Tamoxifen Group Research Articles

Aromatase inhibitor plus ovarian suppression as adjuvant therapy in premenopausal women with breast cancer

The goal of adjuvant hormonal therapy for breast cancer is to prevent recurrence by eradicating micrometastatic disease. Recent studies have shown that the use of aromatase inhibitors (AIs) as adjuvant therapy improves outcomes for postmenopausal women with estrogen receptor (ER)-positive breast cancer compared to adjuvant endocrine therapy with tamoxifen alone. The research question has been raised whether AIs would have similar improvements in disease-free survival (DFS) in premenopausal women with ER-positive breast cancer. Combining 2 phase 3 clinical trials (n = 4,690), Pagani and colleagues randomized premenopausal women with ER-positive early breast cancer to exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 y. After a median follow-up of 68 months, DFS was 91.1% in the AI group and 87.3% in the tamoxifen group. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence.

Effect of tamoxifen on ovarian reserve: A randomized controlled assessor-blind trial in a mouse model.

To determine whether tamoxifen (TMX) exposure causes a permanent decrease in ovarian reserve. A randomized controlled assessor-blind trial including 30 adult female inbred BALB/C mice. Fifteen mice in the TMX group were given a single 0.1-mg dose of TMX intraperitoneally. Fifteen mice in the control group were given a single dose of the vehicle at the same volume intraperitoneally. Two cycles later, blood samples were collected for determination of anti-Müllerian hormone (AMH) levels, and the mice were sacrificed. After gonadectomy, ovarian size was measured, and follicles were counted under light microscopy. Median serum AMH levels were 6.53 and 6.14 ng/ml in the control and TMX groups, respectively (p=0.03). Ovarian size was significantly decreased in the TMX group. While the number of primordial (9 vs 8), primary (6 vs 3), and secondary (4.5 vs 5) follicles were similar, there were significantly fewer preantral (11.5 vs 6, p<0.01) and antral (2 vs 1, p: 0.03) follicles, as well as corpora lutea (6 vs 3, p: 0.04), in the TMX group than in the control group. The number of atretic (2.5 vs 5, p: 0.048) follicles was increased in the TMX group. Tamoxifen administration leads to arrested growth of gonadotropin-sensitive follicles, while insensitive follicles can remain unaffected. TMX is merely an endocrine disruptor, and it does not cause a decrease in primordial follicle pool.

The effect of Shugan-Yishen formula on HER2-ERK/MAPK-ERα Pathway of TAM-resistant breast cancer cell lines

Objective To investigate the effect of Shugan-Yishen formula on Tamoxifen-resistant MCF-7 cell line（LCC9） through HER2-ERK/MAPK-ERα pathway. Methods Four serums were prepared with the method of serum pharmacology：the serum of Shugan-Yishen formula, Shugan-Yishen formula plus Tamoxifen（TAM）, blank and TAM alone. After LCC-9 cells were affected in the above-mentioed serums in vitro, the inhibition rate and the level of mRNA as well as the protein expression of HER2, ERα, ERK/MAPK, p-ERK/MAPK were detected. Results MTT showed that TAM alone group、Shugan-Yishen formula group and the Shugan-Yishen formula plus TAM group had higher inhibition rates at 48th hour, the inhibition rates was（6.61±0.129）%, （47.43±2.24）%, （54.19±3.364）%, compared to the blank group, Shugan-Yishen formula group and the Shugan-Yishen formula plus TAM group had a stronger inhibition on LCC9 at 48th hour （P〈0.05）, and the combination group was better than Shugan-Yishen formula alone（P〈0.05）, there was no difference between TAM group compared to the blank group（P〉0.05）. RT-PCR result showed that compared to the blank group, the expression levels of ESR1 mRNA of group of Shugan Yishen formula plus TAM＆amp;nbsp;werehigher by and large at 48th hour （P〈0.05）, the expression of ESR1 mRNA was（2.282±0.185）;and the levels of ERBB2, MAPK3 mRNAwere lower（P〈0.05）, which levels were（0.71±0.095）, （0.336±0.058）. Western blotting result showed that Shugan-Yishen Formula plus TAM group could markedly decrease the expression of HER2, p-ERK/MAPK of LCC9 at 48th hour （P〈0.05）, which the expressions were（0.708± 0.072）, （0.228±0.034）, and the expression of ER-αelevated（P〈0.05）. There was no significant difference on ERK/MAPK（P〉0.05）. Conclusions ①The combination of Shugan-Yishen formula with tamoxifen can inhibit the LCC9 cells. The inhibition effect reaches the peak at 48th hour. ②The mechanism of Shugan-Yishen formula plus TAM combination effects on human breast cancer TAM-resistant cell line LCC9 may improve the sensitivity of ERαby inhibiting the expression of HER2, ERK/MAPK. Key words: Shugan-Yishen Formula; Breast cancer; HER2-ERK/MAPK-ERαpathway

