他莫西芬联合十一酸睾酮治疗特发性少精及弱精子症的临床观察

目的探讨他莫西芬和十一酸睾酮联合应用对男性特发性少精、弱精症精液参数及生殖激素水平的影响。方法将60例特发性少弱精症患者随机分成Tc组、Tu组及TT组,各20例。分别接受他莫西芬、十一酸睾酮、他莫西芬和十一酸睾酮联合应用,于1个月、3个月取患者精液分别进行精子形态学分析,检测精子数量（密度）、精子活力（a＋b百分率）及血清中FSH、LH、T水平。结果治疗1个月后,他莫西芬和十一酸睾酮联合应用组（TT组）精子的数量、活力及功能明显改善,血清中FSH、LH水平升高,T水平变化不大;3个月后,精子的数量,活力及功能等显著提高,血清中FSH、LH、T水平明显升高,均显著优于Tc组及Tu组（P〈0.01或P〈0.05）。结论他莫西芬与十一酸睾酮联合应用能够显著提高特发性少弱精症患者精液主要参数,改善生殖激素水平。     

乳核散结片联合三苯氧胺 维生素E治疗乳腺囊性增生病

目的探讨乳核散结片联合三苯氧胺、维生素E治疗乳腺囊性增生病的疗效。方法收集本所265例乳腺囊性增生病患者,随机分为治疗组（乳核散结片联合三苯氧胺、维生素E）,对照组（三苯氧胺、维生素E）,疗程均为8周,观察其临床疗效。结果治疗组的总有效率为91．7％,对照组的总有效率为75．8％（P〈0．05）。结论乳核散结片联合三苯氧胺、维生素E治疗乳腺囊性增生病比三苯氧胺加维生素E疗效更显著。     

The Role of ErbB3 and its Binding Partners in Breast Cancer Progression and Resistance to Hormone and Tyrosine Kinase Directed Therapies

An increasingly important role for the ErbB3 receptor in the genesis and progression of breast cancer is emerging. ErbB3 is frequently overexpressed in breast cancer and coexpression of ErbB2/3 is a poor prognostic indicator. ErbB3 has also been implicated in the development of resistance to antiestrogens such as tamoxifen and ErbB tyrosine kinase inhibitors such as gefitinib. Persistent activation of the AKT pathway has been postulated to contribute to ErbB3-mediated resistance to these therapies. This activation may be due in part to the inappropriate production of the ErbB3 ligand heregulin. ErbB3 binding proteins, which negatively regulate ErbB3 protein levels and the ability of ErbB3 to transmit proliferative signals, also contribute to breast cancer progression and treatment resistance. These proteins include the intracellular RING finger E3 ubiquitin ligase Nrdp1 and the leucine-rich protein LRIG-1 that mediate receptor degradation. Ebp1, another ErbB3 binding protein, suppresses HRG driven breast cancer cell growth and contributes to tamoxifen sensitivity. These studies point to the importance of the evaluation of protein levels and functional activity of ErbB3 and its binding proteins in breast cancer prognosis and prediction of clinical response to treatment.     

Profiles of tamoxifen-related side effects by race and smoking status in women with breast cancer

Background: Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) that is widely used as adjuvant therapy in breast cancer patients; however, it is also associated with undesirable side effects. The goal of this study was to investigate TAM-related side effects, and determine profiles of side effects by race and by smoking status. Methods: A secondary data analysis was conducted using cross-sectional study data from 138 African American and Caucasian women with breast cancer taking TAM 20 mg daily for at least 30 days prior to enrollment. Participants completed questionnaires that obtained information about demographic characteristics, reproductive history, health and lifestyle characteristics, TAM use and its related side effects. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals. Results: Compared to never smokers, a significantly greater percentage of current smokers reported ever experiencing TAM-related nausea (28.0% versus 5.0%, P = 0.007), depression (40.0% versus 7.1%, P = 0.001) and migraines (19.2% versus 1.7%, P = 0.02). These differences remained statistically significant after controlling for race, age, obesity, tumor stage, and duration of TAM treatment. No significant differences by race were noted in women reporting TAM side effects. Conclusion: The findings from this study suggest that current smokers with breast cancer should be informed of the increased probability of reporting TAM-related side effects such as nausea, depression and migraines, and counseled about smoking cessation which may reduce the incidence of these side effects.     

The prevention and management of distant metastases in women with breast cancer

About one-third of all women diagnosed with breast cancer face the risk of recurrence, which can occur at any stage of disease, observation time, and after any treatment modality. Most recurrence comes in the form of distant metastasis, which is the major cause of death in women with breast cancer. Treatments shown to decrease the risk of breast cancer recurrence, especially distant metastasis, will likely produce a survival benefit and a potentially significant improvement in quality of life in women with early breast cancer. New third-generation aromatase inhibitors (anastrozole, exemestane, and letrozole) that have been shown to be well tolerated have the potential to contribute to benefits beyond those seen with tamoxifen.     

