubrious effect of vitamin C and vitamin E on tamoxifen-treated women in breast cancer with reference to plasma lipid and lipoprotein levels

Tamoxifen, a non-steroidal antiestrogen, has been used in the hormonal treatment for breast cancer. The hepatic estrogenic effect of tamoxifen causes severe triglyceridemia. The combined effect of tamoxifen, vitamin C and vitamin E on plasma lipid and lipoprotein is important, since, vitamin C and vitamin E encumbered the lipid abnormalities instigated by tamoxifen. Therefore supplementation of vitamin C (Celin 500 mg) and vitamin E (Evion 400 mg) for 90 days along with tamoxifen (10 mg twice a day) to postmenopausal breast cancer patients was ventured. In tamoxifen-treated patients, total cholesterol (TC), free cholesterol (FC), phospholipids (PL), free fatty acids (FFA), low density lipoprotein cholesterol (LDL) levels were decreased and the triglycerides (TG), ester cholesterol (EC), high density lipoprotein cholesterol (HDL) and very low density lipoprotein cholesterol (VLDL) levels were increased. Combination therapy reduce all the cholesterol level and VLDL, LDL. TG levels were significantly decreased and HDL, EC levels were significantly increased. These results suggested that tamoxifen treatment is the most effective during co-administration of vitamin C and vitamin E in that they reduce the tamoxifen-induced hypertriglyceridemia.     

Tamoxifen induces endometrial and vaginal cancer in rats in the absence of endometrial hyperplasia

Tamoxifen was administered orally to neonatal rats on days 2-5 after birth and the subsequent effects on the uterus were characterized, morphometrically, over the following 12 months. Tamoxifen inhibited development of the uterus and glands in the endometrium, indicating a classical oestrogen antagonist action. Between 24 and 35 months after tamoxifen treatment there was a significant increase in the incidence (26%) of uterine adenocarcinomas and a 9% incidence of squamous cell carcinomas of the vagina/cervix in the absence of any oestrogen agonist effect in the uterus. This demonstrates that an oestrogen agonist effect is not an absolute requirement for the carcinogenic effect of tamoxifen in the reproductive tract of the rat. The unopposed oestrogen agonist effect of tamoxifen on the endometrium may not be the only factor involved in the development of endometrial cancers. It is possible that tamoxifen causes these tumours via a genotoxic mechanism similar to that seen in rat liver. However, using (32)P-post-labelling we failed to find evidence of tamoxifen-induced DNA adducts in the uterus. Tamoxifen may affect hormonal imprinting of oestrogen receptor responses in stem cells of the uterus, causing reproductive tract cancers to arise at a later time, in the same way as has been proposed for diethylstilbestrol. If these rodent data extrapolate to humans, then women who are taking tamoxifen as a chemopreventative may have an increased risk of vaginal/cervical cancer, as well as endometrial cancer.