No increased venous thromboembolism risk in Asian breast cancer patients receiving adjuvant tamoxifen.

Tamoxifen is an effective endocrine treatment for early breast cancer (EBC) but increases the risk of venous thromboembolism. Whether Asian EBC patients (pts) bear the same risk when treated with adjuvant tamoxifen is uncertain. EBC pts diagnosed between 2004 and 2009 were selected from a population database in Taiwan. The pts were followed up from the index date to December 31, 2011 to collect events of deep vein thrombosis (DVT) and pulmonary embolism (PE). Cumulative incidence rates and hazard ratios (HRs) were used to compare the risk between pts treated with and without tamoxifen. In addition, comorbidities were included in an adjusted model of the risk of DVT and PE. A total of 28,029 EBC pts, including 17,843 (63.8%) in the tamoxifen group and 10,155 (36.2%) in the nontamoxifen group, were analyzed. The 7-year cumulative incidence rates for DVT and PE were 2.58 and 0.32% in the tamoxifen group and 2.51 and 0.32% in the nontamoxifen group (P=0.92 for DVT, P=0. 65 for PE), respectively. The HR for the nonadjusted and adjusted models showed no differences in DVT and PE risks between the tamoxifen and nontamoxifen groups. The uterine cancer risk was significantly increased in the pts receiving tamoxifen (adjusted HR=2.79, P<0.001), suggesting tamoxifen compliance. The risks of developing DVT and PE are not increased in Asian EBC pts receiving adjuvant tamoxifen. Ethnicity differences should be considered when discussing optimal endocrine treatments with EBC pts.

The effect of tamoxifen on expression of ER, PR, Cerb-B2, and ki-67 in C3H mice spontaneous breast cancer model and the relation with chemotherapeutic effect.

To explore the effect of tamoxifen on expression of ER, PR, Cerb-B2, and ki-67 in C3H mice spontaneous breast cancer model and further explore its relation with chemotherapeutic effect. Forty male C3H mice with spontaneous breast cancer aged 10 months were selected, and randomly divided into model group and tamoxifen group, with 20 mice in either group. Model group received intraperitoneal injection of normal saline, tamoxifen group received 5 mg/Kg tamoxifen injection. Tumor volume was measured every 3 days for 12 days in total. After that the mice were killed to weigh the tumor for tumor growth inhibition rate calculation; breast cancer specimen was collected, and immunohistochemistry was used to detect ER, PR, Cerb-B2, and ki-67 positive cells, western blot was used to detect expression of ER, PR, Cerb-B2, and ki-67 in breast cancer. The tumor growth inhibition rate of tamoxifen on mice was 61.56 %. Compared with model group, tumor weight in mice from tamoxifen group was significantly lower, tumor growth rate in tamoxifen group was significantly lower than model group; immunohistochemical staining results showed that compared with model group, ER, PR, Cerb-B2, and ki-67 positive cells in tumor of tamoxifen group were significantly lower (P < 0.05). Among them, ki-67 expression in tamoxifen group was negative; western blot semi-quantitative results were in accordance with immunohistochemistry results. Tamoxifen is effective on C3H mice spontaneous breast cancer. After being treated with tamoxifen, expression levels of ER, PR, Cerb-B2 and ki-67 are changed, and change of ER, PR, Cerb-B2, and ki-67 can predict the therapeutical effect of tamoxifen.

Aromatase inhibitors associated musculoskeletal disorders and bone fractures in postmenopausal breast cancer patients: a result from Chinese population.

