Tamoxifen-induced CreER-LoxP recombination is often used to induce spatiotemporally controlled gene deletion in genetically modified mice. Prior work has shown that tamoxifen and tamoxifen-induced CreER activation can have off-target effects that should be controlled. However, it has not yet been reported whether tamoxifen administration, independently of CreER expression, interacts adversely with commonly used anaesthetic drugs such as medetomidine or its enantiomer dexmedetomidine in laboratory mice (Mus musculus). Here, we report a high incidence of urinary plug formation and morbidity in male mice on a mixed C57Bl6/J6 and 129/SvEv background when tamoxifen treatment was followed by ketamine-medetomidine anaesthesia. Medetomidine is therefore contra-indicated for male mice after tamoxifen treatment. As dexmedetomidine causes morbidity and mortality in male mice at higher rates than medetomidine even without tamoxifen treatment, our findings suggest that dexmedetomidine is not a suitable alternative for anaesthesia of male mice after tamoxifen treatment. We conclude that the choice of anaesthetic drug needs to be carefully evaluated in studies using male mice that have undergone tamoxifen treatment for inducing CreER-LoxP recombination.

Tamoxifen is commonly prescribed for preventing recurrence in patients with breast cancer. However, the responses of the patients on tamoxifen treatment are variable. Cytochrome P450 genetic variants have been reported to have a significant impact on the clinical outcomes of tamoxifen treatment but no tangible conclusion can be made up till now. The present review attempts to provide a comprehensive review on the associative relationship between genetic polymorphisms in cytochrome P450 enzymes and survival in breast cancer patients on adjuvant tamoxifen therapy. The literature search was conducted using five databases, resulting in the inclusion of 58 studies in the review. An appraisal of the reporting quality of the included studies was conducted using the assessment tool from the Effective Public Health Practice Project (EPHPP). Meta-analyses were performed on CYP2D6 studies using Review Manager 5.3 software. For other studies, descriptive analyses were performed. The results of meta-analyses demonstrated that shorter overall survival, disease-free survival and relapse-free survival were found in the patients with decreased metabolisers when compared to normal metabolisers. The findings also showed that varying and conflicting results were reported by the included studies. The possible explanations for the variable results are discussed in this review.

The treatment of leishmaniasis relies primarily on highly toxic, parenterally administered drugs. Therefore, the search for more effective and safer drugs is considered a priority for leishmaniasis’ control. The antileishmanial activity of the oestrogen receptor modulator tamoxifen was previously described in experimental models of leishmaniasis. However, the mechanisms responsible for the antileishmanial activity of tamoxifen remain unknown. Since tamoxifen has been shown to affect plasma and intracellular membranes in tumour cells, the aim of this study was to investigate the activity of the drug on Leishmania amazonensis membranes. Through morphological analysis and labelling with propidium iodide and DiSBAC2(3), we demonstrated that tamoxifen led to plasma membrane depolarization without general membrane disruption or permeabilization. Tamoxifen also caused mitochondrial damage, with loss of membrane potential, as shown by Rhodamine 123 accumulation. Mitochondrial swelling followed, signalling the mitochondrial dysfunction. Therefore, the effect of tamoxifen on Leishmania is mediated, at least in part, by disorder in parasite's membranes. These alterations are sufficient to trigger a series of lethal events.

The aims of the present work were to test the effect of tamoxifen administered topically and the therapeutic efficacy of tamoxifen and pentavalent antimonial combinations in an experimental model of cutaneous leishmaniasis. BALB/c mice infected with a luciferase expressing line of Leishmania amazonensis were treated with topical tamoxifen in two different formulations (ethanol or oil-free cream) as monotherapy or in co-administration with pentavalent antimonial. Treatment efficacy was evaluated by lesion size and parasite burden, quantified through luminescence, at the end of treatment and 4 weeks later. Topical tamoxifen, formulated in ethanol or as a cream, was shown to be effective. The interaction between tamoxifen and pentavalent antimonial was additive in vitro. Treatment with combined schemes containing tamoxifen and pentavalent antimonial was effective in reducing lesion size and parasite burden. Co-administration of tamoxifen and pentavalent antimonial was superior to monotherapy with antimonial.