Tamoxifen effect on L-DOPA induced response complications in parkinsonian rats and primates

The contribution of striatal protein kinase C (PKC) isoform changes in levodopa (L-DOPA) induced motor response complications in parkinsonian rats was investigated and the ability of tamoxifen, an antiestrogen with a partial PKC antagonist property, to prevent these response alterations in 6-hydroxydopamine (6-OHDA) lesioned rats as well as in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated cynomologous monkeys was studied. Following treatment of adult male rats with L-DOPA twice daily for 3 weeks, protein levels of left (lesioned) and right (intact) striatal PKC isoforms were measured. Western blot analysis showed increased protein expression of both the novel PKC epsilon isoform and the atypical PKC lambda isoform ipsilateral to the lesion (174+/-17% for epsilon, 140+/-9% for lambda, of intact striatum in 6-OHDA lesioned plus chronic L-DOPA treated animals) in acute L-DOPA treated rats. No enhancement was observed in PKC immunoreactivity for other isoforms. Tamoxifen (5.0 mg/kg p.o.) significantly attenuated the L-DOPA induced augmentation of protein expression of PKC epsilon and PKC lambda, but had no effect on immunoreactivity for other PKC isoforms. In chronic L-DOPA treated parkinsonian rats, tamoxifen prevented (5.0 mg/kg p.o.) as well as ameliorated (5.0 mg/kg p.o.) the characteristic shortening in duration of motor response to L-DOPA challenge. In MPTP lesioned primates, similar to the ameliorative effect seen in rats, tamoxifen (1 and 3 mg/kg p.o) reduced the appearance of L-DOPA induced dyskinesia by 61% and 55% respectively (p<0.05). These results suggest that changes in specific striatal PKC isoforms contribute to the pathogenesis of L-DOPA induced motor complications and further that drugs able to selectively inhibit these signaling kinases might provide adjunctive benefit in the treatment of Parkinson's disease.     

Cost-effectiveness analysis of anastrozole versus tamoxifen as primary adjuvant therapy for postmenopausal women with early breast cancer: a US healthcare system perspective. The 5-year completed treatment analysis of the ATAC (‘Arimidex’, Tamoxifen Alone or in Combination) trial

Background This study evaluated the cost-effectiveness of anastrozole versus generic tamoxifen for primary adjuvant treatment of postmenopausal women with hormone receptor-positive (HR+) early breast cancer (EBC), from a US healthcare perspective. Methods A probabilistic Markov model was developed using the 5-year completed treatment analysis of the ATAC (‘Arimidex’, Tamoxifen Alone or in Combination) trial (ISRCTN 18233230) to project outcomes for anastrozole and tamoxifen to 25 years. Resource utilization data were obtained primarily from published literature and a physician survey (including expert opinion from ATAC Steering Committee members). Drug costs were taken from published wholesale acquisition costs (anastrozole $6.56/day, generic tamoxifen $1.33/day). Other unit costs ($US 2003–4) were from standard sources. Utility estimates of relevant health states, used to compute quality-adjusted life-years (QALYs), were collected using the standard gamble technique in a cross-sectional sample of 44 patients. Costs and benefits were discounted 3% annually. Results In a cohort of 1000 postmenopausal women with HR+ EBC, the model showed anastrozole treatment (versus tamoxifen) would lead to 257 QALYs gained (0.26 QALYs gained per patient), at an additional cost of $5.21 million over 25 years ($5,212 per patient). The estimated incremental cost-effectiveness ratio (ICER) of anastrozole compared with tamoxifen was $20,246 per QALY gained ($23,541 per life-year gained). Cost-effectiveness acceptability curves indicated a >90% probability that the cost per QALY gained with anastrozole would be <$50,000. Results were robust in a sensitivity analysis. Conclusion Anastrozole is a cost-effective alternative to tamoxifen for the primary adjuvant treatment of postmenopausal women with HR+ EBC.     

The role of tamoxifen in combination with cisplatin on oral squamous cell carcinoma cell lines

The purpose of this study was to evaluate the effect of tamoxifen (TAM) when used in combination with cisplatin on oral squamous cell carcinoma (OSCC). For this, the relation between estrogen receptor (ER) expression level and the cytotoxic effect of TAM, the apoptotic effect and its molecular mechanisms of TAM were investigated using OSCC cell lines. Combination treatment demonstrated a superior cytotoxic and apoptotic effect on OSCC cell lines. Considerable amount of ER was detected in some OSCC cell lines, but there were no significant differences of cytotoxic effect of TAM. TAM inhibited PKC activity and up-regulated TGF-beta1 secretion.     

Effects of tamoxifen, fluphenazine and estradiol on ATP levels in preoptic area and hypothalamic slices from ovariectomized rats

Tamoxifen, the major adjuvant drug treatment for estrogen-dependent breast cancer, has been shown previously to affect both estrogen-dependent and calcium/calmodulin-dependent pathways. In the current study, we developed an in vitro slice system to study the effects of tamoxifen on ATP levels in hypothalamic (HTH) and preoptic areas (POA) of the rat brain. Baseline data showed that, following a 2-h incubation, HTH and POA slices had comparable ATP levels to hippocampal slices, a system used extensively by researchers examining the metabolic responsiveness of the hippocampal region (HPC) of the brain. HTH–POA slice ATP levels remained steady for 2, 4 and 6 h, but fell to 11% of initial levels by 12 h. Neurons from HTH–POA slices incubated for 4 h appeared healthy and demonstrated robust protein synthesis as measured autoradiographically by incorporation of [³H]leucine. We explored the effects of tamoxifen (TAM), fluphenazine (FLU) and estradiol (E₂) on ATP levels in HTH and POA slices. The effects of TAM were complex: a 4-h incubation with 10⁻⁶ M TAM led to decreased ATP levels in HTH (but not POA), and a 4-h incubation with 10⁻⁸ M led to increased ATP levels in POA (but not HTH); a 15-min exposure to 10⁻⁶ M TAM decreased ATP levels in POA (but not HTH) slices, while the exposure of slices to the lower concentration of TAM was without effect in either area. As with higher concentrations of TAM, 4-h incubation with 10⁻⁶ M FLU decreased ATP levels in HTH (but not POA), while incubation with E₂ did not affect slice ATP levels. These data are consistent with the hypothesis that both TAM and FLU alter ATP levels in HTH slices via calmodulin- or calcium-mediated processes.