As the prognosis of early breast cancer patients improves, the long-term safety of aromatase inhibitors (AIs) is increasingly important. In the present study, we retrospectively investigated the incidences of musculoskeletal disorders (MSDs) and bone fractures in a cohort of Chinese postmenopausal patients with breast cancer. Data of postmenopausal patients with breast cancer were collected. Among which, 70 patients received AIs therapy (median follow-up of 32.5 months), 52 patients received tamoxifen (TAM), and 89 patients received no endocrine therapy (NE). Baseline characteristics, incidence of MSDs and bone fractures were analyzed and compared. When compared with NE group (40.4 %, 36/89), more patients in AIs group developed MSDs (72.9 %, 51/70, adjusted odds ratio (AOR) = 3.30, 95 % confidence interval (CI) = 1.59-6.88, P = 0.001). But no difference was found between TAM group (36.5 %, 19/52, AOR = 0.70, 95 % CI = 0.32-1.52, P = 0.372) and NE group. About 39.7 months after initial AIs therapy, nine patients in AI group developed bone fractures in different sites, and the bone fracture rate was significantly increased (12.9 %, 9/70, adjusted hazard ratio (AHR) = 20.08, 95 % CI = 1.72-234.08, P = 0.017) in comparison with NE group (1.1 %, 1/89). Moreover, the bone fracture rate of TAM group was not different from NE group (1.9 %, 1/52, AHR = 2.64, 95 % CI = 0.14-48.73, P = 0.513). AIs therapy may induce increased rates of MSDs and bone fractures in Chinese population of postmenopausal breast cancer patients, whereas TAM therapy did not help reduce the incidences of MSDs and bone fractures.

Decision-making impairments in breast cancer patients treated with tamoxifen

The selective estrogen receptor modulator tamoxifen (TAM) is most commonly prescribed for patients with hormone-sensitive breast cancer. Although TAM can bind to estrogen receptors in the nervous system, it is unknown whether it acts as an estrogen agonist or antagonist in the human brain. Several studies have reported the negative effects of TAM on cognitive function; however, its effects on decision-making function have not been previously explored. The present study aimed to investigate the decision-making function under ambiguity and risk in breast cancer patients treated with TAM. Participants included breast cancer patients taking TAM (TAM, n=47) and breast cancer patients not taking TAM (non-TAM, n=45) as well as their matched healthy controls (HC, n=50). All participants were given the Iowa Gambling Task (IGT) to assess their decision-making under conditions involving ambiguity, the Game of Dice Task (GDT) to assess their decision-making under conditions involving risk, and a battery of neuropsychological tests. Our results indicated that patients in the TAM group were significantly impaired as assessed by both the IGT and GDT and performed significantly worse on some aspects of various tasks involving memory and information processing. Furthermore, we found that decreased performance on verbal memory testing significantly correlated with IGT performance, and executive dysfunction was associated with poor GDT performance in breast cancer patients undergoing TAM treatment. This study demonstrates that breast cancer patients taking TAM have several decision-making impairments. These findings may support the idea that TAM resulting in cognitive changes plays an antagonistic role in the areas of the brain where estrogen receptors are present, including the prefrontal cortex, hippocampus and amygdala.

Effect of oral tamoxifen on the healing of corrosive oesophageal burns in an experimental rat model.

Corrosive oesophagitis is a common health problem in children. Scar tissue can develop during the recovery period, and as a result, serious narrowing of the oesophagus can develop, in turn causing morbidity and mortality. In previous studies, it was argued that tamoxifen (TAM) may have antifibrotic effects beyond its oestrogen antagonist or agonist properties. We aimed to examine the possible effects of TAM on fibrosis and stricture formation, which are complications of corrosive oesophagitis. Three study groups were formed as follows: a non-oesophageal burn group (NON-EB, n = 6), an oesophageal burn group (EB, n = 6) and an oesophageal burn + tamoxifen group (EB-TAM, n = 6). In the NON-EB rats, the oesophageal lumen was washed with 0.9% NaCl while, in the EB and EB-TAM rats, the distal oesophagus was burned with a 50% NaOH solution. After application of this solution to the EB-TAM group rats, 0.4 mg/kg/day of TAM was administered via gavage for 7 days. Twenty-two days later, the rat oesophagi were examined histopathologically for inflammation, granulation, collagen deposition and stenosis. In the EB group rats, the inflammation, collagen deposition and stenosis scores increased compared with those of the other groups. In the EB-TAM group, these three scores were lower compared with those of the EB group rats, but higher compared with those of the NON-EB group rats. No significant difference was observed in the granulation scores between the EB and EB-TAM groups. It was also observed that the EB-TAM group rats gained more weight than those in the EB group. According to the data obtained, TAM use prevents inflammation, collagenization and stricture development. TAM may be a useful medicine in the treatment of corrosive oesophagitis.

