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PubMed1992

Regulation of transforming growth factor gene expression in human endometrial adenocarcinoma cells.

We have examined the effects of medroxyprogesterone acetate (MPA) and 4-hydroxytamoxifen (OH-TAM) on the cell proliferation and the expression of TGF-alpha and TGF-beta genes in Ishikawa cells and HEC-50 human endometrial adenocarcinoma cells. The effects of exogenous TGF-alpha, TGF-beta and anti-EGF receptor monoclonal antibody on cell proliferation were also determined. Antisense oligonucleotides were used to determine the effects of endogenous expression of TGF-alpha and TGF-beta. In both cell lines, MPA resulted in a time and dose-dependent inhibition of cell proliferation whereas OH-TAM had no effect on HEC-50 cell proliferation. The relative abundance of TGF-alpha mRNA was significantly reduced by MPA in Ishikawa cells but not in HEC-50 cells. In Ishikawa cells, a reduction in TGF-alpha mRNA abundance was observed with OH-TAM under conditions where both inhibition and stimulation of cell proliferation were demonstrated. Anti-EGF receptor monoclonal antibody inhibited Ishikawa cell growth but had little effect on HEC-50 cell proliferation. Exogenous TGF-alpha stimulated proliferation of both cell lines whereas exogenous TGF-beta inhibited proliferation of Ishikawa cells but stimulated proliferation of HEC-50 cells. Antisense oligonucleotides to TGF-beta inhibited proliferation of HEC-50 cells. From these data we conclude that the antiproliferative effects of progestins and OH-TAM on endometrial cancer cells appear to be mediated by different mechanisms.

Adenocarcinoma↗
PubMed1992

11 beta-amidoalkyl estradiols, a new series of pure antiestrogens.

In order to find new antiestrogens, devoid of any agonistic activity, a series of 11 beta-amidoalkyl estradiols were prepared. These compounds have been studied in comparison with tamoxifen (TAM): in vitro, for their relative binding affinities (RBA) for mouse and MCF-7 estrogen receptors (ER) and for their antiproliferative effect on MCF-7 (estradiol or EGF/PDGF stimulated) and Ly2 human breast cancer cell lines; in vivo, for their uterotrophic/antiuterotrophic activities in the mouse and for their antitumoral activities on MCF-7 tumors implanted in nude mice. The most representative compounds are N-methyl-N-isopropyl-(3,17 beta-dihydroxy-estra-1,3,5(10)-trien-11 beta-yl)- undecanamide (RU 51625) and its 17 alpha-ethynyl derivative (RU 53637). They showed good RBAs for ER and a stronger antiproliferative effect than TAM in vitro. Unlike TAM, these compounds inhibited growth factor stimulated MCF-7 proliferation, and the growth of the TAM resistant cell line Ly2. In vivo, they were completely devoid of uterotrophic activity, when given subcutaneously in mice, but exhibited a slight agonistic effect when administered orally. They showed interesting antitumor activities in nude mice by the percutaneous route, but RU 53637 was significantly more potent than RU 51625 when given orally.

Alkylation↗
PubMed2006

Side effects of aromatase inhibitors versus tamoxifen: the patients' perspective.

BACKGROUND: Hormonal therapy is a mainstay in the management of estrogen receptor-positive (ER+) breast cancer. Tamoxifen (TAM) has been the drug widely used until the recent emergence of the aromatase inhibitors (AIs). Although AIs appear to be better tolerated than tamoxifen, they do have a different safety profile and these side effects have not been well characterized in community practice. We surveyed patients with ER+ breast cancers who received adjuvant hormonal therapy to determine how these medications impacted their quality of life and whether side effects or cost influenced decisions to continue therapy. METHODS: A mailed questionnaire and community cancer registry were used. RESULTS: Four hundred fifty-two of 902 surveys were returned for a 50% response rate. Eighty-two percent of respondents were placed on (adjuvant hormonal therapy) some form of estrogen-blocking therapy. Fifty-four percent of these were placed on tamoxifen and 46% on an AI. The most troublesome symptoms for tamoxifen and AI users, respectively, included hot flashes (35%/30%), weight gain (14%/15%), insomnia (17%/17%), and joint aches (12%/23%, P = .002). Thirty-nine percent of TAM users and 46% of AI users were taking medications to control their symptoms. Fifty percent of TAM users and 39% of AI users took vitamin E to help control hot flashes. Forty-two percent of TAM users versus 32% of AI users took Advil (Wyeth, Richmond, VA) for muscle/joint aches; 47.5% of AI users switched medication to improve symptoms as compared with only 37% of tamoxifen users (P = .015). The average cost of medications to control side effects for both tamoxifen and AI users was $67.36 per month. CONCLUSIONS: In our survey, both tamoxifen and AI users reported significant and different side effects. AI users suffered more frequently from musculoskeletal complaints, and more AI users switched therapy. Both AI and tamoxifen users used adjunctive medications for symptom control. In both groups, a large number used vitamin E to help hot flashes despite weak evidence to support its effectiveness in this setting. Cost of therapy and symptom control was not a major barrier to care.

