Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new tamoxifen research articles will be listed here shortly after becoming available to us.
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Medical research on tamoxifen
J Clin Invest. 2008 Nov 20;
Coakley RD, Sun H, Clunes LA, Rasmussen JE, Stackhouse JR, Okada SF, Fricks I, Young SL, Tarran R
Normal airways homeostatically regulate the volume of airway surface liquid (ASL) through both cAMP- and Ca(2+)-dependent regulation of ion and water transport. In cystic fibrosis (CF), a genetic defect causes a lack of cAMP-regulated CFTR activity, leading to diminished Cl(- )and water secretion from airway epithelial cells and subsequent mucus plugging, which serves as the focus for infections. Females with CF exhibit reduced survival compared with males with CF, although the mechanisms underlying this sex-related disadvantage are unknown. Despite the lack of CFTR, CF airways retain a limited capability to regulate ASL volume, as breathing-induced ATP release activates salvage purinergic pathways that raise intracellular Ca(2+) concentration to stimulate an alternate pathway to Cl(-) secretion. We hypothesized that estrogen might affect this pathway by reducing the ability of airway epithelia to respond appropriately to nucleotides. We found that uridine triphosphate-mediated (UTP-mediated) Cl(-) secretion was reduced during the periovulatory estrogen maxima in both women with CF and normal, healthy women. Estrogen also inhibited Ca(2+) signaling and ASL volume homeostasis in non-CF and CF airway epithelia by attenuating Ca(2+) influx. This inhibition of Ca(2+) signaling was prevented and even potentiated by estrogen antagonists such as tamoxifen, suggesting that antiestrogens may be beneficial in the treatment of CF lung disease because they increase Cl(-) secretion in the airways.
Estrogen receptor status in CHEK2-positive breast cancers: implications for chemoprevention.
Clin Genet. 2008 Nov 17;
Cybulski C, Huzarski T, Byrski T, Gronwald J, Dębniak T, Jakubowska A, Górski B, Wokołorczyk D, Masojć B, Narod SA, Lubiński J
To investigate the relationship between CHEK2 mutation status and estrogen receptor (ER) status in unselected cases of early-onset breast cancer from Poland, we screened 4441 women diagnosed with breast cancer younger than 51 years and 7217 controls for three inherited mutations in CHEK2 (1100delC, IVS2+1G>A, del5395). ER status was compared between CHEK2-positive and CHEK2-negative breast cancer cases. A truncating mutation in CHEK2 was seen in 140 of 4441 cases and in 70 of 7217 controls [odds ratio (OR) = 3.3; 95% CI = 2.5-4.4; p < 0.0001]. ER status was available for 92 of 140 mutation carriers and for 3001 of 4301 non-carriers with breast cancer. The OR was higher for ER-positive cancers (OR = 3.9; 95% CI = 2.7-5.4; p < 0.0001) than for ER-negative cancers (OR = 2.1; 95% CI = 1.3-3.3; p = 0.002). Sixty-six of the 92 breast cancers in carriers of CHEK2 truncating mutations were ER positive compared with 1742 of the 3001 breast cancers in non-carriers (72% vs 58%; p = 0.01). Women with a CHEK2 mutation face a fourfold increase in the risk of ER-positive breast cancer and might be candidates for tamoxifen chemoprevention.
Breast Cancer Res Treat. 2008 Nov 20;
Falandry C, Debled M, Bachelot T, Delozier T, Crétin J, Romestaing P, Mille D, You B, Mauriac L, Pujade-Lauraine E, Freyer G
The aim of this study was to evaluate antitumor effects of cyclooxygenase-2 inhibitors in breast carcinoma and their ability to act synergistically with aromatase inhibitors (AIs). Postmenopausal metastatic breast cancer patients without previous adjuvant AI treatment received exemestane 25 mg/days plus either celecoxib 400 mg twice daily or placebo. The primary endpoint was progression-free survival (PFS). This trial was prematurely terminated (N = 157 of 342 planned) after cardiovascular toxicity was reported in other celecoxib trials. Although no PFS difference was observed between the two arms (9.8 months for both, P = 0.72), a trend favoring celecoxib was observed in 60 tamoxifen-resistant patients (9.6 vs. 5.1 months; P = 0.14) and in 126 patients treated >/=3 months before study termination (12.2 vs. 9.8 months; P = 0.09). No severe adverse events were reported. Cyclooxygenase-2 inhibitors seemingly contribute to reverse endocrine resistance in breast cancer patients, although further study is necessary to allow development of a new therapeutic strategy.