Clinico-pathology and prognosis of endometrial cancer in patients previously treated for breast cancer, with or without tamoxifen: A comparative study in 363 patients

ObjectiveTo compare the clinic-pathologic variables and the prognosis of endometrial cancer in patients with and without previous breast cancer, with and without Tamoxifen. MethodsWe analyzed patients treated for an endometrial carcinoma from 1994 to 2004: patients without breast cancer (group 1), patients with a previous breast cancer without tamoxifen (group 2) and patients treated for breast cancer with tamoxifen (group 3). Survival rates were calculated according to Kaplan–Meier method and compared using a Log rank test, multivariate analysis was performed with a Cox regression model. Results363 patients were analyzed. 80 patients had a previous history of breast cancer (43 received tamoxifen). Although it was not statistically significant, more carcinosarcomas were observed in patients in group 3 than patients in groups 1 and 2 (11.7% versus 4.2% and 5.4% respectively, p = 0.17).) Median follow-up was 87 months [2–185]. 5-year overall survival rate was respectively in groups 1, 2 and 3: 82%, 73.2%, and 61% (p = 0.0006). 5-year local relapse-free survival rate was respectively: 95.9%, 93.1% and 82.5% (p = 0.02). In multivariate analysis, factors affecting overall survival rate were: age ≥65 ans (HR 3.62, p < 0.0001), FIGO stage (HR 3.33 p < 0.0001 for locally advanced stage versus early stage, HR 8.87 p = 0.03 for distant extension versus early stage), and group 3 (HR 2.83 p < 0.001 versus group 1). ConclusionPatients with endometrial cancer previously treated for breast cancer show a worse prognostic, particularly if they reveived tamoxifen.

Tamoxifen reduces infiltration of inflammatory cells, apoptosis and inhibits IKK/NF-kB pathway after spinal cord injury in rats.

In this study, neuroprotective effect of tamoxifen has been explored in spinal cord injury (SCI) in rats by examining factors influencing IKK/NF-kB pathway in SCI in rats. It has been shown in several studies that IKK/NF-kB signaling pathway plays a key role in pathophysiology of SCI. In this study, three groups of rats (n = 17 each) were selected that included, tamoxifen group (here tamoxifen was injected after SCI in rats), SCI group (here only dimethylsulfoxide was administered after inducing SCI in rats) and sham group (here only laminectomy was performed). The effect of tamoxifen (5 mg/kg) on various factors responsible for activation of IKK/NF-kB signaling pathway including NF-kB p65, phosphorylated I-kBα was studied through Western blotting as well as densitometry. The examination of expression of active caspase-3 and myeloperoxidase activity was also carried out through Western blot analysis and densitometry. A comparison of three groups of rats showed that administration of tamoxifen significantly reduced the expression of NF-kB p65 and phosphorylated I-kBα (P < 0.05) compared to control. It also attenuated the expression of active caspase-3 resulting in the reduction of apoptosis, and infiltration of leukocytes to the injury site was also greatly reduced in the group where tamoxifen was administered. Statistical analysis through SPSS 13.0 software showed a significant decrease in the expression of inflammatory factors in groups where tamoxifen was administered. We conclude that tamoxifen possesses the potential neuroprotective effects that can be explored further for future therapeutic techniques in treating spinal cord injuries.

A prospective assessment of musculoskeletal toxicity and loss of grip strength in breast cancer patients receiving adjuvant aromatase inhibitors and tamoxifen, and relation with BMI.