Antineoplastic Agents, Hormonal↗
PubMed2005

Systematic review of LHRH agonists for the adjuvant treatment of early breast cancer.

There is increasing use of luteinising hormone-releasing hormone (LHRH) agonists in the adjuvant treatment of breast cancer (J. Clin. Oncol. 19(2) (2001) 343). However, few mature studies are available and there is uncertainty regarding the optimal use of these agents. We performed a systematic review to address the role of LHRH agonists in the adjuvant treatment of pre-menopausal women with early breast cancer. As ovarian suppression is unlikely to benefit women with ER-negative tumours, the review is limited to women with ER-positive disease. The objectives of this review were to address the following issues; the role of LHRH agonists compared to tamoxifen (TAM), LHRH agonists in place of chemotherapy and LHRH agonists integrated into chemo-hormonal regimens. We identified 11 randomised trials. In three trials, adjuvant suppression of ovarian function using LHRH agonists, with or without TAM, had similar benefits at 5-6 years follow-up in terms of disease-free survival (DFS) and overall survival (OS) to adjuvant CMF chemotherapy (J. Clin. Oncol 20(24) (2002) 4628; J. Natl. Cancer Inst. 95(24) (2003) 1833; Anticancer Res. 22 (2002) 2325; In: San Antonio Breast Cancer Symposium, San Antonio, TX, 2003, Abstr 40). These findings suggest that ovarian suppression using LHRH agonists (+/-TAM) is a reasonable alternative to CMF chemotherapy in women with oestrogen receptor (ER) positive tumours. The role of chemotherapy in addition to LHRH agonists is not clearly defined and mature results of four trials are awaited (J. Clin. Oncol. 20(24) (2002) 4621; J. Clin. Oncol. 18(14) (2000) 2718; Proc. Am. Soc. Clin. Oncol. 2000, Abstr 279; Proc. Am. Soc. Clin. Oncol. 20 (2001) Abstr 104; Proc. Am. Soc. Clin. Oncol. 2001, Abstr. 1777). Data is also inadequate at the time of publication to inform decisions about the efficacy of LHRH agonists in comparison with TAM for the treatment of ER-positive early breast cancer (Proc. Am. Soc. Clin. Oncol. 21 (2001) Abstr. 103; Eur. J. Surg. Oncol. 28(5) (2002) 505; Proc. Am. Soc. Clin. Oncol. 22 (2003), Abstr. 15).

Adult↗
PubMed2006

Pilot study of the impact of letrozole vs. placebo on breast density in women completing 5 years of tamoxifen.

Breast density, a strong risk factor for breast cancer, is reduced by the anti-estrogen, tamoxifen (TAM). We examined whether aromatase inhibitor (AI) therapy results in further reductions in breast density among women completing 5 years of TAM. Among a sample of women with early-onset breast cancer who were randomized to letrozole (LET)(n=56) or placebo (PLAC)(n=48) after 5 years of TAM, we examine the change in percent density at 9-15 months as well as a per-year change in PD by treatment group. There was no difference in the adjusted mean change (-1.0%, LET; -0.3%, PLAC (P=0.58)) or the percentage change (-2.7%, LET; -3.0%, PLAC (P=0.96)) in PD between treatment groups at 9-15 months. Results were similar for longitudinal change (-0.68% per year, LET; -0.12% per year, PLAC (P=0.23)). Breast density does not appear to be a clinically relevant biomarker in women who already have low PD following 5 years of TAM.

Adult↗
PubMed2007

Cost-utility of adjuvant hormone therapies with aromatase inhibitors in post-menopausal women with breast cancer: upfront anastrozole, sequential tamoxifen-exemestane and extended tamoxifen-letrozole.