We describe the case of a 56-year old woman with no prior psychiatric history who was diagnosed with hormone receptor positive early-stage breast cancer and who developed severe mood changes after administration of anastrozole, which resolved after discontinuation of treatment. Aromatase inhibitors (AIs) are the preferred hormonal approach for postmenopausal women with estrogen hormone sensitive breast cancer. The third-generation agents (anastrozole, letrozole, and exemestane) have been shown to be more effective and safer than the selective estrogen receptor modulators tamoxifen and raloxifen. Treatment strategies with these agents include the use of an AI as an upfront strategy for 5 years, as a sequential approach after 2–3 years of tamoxifen, or as extended use after the classical 5 years of tamoxifen. The side effects of AIs, as compared with selective estrogen receptor modulators, are different, reflecting the specific mechanism of action of these drugs. AIs are well tolerated and cause a lower incidence of gynecological symptoms (vaginal bleeding, discharge, and endometrial neoplasia), venous thromboembolic events, and hot flashes compared with tamoxifen. However, the use of AIs have been associated with loss of bone density, arthralgia, myalgia, a negative effect on lipid metabolism, and cardiovascular risk (Tomao et al., 2011). Mood disturbances, somnolence, anxiety, fatigue, hot flashes, and memory impairment have been reported among patients receiving anastrozole as adjuvant therapy.

There is evidence that tamoxifen treatment of BRCA1 and BRCA2 carriers for prior breast cancer increases risk of endometrioid subtype endometrial cancer (EC), and suggestive evidence that BRCA1 and BRCA2 mutation carriers may be predisposed to EC in the absence of tamoxifen exposure. We assessed the association of EC with BRCA1 or BRCA2 mutation status in Australasian breast-ovarian families. Report of at least one case of EC was significantly greater in BRCA1-positive families (35/218 (16%); p = .03) and non-significantly greater in BRCA2-positive families (23/189 (12%); p = .6), compared to high-risk breast cancer families without a BRCA1/2 mutation (86/796 (11%)). EC was the first/concurrent cancer for 41% of EC cases with multiple cancer diagnoses from BRCA1/2 families, and early onset for most of these diagnoses. Mutation status was imputed for ungeno-typed individuals from 57 BRCA1/2 pedigrees reporting EC using BRCAPRO. Effects of genotype on EC diagnosis age, and interaction with tamoxifen therapy, were assessed using Cox proportional hazards regression analysis. EC risk was non-significantly marginally greater for BRCA1 carriers (hazard ratio = 1.25, 95%CI = 0.65–2.41), and BRCA2 carriers (HR = 1.12, 95%CI = 0.51–2.45), compared to non-carrier family members. Tamoxifen therapy was highly significantly associated with EC (HR = 6.68, 95%CI = 3.12–15.15; p = 1.7 x 10-6) in BRCA1/2 families, with no evidence for interaction between tamoxifen therapy and BRCA1/2 genotype. Our family-based study supports a 7-fold increase in EC risk with tamoxifen exposure for female family members from BRCA1/2 families. Early onset EC in carriers without tamoxifen use suggests that further study is required to assess association of modest EC risk with BRCA1/2 mutation status alone.