Aromatase inhibitor (AI) therapy for estrogen receptor-positive breast cancer is known to induce or enhance musculoskeletal problems. We have previously reported that loss of grip strength is more pronounced in AI-users with extremes in BMI. We here report results from a larger prospective study. Postmenopausal early breast cancer patients scheduled to start AI or tamoxifen therapy were recruited. A functional assessment grip strength test was performed at baseline, 3, 6, and 12months of therapy. BMI was assessed, and a rheumatologic questionnaire was completed at each visit. 188 patients on an AI and 104 patients on tamoxifen were enrolled. 74% of AI-users reported new/worsened musculoskeletal complaints compared with 37% in the tamoxifen group. This was translated in a larger grip strength decrease in patients experiencing AI-induced pain opposed to patients without new/worsened complaints (p=0.0002). 15% of AI-users discontinued therapy due to musculoskeletal symptoms, who were characterized by a larger grip strength reduction versus adherent patients (p=0.0107). Young age (p=0.0135), taxane-based chemotherapy (p=0.0223), and baseline VAS score >4 (p=0.0155) were predictors for AI-related musculoskeletal pain. In addition, a quadratic trend of BMI with grip strength change (p=0.0090) and probability of discontinuation was observed (p=0.0424). Musculoskeletal events were a substantial problem in AI-treated patients and an important reason for treatment discontinuation. The decrease in grip strength was larger in AI- than in tamoxifen-users, with a more pronounced change in symptomatic patients. The inverse relationship between BMI extremes and grip strength change was confirmed in this large group of AI-patients.

P0051 Immunomodulator effect of black cumin seed oil (BCO) in the inhibition of breast cancer carcinogenesis in Dimenthylbenzantracene (DMBA)-induced SD rats

Background Dimenthylbenzantracene (DMBA) suppresses bone marrow and splenocyte activity, and consequently decreases T lymphocyte, CD4Th, and CD8/CTL proliferation activity. CD4Th, CD4CD25Treg, and cytolytic T lymphocytes have an important role in immunosurveillance on carcinogenesis. Methods A study was conducted to eludcidate the chemopreventive and immunomodular effects of black cumin seed oil (BCO) administration, before and during DMBA induction (10 × 20 mg/KgBW over 5 weeks), in 80 SD rats. The test animals were divided into eight groups of ten mice. Group 1 was the normal control group; groups 2, 3 and 4 were treated with 6.85, 13.7, and 137 mg/kgBW/day BCO, respectively, and induced with DMBA; group 5 was positive control I (thymoquinone group); group 6 was positive control II (tamoxifen group); group 7 was the sick group (DMBA group); and group 8 was the solvent control group. All experimental and control groups were induced with 20 mg/kgBW DMBA, twice a week for 5 weeks. In week 27 a dissection and data collection were conducted. The nodule formation was observed starting from week 10 to week 27. The level of IFNγ was measured with ELISA. The calculation of the number of lymphocyte CD4Th, CD8 (CTL), and CD4CD25Treg of peripheral blood was conducted by flow cytometer. The chemopreventive effect was specified by determining the nodule incidence, the time of nodule formation, and histopathology image. The difference of the mean among all groups was measured by one-way ANOVA. Subsequently, the average difference between the test groups was tested and the LSD test was conducted. Findings Administration of BCO before and during induction with DMBA 10 × 20 mg/kgBW/day for 5 weeks decreased nodule formation and nodule number, increased the number of CD8 and CD4Th cytotoxic lymphocytes, and decreased the percentage of CD4CD25Treg in SD rats. 6.85 mg/kgBW/day dosage of BCO has the same chemopreventive and immunomodulator effect as the 68.5 mg/kgBW/day dosage but it is safer. Interpretation BCO administration of 6.85 mg/kgBW/day has chemopreventive and immunoprotective effects on DMBA-induced SD rats with breast cancer carcinogenesis.