This evaluation adapts a previous Canadian analysis of upfront and sequential adjuvant AI strategies in postmenopausal women with breast cancer to a Belgian perspective and includes an extended aromatase inhibitor (AI) strategy. A Markov model calculated monthly costs and outcomes in a hypothetical cohort of postmenopausal women with early-stage breast cancer. Baseline event rates and hazard ratios were derived from the Arimidex, Tamoxifen Alone or in Combination trial, International Exemestane Study and MA.17 trials. The analysis took a Belgian healthcare payer perspective with a 20-year time horizon. Costs and outcomes were discounted by 3%. Costs are in 2005 Euros. The cost-utility of all three strategies was favourable (<30,000 euros per QALY gained). Based on indirect comparisons using tamoxifen (TAM) alone as a common comparator, sequential TAM-AI was less costly and more effective than upfront or extended strategies. All three AI strategies were cost-effective alternatives to TAM alone, but sequential TAM-AI appears to be the economically preferred strategy.

Aged↗
PubMed2004

Cytotoxicity of tamoxifen in normal and tumoral cell lines and its ability to induce cellular transformation in vitro.

Tamoxifen (TAM) is a non-steroidal anti-estrogen used to treat patients with estrogen receptor-positive breast cancer and as a chemopreventive agent against breast cancer in high risk pre- and post-menopausal women. However, recent studies have shown that tamoxifen causes endometrial and hepatic cancer. In this study, we examined the effects of tamoxifen (5, 10, 25 and 50 microM) on the growth and proliferation of nine tumoral cell lines (UACC62, MCF-7, NCI-460, K-562, OVCAR-03, PC-03, HT-29, 786-0, NCI-ADR) and non-tumoral cell lines (3T3, V79, MDCK, VERO). Chinese hamster lung fibroblasts (V79) were the most sensitive lineage to tamoxifen, with 21.6% of the cells showing apoptosis at 50 microM TAM. Microscopic analysis showed that, the cellular transformation caused by TAM in V79 cells was similar to that seen with 7,12-dimethylbenz(a)anthracene, thus indicating the carcinogenicity of TAM.

Animals↗
PubMed2004

Decreased right ventricular function after coronary artery bypass grafting and its relation to exercise capacity: a tricuspid annular motion-based study.

BACKGROUND: Decreased right ventricular (RV) function is a known echocardiographic finding after coronary artery bypass grafting (CABG). For patients with heart failure, RV dysfunction is a predictor of poor exercise capacity. The significance and time course of RV dysfunction and its relation to exercise capacity after CABG have not been elucidated, however. OBJECTIVES: In this prospective study, we assessed RV function measured from echocardiographic tricuspid annular motion (TAM) before and after CABG and its relation to exercise capacity. METHODS: In 99 patients accepted for CABG, we did a baseline echocardiographic investigation before operation, followed by repeated echocardiograms 3 months and 1 year after CABG. RV function was assessed using the magnitude of TAM measured at the RV free wall. An exercise stress test and coronary angiography were performed before and 3 months after CABG. RESULTS: RV function assessed by TAM was significantly reduced 3 months after CABG (22.4 vs 14.5 mm, P <.001) compared with preoperative measurements and remained so after 1 year (14.7 mm, P <.001). Left ventricular systolic function was unchanged 3 months after CABG. The 1-year echocardiographic follow-up showed paradoxical septal movement in 96% of the patients. Exercise capacity improved significantly 3 months after CABG compared with before (1.6 vs 1.83 W/kg, P <.001). These finding are independent of the state of the right coronary artery. CONCLUSIONS: One year after CABG, RV function remained depressed and septal motion remained paradoxical compared with the preoperative investigation, suggesting that these postoperative findings might be permanent in the majority of patients. Despite the reduced RV function, exercise performance 3 months after CABG was improved. The depressed RV function, measured from TAM after CABG, probably lacks clinical significance.

Aged↗
PubMed2006

Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy.

Tumour-associated macrophages (TAM) represent the major inflammatory component of the stroma of many tumours, and can affect different aspects of the neoplastic tissue. Many observations indicate that TAM express several M2-associated pro-tumoural functions, including promotion of angiogenesis, matrix remodelling and suppression of adaptive immunity. The pro-tumoural role of TAM in cancer is further supported by clinical studies that found a correlation between the high macrophage content of tumours and poor patient prognosis. Evidence is presented here supporting the view that TAM represent a unique and distinct M2-skewed myeloid population and are a potential target for anti-cancer therapy.