Dietary flaxseed (FS) inhibited the growth of human breast tumours and enhanced the effectiveness of tamoxifen (TAM) in athymic mice with low oestradiol (E2) levels. The present study determined whether the n-3 fatty acid-rich cotyledon fraction of FS (FC), alone or in combination with TAM, has a similar effect and thus can substitute for FS. In a 2 × 2 factorial design, ovariectomised mice with established oestrogen receptor (ER)-positive breast tumours (MCF-7) were treated as follows: groups 1 and 2 were fed the basal diet (BD, control) and FC diet (82 g FC/kg), respectively. Groups 3 and 4 with TAM implants (5 mg) were fed the BD and FC diet, respectively. At 8 weeks post-treatment, mice were euthanised, and tumours were analysed by immunohistochemistry and real-time PCR. BD, FC and FC/TAM groups significantly decreased tumour area, but the TAM group did not. Tumour regression in the FC/TAM group was greater compared to the TAM group. FC lowered cell proliferation but had no effect on apoptosis; the opposite was observed with TAM. FC suppressed mRNA expressions of pS2 and insulin-like growth factor 1 receptor (IGF-1R) and protein expressions of ERα, phosphospecific ERα, human epidermal growth factor receptor 2 (HER2), phosphospecific HER2 (pHER2) and amplified in breast 1 (AIB1), while TAM up-regulated mRNA expressions of Bcl2, progesterone receptor and IGF-1R and protein expression of pHER2, and down-regulated ERβ mRNA. FC modulated the effect of TAM on tumour growth biomarkers. In conclusion, FC reduced the growth of ER+human breast tumours at low circulating E2, alone and combined with TAM, in part through modulation of ER −  and growth factor-mediated signalling pathways; it may substitute for FS in increasing the effectiveness of TAM.

The somatic muscle of Ascaris suum is principally under the excitatory control of neuromuscular junction transmitter, acetylcholine (ACh). However, it has recently been shown that neuropeptides also play an important role in the motor-nervous system and one of these, AF3 (AVPGVLRFamide), also contracts muscle. The events which trigger contraction to ACh and AF3 would appear to be different, with ACh activating a nicotinic acetylcholine receptor whilst the response to AF3 is most likely to involve a G-protein coupled receptor negatively coupled to adenylate cyclase. In order to further elucidate differences in the cellular signalling pathways through which ACh and AF3 elicit muscle contraction, we investigated the actions of protein kinase C inhibitors, tamoxifen and chelerythrine, on the dorsal somatic muscle strip of A. suum. Contractions in response to 1 μM AF3 were potentiated by 17% in the presence of 10 μM tamoxifen (P<0·05; n=8); however, contractions in response to 10 μM ACh were markedly inhibited (tamoxifen IC50 44±18 μM; n=6). Tamoxifen also blocked muscle cell depolarizations to 5 μM ACh (IC50 4±1 μM; n=6) and 1 μM levamisole (IC50 14±6 μM; n=4). This was unlikely to be a non-specific effect on the membrane as hyperpolarizations to 10 μM GABA were unaffected (93% of control with 10 μM tamoxifen; n=6; P>0·05). However, another inhibitor of mammalian protein kinase C, chelerythrine, did not affect the response either to ACh or AF3 (n=6).

In the present study, eighty-four breast cancer patients were randomized to receive a daily supplement of 100 mg co-enzyme Q10, 10 mg riboflavin and 50 mg niacin (CoRN), one dosage per d along with 10 mg tamoxifen twice per d. A significant increase in poly(ADP-ribose) polymerase levels and disappearance of RASSF1A DNA methylation patterns were found in patients treated with supplement therapy along with tamoxifen compared to untreated breast cancer patients and tamoxifen alone-treated patients. An increase in DNA repair enzymes and disappearance of DNA methylation patterns attributes to reduction in tumour burden and may suggest good prognosis and efficacy of the treatment.

Tamoxifen can be considered a classic ‘pro-drug’, requiring metabolic activation to elicit pharmacological activity. Our findings suggest that both genetic and drug-induced factors that alter CYP2D6 enzyme activity influence the clinical response to tamoxifen. Given the small differences in disease-free survival comparing tamoxifen to third-generation aromatase inhibitors, knowledge of the genetic and environmental factors that influence CYP2D6 enzyme activity may provide a robust tool to individualize the hormonal therapy to breast cancer.