High-Dosage Tamoxifen as Neoadjuvant Treatment in Minimally Invasive Surgery for Dupuytren Disease in Patients with a Strong Predisposition Toward Fibrosis

Tamoxifen, a synthetic nonsteroidal anti-estrogen known to modulate the production of transforming growth factor-beta (TGF-β), has demonstrated effectiveness on fibroblast activity in vitro and in vivo. The main purpose of this study was to investigate the effect of tamoxifen on the outcome of surgery for Dupuytren contractures in patients with a strong predisposition toward fibrosis. We used a prospective, randomized, double-blind study protocol (conforming to the CONSORT standards) to investigate the influence of tamoxifen compared with placebo on the total passive extension deficit in the finger and patient satisfaction after subtotal fasciectomy in thirty patients with a strong predisposition toward fibrosis (grade, >4 according to the Abe scale). High-dosage tamoxifen (80 mg/day) was administered from six weeks prior until twelve weeks after surgery, and patients were monitored for two years. Three months after surgery, patients in the tamoxifen group had a smaller total passive extension deficit and higher satisfaction compared with the placebo group. This positive effect was lost over the two years following cessation of the medication. This study demonstrated that the short-term outcome of Dupuytren disease treatment could be influenced by use of tamoxifen as a neoadjuvant from six weeks prior to three months after subtotal fasciectomy in patients with a strong predisposition toward fibrosis. However, the beneficial effect disappeared within two years after surgery, with worsening of the contractures after the medication was discontinued. Thus, tamoxifen may have a short-term effect on the outcome of surgery for Dupuytren disease.

Morphological and immunohistochemical study of ovarian and tubal dysplasia associated with tamoxifen.

Ovarian epithelial dysplasia was initially described in material from prophylactic oophorectomies for BReast CAncer gene (BRCA) mutation. Similar histopathological abnormalities have been revealed after ovulation stimulation. Given that tamoxifen (TAM) has a clomid-like effect and is sometimes used to induce ovulation, we studied the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in adnexectomies previously exposed to TAM for breast cancer. We blindly reviewed 173 histopathological slides of adnexectomies according to three groups – oophorectomies associated with TAM exposure (n=42), oophorectomies associated with clomiphene exposure (n=15) and a spontaneously fertile non cancerous control group (n=116). Morphological features (with an ovarian and tubal dysplasia scoring system) and immunohistochemical expression patterns of Ki-67, p53 and Aldehyde dehydrogenase 1 (ALDH1 is an enzyme significantly associated with earlystage ovarian cancer) were evaluated and correlated. Mean tubal dysplasia score was significantly higher in the TAM group and clomiphen group than in controls (respectively 7.8 vs 3.5, P<0.007 and 6.8 vs 3.5, P=0.008). There is no statistical difference for the ovarian score in TAM group in comparison with the control group whereas we found a significant score for clomiphen group (6.5, P=0.009). Increased ALDH1 expression was observed in the two exposed group whereas expression patterns of Ki67 and p53 were moderate. Interestingly, ALDH1 expression was low in non-dysplastic epithelium, high in dysplasia, and constantly low in the two carcinoma.Furthemore, we confirm our previous results showing that ALDH1 may be a useful tissue biomarker in the subtle histopathological diagnosis of tubo-ovarian dysplasia.

Morphological and immunohistochemical analysis in ovaries and fallopian tubes of tamoxifen, letrozole and clomiphene-treated rats.

Ovarian and tubal dysplasia may be precursors to ovarian cancer. The goal of this study was to check whether these histopathological lesions would be found after ovulation induction using tamoxifen, clomiphene citrate and letrozole. Seventy-two rats were divided into four groups. In the first group, 24 rats received normal saline. The second group (16 rats) received clomiphene citrate for six cycles. The third group, divided into two sub-groups of eight rats each, were stimulated with tamoxifen for six cycles, with a dosage, respectively, of 0.4 and 0.8mg/kg/day. In the last group, eight rats received letrozole 0.1mg/kg/day and eight other rats received letrozole 0.5mg/kg/day, for six cycles. Once the six cycles had been completed the rats were killed in order to remove ovaries and tubes for histopathological analysis (morphological, p53 and Ki67 immunohistochemical assessment). Histopathological lesions were found in both ovaries and tubes. The mean ovarian dysplasia score was significantly higher in the tamoxifen group whatever the dosage (p=0.006 and 0.0002) and in the letrozole group with 0.5mg/kg/day (p=0.0002) compared with the control group. The mean tubal dysplasia score was significantly higher in all groups that received drug treatment compared with the control group, whatever the dosage used. The proliferation index (Ki67) was significantly higher in the tamoxifen and letrozole groups while no significant difference was found for apoptosis marker p53. Ovulation induction may induce histopathological abnormalities in ovaries and tubes with a different immunohistochemical profile in comparison with salpingo-oophorectomies for genetic risk.