Cell Transformation, Neoplastic↗
PubMed2006

An oligonucleotide decoy for Stat3 activates the immune response of macrophages to breast cancer.

Tumor-associated macrophages (TAMs) have the potential to induce both immune activation and immune tolerance. Recent studies have indicated that in breast cancers the pro-tumor role of TAMs is dominant. We induced rat peritoneal macrophages with rat breast cancer cell-conditioned medium and analyzed signal transducer and activators of transcription 3 (Stat3) activities of the cells. Then these cells were transfected with Stat3 decoy oligonucleotides (ODNs) and were stimulated by lipopolysaccharide (LPS). The results demonstrate that induced macrophages displayed a reduction of cytotoxicity and antigen-presenting function in comparison with control but transfection with Stat3 decoy ODNs enhanced cytotoxicity and antigen-presenting function of the macrophages. Furthermore, injection of induced macrophages promoted tumor growth accompanied by immunosuppression in the rat tumor models, but injection of induced macrophages transfected with Stat3 decoy ODNs led to retarded tumor growth accompanied by immune activation. The data suggest that immunosuppressive activities of TAMs correlate with over-activated Stat3 signaling of the cells and disruption of Stat3 activity of TAMs can enhance rat immune response to breast cancer.

Animals↗
PubMed2004

Thioacetamide-induced liver regeneration involves the expression of cyclooxygenase 2 and nitric oxide synthase 2 in hepatocytes.

BACKGROUND/AIMS: A regeneration process intended to restore organ function follows liver hepatotoxicity induced by a necrogenic dose of thioacetamide (TAM). METHODS: The expression of genes related to inflammation such as nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) has been analyzed in the course of the regenerative response, using NOS-2 KO mice or animals treated with selective inhibitors of COX-2. RESULTS: All animals lacking both activities survived to the hepatotoxic administration. However, animals deficient for NOS-2 exhibited more severe organ damage in view of the levels of hepatic serum markers of function, as well as an attenuated activation of NF-kappaB. The levels of C/EBPs were determined as markers of hepatocyte de-differentiation and regeneration, and the expression of COX-2 in TAM treated animals was concomitant with a decrease in C/EBP-alpha level. Analysis of cyclin D1, E and PCNA correlated with hepatocytes entering into the S phase of cell cycle by the effect of TAM. CONCLUSIONS: These data indicate that hepatocytes from TAM-treated mice express NOS-2 and COX-2 proteins and initiate the regeneration process that follows acute liver injury. However, the absence of NO delays hepatocyte regeneration, whereas COX-2-inhibition appears to decrease liver damage.

Animals↗
PubMed2003

Mechanisms governing the accumulation of estrogen receptor alpha in MCF-7 breast cancer cells treated with hydroxytamoxifen and related antiestrogens.

This study aimed at a better understanding of estrogen receptor alpha (ER) up regulation induced by partial estrogen antagonists. Effect of treatment with hydroxytamoxifen (OH-Tam) on ER level in MCF-7 cells was investigated by an approach combining ER measurement (enzyme immunoassay) and morphological demonstration (immunofluorescence). Furthermore, the influence of drug exposure on the rates of ER synthesis and degradation was assessed by determining [35S]methionine incorporated into the receptor in different experimental conditions (measurement of synthesis or pulse-chase experiments). ER up regulation was already induced by a 1-h pulse treatment with OH-Tam, thus a continuous exposure was not required. This process appeared reversible (i.e. ER accumulation due to OH-Tam rapidly vanished upon subsequent exposure to 17beta-estradiol (E2) or the pure antiestrogen RU 58668). While OH-Tam did not affect the rate of [35S]methionine incorporation into ER, it clearly caused an impairment of ER degradation (pulse-chase experiments) indicating that up regulation results from a stabilization of the receptor associated with the maintenance of its synthesis. Various tamoxifen derivatives, as well as a few related partial antiestrogens, were compared on the basis of binding ability and propensity to induce ER up regulation. A close relationship was found between both properties. Structure-activity analysis revealed that the capacity of these compounds to induce ER up regulation is associated with characteristics of their aminoalkyle side-chain, similar to those required for antiestrogenicity.

