Molecular mechanisms of antiestrogen action in breast cancer

The success of antiestrogen therapy to treat all stages of breast cancer, and the evaluation of tamoxifen as a preventive for breast cancer in normal women, have focused attention on the molecular mechanisms of antiestrogen action and mechanisms of drug resistance. The overall goal of research is to enhance current therapies and to develop new approaches for breast cancer treatment and prevention. Recent studies show that tamoxifen and the new pure antiestrogens appear to have different mechanisms of action: tamoxifen and related compounds cause a change in the folding of the steroid binding domain that prevents gene activation whereas the pure antiestrogens cause a reduced interaction at response elements and cause a rapid loss of receptor complexes. Tamoxifen treatment produces changes in the cellular and circulating levels of growth factors that could influence both receptor negative or receptor positive tumor growth and the metastatic potential of a tumor. These events may explain the survival advantage observed with tamoxifen therapy. However, the current therapeutic challenge is to avoid drug resistance during long-term tamoxifen therapy. Numerous explanations for drug resistance to tamoxifen have been suggested, including elevated estrogen levels, increased tumor antiestrogen binding sites, receptor mutations, and impaired signal transduction. However, it is probable that multiple mechanisms evolve to facilitate tumor survival. Most importantly, current research is examining mechanisms responsible for the beneficial actions of tamoxifen on bones and lipids as well as the potentially deleterious effects of tamoxifen on liver and endometrial carcinogenesis and retinopathy. The urgent need to understand antiestrogenic drug mechanisms and toxicity is being facilitated by the application of the technology developed for basic molecular biology.     

右美托咪定对乳腺癌根治术后患者苏醒及免疫功能的影响

目的探讨右美托咪定对乳腺癌根治术后患者苏醒及免疫功能的影响。方法选取2014年2月至2016年6月间在广东省第二人民医院行乳腺癌根治术的86例乳腺癌患者,采用随机数表法分为观察组和对照组,每组43例。两组患者均给予舒芬太尼及顺式阿曲库铵诱导全身麻醉,观察组患者于麻醉诱导前30min静脉给予0.5μg/kg的右美托咪定,并持续至麻醉诱导插管,对照组患者给予等量的生理盐水。观察并比较两组患者术后睁眼时间和拔管时间,采用Riker镇静躁动评分及Ramsay镇静评分评价患者镇静和躁动程度,采用流式细胞术检测术前(T_0)、手术开始2 h(T_2)、术后24 h(T_(24))及术后72h(T_(72))的全血CD3~+、CD4~+、CD8~+和自然杀伤细胞(NK)水平,采用酶联免疫吸附测定(Elisa)法检测两组血清应激指标脂质过氧化物(LPO)、皮质醇(Cor)、促肾上腺皮质激素(ACT_H)及醛固酮(ALD)水平并进行比较。结果观察组患者的睁眼时间和拔管时间显著低于对照组患者,差异有统计学意义(P<0.05)。观察组患者的Riker镇静躁动评分高于对照组患者,Ramsay镇静评分均低于对照组患者,差异均有统计学意义(均P<0.05)。在T_2、T_(24)和T_(72)时,观察组患者的CD3~+、CD4~+、CD8~+和NK细胞水平显著高于对照组患者,差异均有统计学意义(均P<0.05)。T_2、T_(24)和T_(72)时,观察组患者的LPO、Cor、ACT_H和ALD水平均显著低于对照组患者,差异均有统计学意义(均P<0.05)。结论右美托咪定应用于乳腺癌根治术后患者可加速患者的苏醒,改善镇静和躁动程度,减轻免疫抑制和应激反应。     

Effects of SP500263, a novel, potent antiestrogen, on breast cancer cells and in xenograft models

We have compared the antitumor activities of SP500263, a novel next-generation selective estrogen receptor modulator (SERM), tamoxifen, and raloxifene side-by-side in in vitro and in vivo MCF-7 breast cancer models. In vitro, SP500263 acted as an antiestrogen and potently inhibited estrogen-dependent MCF-7 proliferation with IC(50) values in the nanomolar range. SP500263 also strongly inhibited MCF-7 proliferation in the absence of estrogen at all of the concentrations tested. To investigate the antitumor activity of SP500263 in animals, athymic nude mice were implanted with MCF-7 tumor in the presence of a tumor growth-supporting sustained release estrogen pellet. Treatment was initiated after tumors were established. SP500263, administered for 28 days through daily i.p. dosing, effectively reduced estrogen-stimulated tumor growth at 3 and 30 mg/kg. SP500263 was as efficacious as tamoxifen and superior to raloxifene at the corresponding doses. Maximum efficacy was reached with the 30 mg/kg dose. The observed effects were highly significant. SP500263 represents a member of a novel series of SERMs that is structurally unrelated to SERMs currently on the market or in clinical development. The experiments described herein demonstrate that SP500263 is efficacious in the MCF-7 proliferation assay and in a murine model of breast cancer.     