Desmoid tumors of the right rectus abdominus muscle in postpartum women.
Arch Gynecol Obstet. 2008 Nov 20;
Carneiro C, Hurtubis C, Singh M, Robinson W
BACKGROUND: Desmoid tumors are benign neoplasms that most often arise from muscle aponeurosis and have been associated with both trauma and pregnancy. The etiology of desmoids has not been determined. CLINICAL CHARACTERISTICS: We present here four almost identical cases with desmoids occurring in the same location, the right rectus abdominus muscle in young post partum females. All were over the age of 30 at the time of diagnosis. Three of them had previously used oral contraceptive agents for an average of 3 years. None had a history of trauma to the area of involvement. Three had early surgical resection and one was treated with tamoxifen and imatinib without response and then had surgical resection. DISCUSSION: All four patients are disease free at a median follow-up of 2.5 years. The possible etiology of desmoids tumors in this location in postpartum females is discussed.
Chemoprevention of breast cancer.
Am J Health Syst Pharm. 2008 Dec 1; 65(23): 2221-2228
Thomsen A, Kolesar JM
PURPOSE: The risk factors for and risk assessment of breast cancer, recommendations for risk reduction, and roles of tamoxifen and raloxifene in the prevention of breast cancer are discussed. SUMMARY: Breast cancer either may be a familial syndrome or develop sporadically. In familial syndromes, cancer occurs in multiple family members and the risk factors are primarily genetic. The majority of breast cancers are sporadic, and risk factors are primarily related to estrogen exposure. Recommendation strategies for reducing breast cancer risk include engaging in a healthy lifestyle by decreasing alcohol consumption, following a low-fat diet enriched with fruits and vegetables, exercising, and reducing weight if obese. Breast self-examinations, clinical breast examinations, and screening mammographies are strategies for the early detection of breast cancer. Recommendations for the use of tamoxifen for risk reduction are intended only for women who are at an increased risk for the development of breast cancer as assessed by the Gail model. One study found a significantly increased risk of cardiovascular events and hypertriglyceridemia in the tamoxifen group compared to placebo. Raloxifene is also intended for women at high risk for breast cancer. During clinical trials, hot flashes, influenzalike syndromes, peripheral edema, and leg cramps were reported more frequently in patients receiving raloxifene when compared with patients receiving placebo, and the risk of thromboembolic disease was 3.1 times higher in the raloxifene group compared with the placebo. CONCLUSION: Tamoxifen and raloxifene are both indicated for and equally effective in the prevention of breast cancer in women at high risk for development of the disease. Raloxifene may have a more favorable adverse-effect profile, with fewer thromboembolic events and less uterine hyperplasia when compared with tamoxifen. Despite being at high risk, many women decide against breast cancer chemoprevention with either tamoxifen or raloxifene.
Biomed Pharmacother. 2008 Nov 6;
Kubarek L, Kozłowska A, Przybylski M, Lianeri M, Jagodzinski PP
The CXCR4 chemokine receptor is a seven transmembrane G protein-coupled receptor present on the surface of various cells including cancer cells. The CXCR4 receptor contributes to the induction of several intracellular signalling pathways that enhance survival, proliferation, and migration of malignant cells. We observed that tamoxifen (Tam) reduced the CXCR4 transcript and protein levels in MCF-7 breast cancer cells. However, we did not see a Tam effect on CXCR4 transcript and protein levels in MCF-7(LVMT3B) cells with RNA interference-mediated knockdown of DNMT3B. We also observed that Tam significantly increased, for several hours, the expression of enzymatically active DNMT3B splice variants in MCF-7 cells. However, there was no Tam effect on these DNMT3B splice variants' expression in MCF-7(LVMT3B) cells. Bisulfite sequencing suggests that Tam may reduce CXCR4 expression via increased methylation of cytosine in the cytosine-guanosine (CpG) dinucleotide island of the CXCR4 promoter of MCF-7 breast cancer cells. Our findings suggest that Tam induces an increase in DNMT3B expression that is associated with the increase of CpG dinucleotide methylation in the CXCR4 promoter and significant reduction of CXCR4 gene expression in MCF-7 cells.