Chemoprevention with tamoxifen and oophorectomy are thought to be effective in decreasing the incidence of breast cancer in women at increased risk for the disease. There is mounting data supporting the idea that hormonal interventions that reduce estrogen exposure to breast epithelium, such as prophylactic oophorectomy and tamoxifen, are effective in breast cancer prevention in both BRCA1 and BRCA2 mutations carriers. Several recent studies directly address the protective effect of tamoxifen and oophorectomy in BRCA mutation carriers and suggest that these endocrine manipulations decrease the risk of primary and secondary breast cancers. Ongoing studies aim to better define the effect of tamoxifen in these very high-risk women and determining whether factors, such as earlier age of use or prior prophylactic oophorectomy, impact tamoxifen's effect. Based on existing data, we recommend that women with deleterious mutations in BRCA1 or BRCA2 be informed of the beneficial effect of oophorectomy on breast cancer risk and that women who choose breast cancer screening instead of prophylactic mastectomy be offered tamoxifen as a prevention option.

Since 1985, 5411 patients were randomized in four large randomized clinical trials assessing the role of adjuvant radiotherapy and/or tamoxifen in breast conserving surgery for patients with ductal carcinoma in situ (DCIS).

First the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial proved relevance of postoperative radiotherapy in breast conserving surgery in DCIS patients: an approximately 50% reduction of ipsilateral tumour recurrences. This is confirmed by longer time of follow-up and validated by data from the European Organization for Research and Treatment of Cancer (EORTC) 10853 and UK Coordinating Committee on Cancer Research (UKCCCR) DCIS trials. A subset of patients who do not benefit of adjuvant radiotherapy cannot be identified. Completeness of excision proved to be the most important treatment variable to reduce local recurrence.

Both the NSABP B-24 and UKCCCR DCIS trials investigated the effect of tamoxifen resulting in contradictory findings. In addition a possible benefit seems to be restricted to oestrogen receptor-positive DCIS lesions nourishing the existent reserve in prescribing tamoxifen for all patients with DCIS.

The failure to materialize a difference in survival by the effect of either adjuvant radiotherapy or tamoxifen endorses the favourable outcome of DCIS. Currently, four other randomized clinical trials investigate the role of radiotherapy, tamoxifen, anastrazole, or no further treatment for a selected group of patients.

Alterations in the rate of oocyte meiotic maturation (OM) and the timing of the metaphase-anaphase transition may predispose oocytes to premature centromere separation (PCS) and aneuploidy. Tamoxifen has the potential for perturbing the rate of OM since it can function as a calcium antagonist by binding to calmodulin and inhibiting the formation of a calcium-calmodulin complex which is needed for activating calmodulin-dependent cAMP phosphodiesterase and initiating OM. The objective of this study was to test the hypothesis that tamoxifen alters the rate of OM and predisposes oocytes to PCS and aneuploidy. Different does of tamoxifen were administered by oral gavage to female mice preovulation. Metaphase II oocyte and 1-cell zygote chromosomes were C-banded and cytogenetically analysed. Tamoxifen treatment resulted in a modest, but significant (p < 0.05), increase in oocytes with PCS. Similar frequencies of hyperploidy and oocytes with unpaired, single chromatids (SC) were found. Metaphase I, diploid and premature anaphase (PA) oocytes were not detected. Hyperploidy, polyploidy, PCS, PA and SC were not detected in zygotes. These data indicate that the levels of tamoxifen-induced PCS found in mouse oocytes did not predispose zygotes to aneuploidy. Tamoxifen did, however, reduce the proportion of females exhibiting oestrus.

Adenoid cystic carcinoma of the parotid gland often recurs locally, or metastases develop, after initial treatment with surgery and radiotherapy. We report a patient with an inoperable local recurrence of previously irradiated adenoid cystic carcinoma, who was treated with tamoxifen, an oestrogen receptor antagonist. After 18 months of treatment with tamoxifen, MRI showed a partial response, and further clinical progression of the disease was halted.