Assessment of host immune response in breast cancer patients

Cell-mediated immune status of breast cancer patients was evaluated by percentage of T gamma cells, natural killer (NK) activity, and the augmentation of NK cells by interferon. The patients with breast cancer did not show impaired cell-mediated immune responses until they were in the late stage of cancer. Sixty-one patients with breast cancer revealed higher proportions of T gamma cells measured by a new method utilizing microplate compared with those of 50 healthy subjects. Reduced NK activity was seen in the patients with stage III or IV breast cancer. Natural cytotoxicity against K-562 target cells was strongly augmentated by treatment with interferon in vitro for 2 hr, both in the patients with breast cancer and in healthy donors, except for far advanced breast cancer patients. A negative correlation between the percentage of T gamma cells and T cell was significant in the patients with primary breast cancer prior to radical mastectomy.     

Benign hepatic cyst in a patient on antiestrogen therapy for metastatic breast cancer

Tamoxifen is a useful agent in the management of metastatic breast cancer. We describe a patient who was treated sucessfully with Tamoxifen but developed a benign but symptomatic hepatic cyst during treatment. Development of a solitary hepatic lesion during Tamoxifen therapy should be thoroughly investigated before treatment is changed. Cancer 50:1882-1883, 1982.     

Steroid receptor-mediated cytotoxicity of an antiestrogen and an antiprogestin in breast cancer cells

The antiproliferative and cytotoxic effects of 4-hydroxytamoxifen, an antiestrogen with a high affinity for the estrogen receptor, and of 17 beta-hydroxy-11 beta-(4-methylaminophenyl)-17-(1-propynyl)estra-4,9-dien-3- one-6-7 (RU486), an antiprogestin with a high affinity for the progestin receptor, have been studied on human breast cancer cell lines in culture. The number of dead cells was evaluated by several techniques (trypan blue stain exclusion, DNA cleavage, lactic dehydrogenase activity, morphological changes, and cloning efficiency in soft agar) and found to be increased both by the antiestrogen and the antiprogestin at concentrations correlating with the affinities for their respective receptors. This cytotoxic effect was prevented by the occupation of the respective receptors with estrogen and progestin and was not found in the estrogen receptor- and progestin receptor-negative MDA MB 231 and BT20 cell lines. The contrast between the ultrastructural modifications of chromatin and the integrity of mitochondria suggested that the antihormone-induced cell death was by apoptosis. We conclude that in addition to the receptor-mediated cytostatic activity and the nonspecific cytotoxic activity, antiestrogens trigger a third type of effect that we designate as "receptor-mediated cytotoxic." Similar conclusions can be drawn for the antiprogestin RU486, indicating moreover that the antihormone and antiproliferative activities of this drug are clearly dissociated. The mechanism of these receptor-mediated cytotoxic activities of antiestrogen and antiprogesterone is not known but does not seem to be explained entirely by the antihormone activity of these drugs.     

麻醉药物对围术期癌症患者免疫功能的影响

癌症引起的免疫抑制可加速癌细胞的扩散和转移,导致围术期癌症患者病情进一步恶化。手术作为治疗癌症的重要手段在临床中应用广泛,但手术引起的过度应激反应同样会引起免疫抑制。麻醉药物可抑制围术期内由手术创伤及疼痛导致的过度应激反应,但同时又直接或间接地影响着人体的免疫功能。本文将回顾不同麻醉药物与围术期癌症患者免疫功能之间的关系,为临床治疗提供依据。     