Thymoquinone, a component of the Middle East spicy seed Nigella sativa, decreases oxidative DNA damage in a rat model of mammary cancer (693.21)

Tamoxifen (TAM) is used widely for treatment and prevention of breast cancer. However, TAM has been reported to have a negative effect on the antioxidant glutathione (GSH) levels and 8‐hydroxydeoxyguanosine (8‐OHdG), a fingerprint of free radial attack on DNA. Thymoquinone (TQ), the main active ingredient of Nigella sativa, is used in the Middle East for treatment of several diseases like cancer. The aim of my research was to investigate the role of TQ in improving 8‐OHdG and GSH compared with TAM in female Sprague Dawley rats treated with DMBA, a drug used to induce mammary carcinoma in experimental rodents. Five groups of 10 rats (Controls, DMBA, TAM, TQ, and TAM+TQ) were treated for 10 weeks after injection of DMBA. 8‐OHdG in blood samples was significantly higher in the TAM group compared with the controls (P=0.008), the DMBA group (P=0.041), and the TQ group (P &lt;0.001). TQ significantly decreased 8‐OHdG by itself compared with DMBA (P=0.039) and TAM (P=0.001), but did not significantly reduce the effect of TAM in the TAM+TQ group. On the other hand, GSH did not differ among treatments. Body weight gain over 12 weeks was significantly different among the groups (P&lt;0.001). The TAM and TAM+TQ groups had the lowest weight gain compared with the other groups. This is the first study to show that TQ protects against oxidative DNA damage. I conclude that TQ could be a better anticancer drug than TAM because it decreased 8‐OHdG and protected growth.

Ocular findings in breast cancer patients using tamoxifen

Aim: To examine ocular findings of breast cancer patients using tamoxifen.Methods: The records of 79 consecutive breast cancer patients were examined, retrospectively. Female patients who had previously been diagnosed to have breast cancer with either stage I, II, or III disease, and were older than 25 years of age were included in the study. Results of the ophthalmic examination, color discrimination, and contrast sensitivity tests were recorded. Short wavelength automated perimetry (SWAP) sensitivity values were obtained, and average sensitivity values of test points at 5°, 9°, 15°, and 21° from the fixation were calculated.Results: Forty-nine of the patients had received 20 mg daily dose of tamoxifen therapy (tamoxifen group), while remaining 30 patients had not used tamoxifen (control group). Anterior and posterior segment examination revealed no pathologic findings in both groups. Two patients (5%) in the tamoxifen group had diffuse color loss, while none did in the control group (p = 0.523). Statistically significant differences were not detected between two groups when square roots of total error in color vision, red-green, and blue-yellow partial error scores were compared. Contrast sensitivity values were similar in both groups. Average mean deviation (MD) and average sensitivity values of test points at each 4° were statistically significantly lower in the tamoxifen group than the control group (p = 0.002, p = 0.001, p < 0.001 and p < 0.001 for right eye; p = 0.002, p = 0.001, p < 0.001 and p < 0.001 for left eye). Strong correlation was detected between MD, and duration (r = −0.832 and r = −0.842 for right and left eyes, respectively) and cumulative dose of tamoxifen use (r = −0.864 and r = −0.854 for right and left eyes, respectively).Conclusion: Clinically significant ocular toxicity is not frequently encountered in breast cancer patients, however, SWAP changes may occur early after tamoxifen utilization.

Comparative uterotrophic effects of endoxifen and tamoxifen in ovariectomized Sprague-Dawley rats.