Am J Obstet Gynecol. 2008 Nov 17;
Duffy SR, Distler W, Howell A, Cuzick J, Baum M
OBJECTIVE: Results of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial have shown that tamoxifen is associated with a significantly higher incidence of gynecologic adverse events than anastrozole. STUDY DESIGN: This was a retrospective analysis of all gynecologic adverse events and interventions conducted in patients receiving anastrozole or tamoxifen in the main ATAC trial database. RESULTS: Women taking tamoxifen experienced significantly more gynecologic adverse events than those taking anastrozole (34.2% vs 20.5%; P < .0001) and this led to more diagnostic and/or therapeutic interventions, including an almost 4-fold increase in the number of hysterectomies (5.1% vs 1.3%; P < .0001). The majority of the gynecologic adverse events with tamoxifen occurred during the first 2.5 years. CONCLUSION: The lower incidence of gynecologic adverse events and interventions with anastrozole and the early occurrence of these events provide further support for using anastrozole as the initial adjuvant treatment for early hormone receptor-positive breast cancer.
Expert Rev Mol Med. 2008; 10: e34
Stearns V, Rae JM
The identification of genetic polymorphisms that influence the efficacy and safety of therapies for breast cancer may allow future treatments to be individualised based not only on tumour characteristics but also on host genetics. Genetic factors that affect the metabolism, efficacy and safety of tamoxifen, one of the most common drugs used for the treatment and prevention of breast cancer, have received particular attention. Cytochrome P450 2D6 (CYP2D6) is crucial in the metabolism of tamoxifen to its active metabolite endoxifen. Women with genetic variants of CYP2D6 or who take drugs that inhibit the enzyme have low endoxifen plasma concentrations and may show reduced benefits to tamoxifen treatment. CYP2D6 polymorphisms and variants in other candidate genes may also influence secondary benefits and side effects of tamoxifen. Here, we summarise data suggesting that CYP2D6 status may be an important predictor of the benefits of tamoxifen to an individual; in addition, we briefly discuss the role of variants in other candidate genes. Whether CYP2D6 status should be determined prior to initiating tamoxifen therapy is currently under debate and may be appropriate only for select women who are candidates for tamoxifen alone but for whom alternative standard options are available.
Br J Cancer. 2008 Nov 18;
Campbell EJ, McDuff E, Tatarov O, Tovey S, Brunton V, Cooke TG, Edwards J
Elevated c-Src protein expression has been shown in breast cancer and in vitro evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan-Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (P=0.047) and lower recurrence rates on tamoxifen (P=0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (P
J Clin Oncol. 2008 Nov 17;
Jin Y, Hayes DF, Li L, Robarge JD, Skaar TC, Philips S, Nguyen A, Schott A, Hayden J, Lemler S, Storniolo AM, Flockhart DA, Stearns V
PURPOSE: Hot flashes are common and frequently lead to drug discontinuation among women prescribed tamoxifen. We determined whether genetic polymorphisms in estrogen receptors (ESRs) alpha and beta (ESR1 and ESR2, respectively) are associated with tamoxifen-induced hot flashes. PATIENTS AND METHODS: We determined ESR1 PvuII and XbaI and ESR2-02 genotypes in 297 women who were initiating tamoxifen. One-week hot flash diaries were collected to calculate a hot flash score (frequency x severity) before and 1, 4, 8, and 12 months after starting tamoxifen. RESULTS: Approximately 80% of 297 participants reported hot flashes before or during the first year of tamoxifen. After 4 months of tamoxifen, premenopausal women who did not receive adjuvant chemotherapy had a four-fold increase in hot flash score (from 5.9 to 23.6; P = .003) compared with a 1.17-fold increase (from 19.6 to 23; P = .34) in those who received chemotherapy. In premenopausal women, increased number of ESR1 PvuII and XbaI CG alleles was associated with higher baseline hot flash scores compared with those who had other haplotypes (P = .0026). At 4 months, postmenopausal women with ESR1 PvuII CC and ESR2-02 GG genotypes had 4.6 times increases in hot flash scores than other postmenopausal women (56 v 12; P = .0007). Women who had the ESR2-02 AA genotype were significantly less likely to experience tamoxifen-induced hot flashes than women who carried at least one ESR-02 G allele (hazard ratio, 0.26; 95% CI, 0.10 to 0.63; P = .001). CONCLUSION: Knowledge of menopausal status, prior chemotherapy, and ESR genotype may help predict which women are most likely to suffer hot flashes during tamoxifen treatment.