中药配合化疗对乳腺癌患者术后细胞免疫功能和生存质量的影响

目的探讨疏肝健脾与扶正消瘀汤配合化疗对乳腺癌术后患者胃肠功能、细胞免疫及生存质量的影响。方法选取2017年8月至2018年8月间荆州市中医医院收治的114例乳腺癌患者,采用随机数字表法分为观察组和对照组,每组57例。对照组患者采用常规化疗治疗,观察组患者在对照组基础上配以疏肝健脾与扶正消瘀汤治疗,比较两组患者术后胃肠功能、细胞免疫功能和生存质量。结果观察组患者胃肠功能改善情况优于对照组,总有效率为93. 0%,优于对照组患者的78. 9%,差异有统计学意义(P <0. 05)。治疗后,观察组患者CD3~+、CD4~+水平和CD4~+/CD8~+较治疗前升高,CD8~+水平较治疗前降低,对照组患者的CD3~+和CD4~+水平较治疗前降低,CD8~+水平和CD4~+/CD8~+较治疗前无明显变化,但组间比较,差异均有统计学意义(P <0. 05)。治疗后,观察组患者的社会功能、情绪功能、躯体功能、呕吐恶心、疲劳评分和总健康评分均优于对照组,差异均有统计学意义(P <0. 05),而两组患者认知功能、角色功能及疼痛评分比较,差异均无统计学意义(P>0. 05)。结论乳腺癌患者术后化疗阶段配以疏肝健脾与扶正消瘀汤,可有效改善患者胃肠功能及细胞免疫功能,提高生存质量,值得临床应用。     

Changes in vascularization of human breast cancer xenografts responding to antiestrogen therapy

To elucidate the previously suggested vascular effect(s) of antiestrogen therapy, we studied the effect of estrogen withdrawal and tamoxifen on 1) vascular resistance, 2) glucose and oxygen consumption, and 3) vascular density in a perfused breast cancer line (ZR75-1). Furthermore, we examined ZR75-1 tumors by functional CT-scanning (fCT) to determine changes in parameters related to tumor capillary transfer constants and vascular volume fraction in response to antiestrogenic manipulations. The vascular resistance decreased significantly from 42.7 to 20.8 mmHg x min x g x ml^-1 (P< .03) on day 9 after estrogen withdrawal, but not after 9 days of tamoxifen treatment. The estrogen-depleted tumors were significantly smaller than controls on day 9. There was no difference in nutrient consumption or vascular density in any of the experimental groups compared to controls. fCT showed an increase (P < .03) in vascular volume fraction during tumor growth, and this parameter was significantly lower after estrogen withdrawal when compared to controls (P < .05). Vascular resistance correlated with tumor size (R = 0.7, P < .0001), indicating that vascular resistance increases during tumor growth. The changes in vascular parameters after estrogen withdrawal indicate a vascular remodeling effect. This inhibition of vascular development by hormone deprivation may have important implications for future planning of multimodal treatment regimens.     

Current status of high dose progestin treatment in advanced breast cancer

Progestins, especially high dose medroxyprogesterone acetate, are receiving renewed attention in treatment of advanced breast cancer. The trials reviewed here indicate that such regimens may be as effective as tamoxifen in postmenopausal unselected cases, and that they may be effective as second-line treatment in patients resistant to tamoxifen and/or to cytotoxic chemotherapy.     

Droloxifene,a new antiestrogen: Its role in metastatic breast cancer

Droloxifene, a new antiestrogen, has theoretical advantages over tamoxifen based on preclinical data. These include higher affinity to the estrogen receptor, higher antiestrogenic to estrogenic ratio, and more effective inhibition of cell growth and division in ER positive cell lines, as well as less toxicity, including reduced carcinogenicity in animal models. Droloxifene also exhibits more rapid pharmacokinetics, reaching peak concentrations and being eliminated much more rapidly than tamoxifen. A phase II study compared droloxifene in dosages of 20, 40, and 100 mg daily in postmenopausal women with metastatic, or inoperable recurrent, or primary locoregional breast cancer who had not received prior hormonal therapy. Of 369 patients randomized, 292 were eligible and 268 evaluable for response. Response rates (CR + PR) were 30% in the 20 mg group, 47% in the 40 mg group, and 44% in the 100 mg group (40 mg vs 20 mg, p = 0.02; 100 mg vs 20 mg, p = 0.04; pooled 40 + 100 mg vs 20 mg, p = 0.01). Median response duration also favoured the higher dosages (20 mg group = 12 months; 40 mg group = 15 months; 100 mg group = 18 months). When adjusted for prognostic factors, time to progression was significantly better for the 100 mg (p = 0.01) and the 40 mg (p = 0.02) group compared to the 20 mg group. Droloxifene increased SHBG and suppressed FSH at all dosages and suppressed LH at the 40 and 100 mg dosages. These hormonal effects increased with increasing dosage. Shortterm toxicity was generally mild, and similar to that seen with other antiestrogens. Droloxifene appears active and tolerable. It may have a particular role in situations in which rapid pharmacokinetics, or an increased antiestrogenic to estrogenic ratio, are required.