Endoxifen (4-hydroxy-N-desmethyl-tamoxifen), one of the major active metabolites of tamoxifen, has substantially greater estrogen antagonist properties and antiproliferative effects in breast tumor cells than tamoxifen, a mixed estrogen agonist/antagonist. An associated risk of endometrial cancer and hyperplasia has been linked to the estrogen agonist properties of tamoxifen. We evaluated endoxifen using a classic uterotrophic effects method. Rats were given endoxifen or tamoxifen orally for 3 days. Estradiol was the positive control. Endoxifen and tamoxifen plasma levels exceeded those previously observed clinically. Uterine weight was 3-fold higher in the estradiol group than in the tamoxifen or endoxifen groups, which did not differ from vehicle controls. Tamoxifen and endoxifen caused a greater increase in luminal epithelial cell height than estradiol. Both tamoxifen and endoxifen produced an increase in the stromal BrdU labeling index (LI) that was ≤ estradiol and inversely related to dose, but did not affect luminal epithelial cell BrdU LI. As expected, estradiol increased luminal epithelial cell proliferation. These results indicate that endoxifen induces uterotrophic effects, but is less potent than estradiol in eliciting these effects. Given prior preclinical observations that endoxifen has superior antitumor activity than tamoxifen, the observations of similar uterine effects suggest that the endoxifen risk/benefit ratio may be superior to tamoxifen.

Allicin enhances chemotherapeutic response and ameliorates tamoxifen-induced liver injury in experimental animals

Context: Tamoxifen (TAM) is widely used for treatment of hormone-dependent breast cancer; however, it may be accompanied with hepatic injury. Allicin is the most abundant thiosulfinate molecule from garlic with the potential to provide beneficial effects on various diseases.Objective: To elucidate the effect of commercially available allicin on both antitumor activity and liver injury of TAM.Materials and methods: The cytotoxicity of TAM and/or allicin was evaluated in vitro using cultured Ehrlich ascites carcinoma (EAC) cells and in vivo against murine tumor (solid) model of EAC. TAM induced liver injury in rats by intraperitoneally (i.p.) injection at a dose of 45 mg/kg, for 7 successive days.Results: TAM at a dose of 3 µM (IC50) significantly decreased percent survival of EAC to 52%. TAM combination with allicin (5 or 10 µM) showed a significant cytotoxic effect compared with the TAM-treated group as manifested by a decrease in percent survival of EAC to 35% and 29%, respectively. Allicin (10 mg/kg, orally) enhanced the efficacy of TAM (1 mg/kg, i.p.) in mice as manifested by a significant increase in solid tumor growth inhibition by 82% compared with 70% in the TAM group. In rats, TAM intoxication resulted in a significant decline in SOD, GSH, and total protein with significant elevation in TBARS, ALT and AST, ALP, LDH, total bilirubin, γGT, and TNF-α levels. These changes are abrogated by allicin treatment.Discussion and conclusion: The results suggest the beneficial role of allicin as an adjuvant to TAM in cancer treatment by alleviating liver injury.

Analysis of quantitative changes in hair growth during treatment with chemotherapy or tamoxifen in patients with breast cancer: a cohort study

In women with breast cancer, chemotherapy-induced alopecia is a highly feared but common side-effect of antineoplastic treatment. The onset, pattern and amount of hair loss differ depending on the therapy regimen and have not yet been quantified using standardized techniques. To evaluate objectively and compare the effect of antineoplastic therapy with chemotherapy or tamoxifen on hair loss, quantifying trichological parameters. Female patients with breast cancer were included (n = 34), who were receiving chemotherapy (group C, n = 17) or tamoxifen (group T, n = 17) after surgery. Trichological parameters were evaluated once before [week 0 (w0)], twice during (w3, w6) and twice after (w18, w28) the normal 16-week course of chemotherapy, or at corresponding time points during continuous tamoxifen intake. At each visit, anagen and telogen hairs and hair density were quantified by automated phototrichogram in two defined areas: frontal and occipital. Group T generally showed no changes in anagen and telogen hairs or hair density. In group C, anagen hairs and hair density generally followed the same course, decreasing until w6, remaining at a low level during w6-18 and increasing after cessation of chemotherapy, reaching values comparable with or higher than baseline at w28. Telogen hairs increased until w3 then decreased until w6, remaining stable afterwards. Diffuse hair loss begins shortly after initiation of chemotherapy, mainly as anagen effluvium, with a proportion of anagen to telogen conversion. Hair loss is most prominent after 6 weeks of chemotherapy. Within 3 months after cessation of chemotherapy, hair growth rate returns to baseline values. Tamoxifen did not affect hair growth parameters.