Breast Neoplasms↗
PubMed2006

Pro-inflammatory cytokinemia is frequently found in Down syndrome patients with hematological disorders.

Down syndrome (DS) patients are frequently complicated with infections, autoimmune phenomena and hematological disorders, including transient abnormal myelopoiesis (TAM) in infancy and acute megakaryoblastic leukaemia (AMKL) in later life. In this study, serum levels of cytokines from 23 TAM and 15 AMKL patients were examined using the highly sensitive microsphere fluorescence system. Statistical differences between DS neonates with or without TAM were found in IL-1beta [median 7.0 pg/ml (0.34-271.6) verses 0.05 pg/ml (0.0-2.4), p=0.034], TNF-alpha [8.11 pg/ml (0.1-253.0) verses 0.41 pg/ml (0.1-1.5), p=0.041], and IFN-gamma [20.0 pg/ml (0.14-406.3) verses 1.5 pg/ml (0.14-5.79), p=0.036]. Moreover, abnormal inflammatory cytokinemia was also found in myelodysplastic syndrome (MDS) and AMKL with DS. These abnormal cytokinemia may have a role in the pathophysiology of TAM, MDS and AMKL in DS, especially in liver fibrosis or myelofibrosis.

Child, Preschool↗
PubMed2004

Estrogen- and tamoxifen-associated effects on brain structure and function.

We evaluated the effects of estrogen and tamoxifen, a selective estrogen receptor modulator, on positron emission tomography (PET) measures of brain glucose metabolism and magnetic resonance imaging (MRI) measures of hippocampal atrophy. Three groups of postmenopausal women were studied, women taking estrogen (ERT+), women with breast cancer taking tamoxifen (TAM), and women not taking estrogen or tamoxifen (ERT-). All subjects received a PET scan, an MRI scan, and cognitive testing. The TAM group showed widespread areas of hypometabolism in the inferior and dorsal lateral frontal lobes relative to the other two groups. The ERT- group showed lower metabolism in the inferior frontal cortex and temporal cortex with respect to the ERT+ group. The TAM group also showed significantly lower semantic memory scores than the other two groups. Finally, the TAM group had smaller right hippocampal volumes than the ERT+ group, an effect that was of borderline significance. Both right and left hippocampal volumes were significantly smaller than the ERT+ group when a single outlier was removed. The ERT- group had hippocampal volumes that were intermediate to the other two groups. These findings provide physiological and anatomical evidence for neuroprotective effects of estrogen.

Aged↗
PubMed2006

VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival.

BACKGROUND: The ability of malignant tumors to metastasize presents a severe challenge in cancer treatment. Lymphatic vessels provide one of the main routes for tumor-metastasis on the way to regional lymph nodes. Increasing evidence suggests that inflammatory cells play an important role in tumor-associated angiogenesis and lymphangiogenesis. Recent data show that a specialized sub fraction of tumor-associated macrophages (TAMs) expressing the lymphoangiogenic growth factors vascular endothelial growth factor-C and -D (VEGF-C/D) at the tumor site, is related to lymphangiogenesis, lymphovascular invasion, and lymph node metastasis. Aim of this study was to clear the role of VEGF-C/D expressing TAMs in invasive breast cancer. METHODS: One hundred-seven cases of lymph node positive invasive breast cancer were included into the study. Lymphatic microvessel density (LMVD), lymphovascular invasion (LVI), peritumoral inflammatory reaction (PI), and VEGF-C expression in tumors (VEGF-C(T)) and TAMs (VEGF-C(C)) were evaluated by immunohistochemistry and in situ hybridization. RESULTS: Significant associations were seen between LMVD and LVI, LMVD and VEGF-C(T), and between VEGF-C(T) and VEGF-C(C). Further significant correlations were evaluated between VEGF-C(C)/VEGF-C(T) and PI as well as between PI and LVI. LVI remained an independent prognostic factor for disease-free survival and overall survival. CONCLUSIONS: Our data provide evidence that the peritumoral inflammatory reaction and VEGF-C expressing TAMs may play an important role in tumor lymphangiogenesis and lymphovascular invasion in invasive breast cancer, implying new potential anti-tumor targets.

Adult↗
PubMed2006

Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells.

OBJECTIVE: Interactions between estrogen receptor signaling and the PI3K/Akt pathway are present in estrogen-dependent cancer cells. Therapeutical inhibition of each of these pathways has been proven to exert antitumoral effects. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of Akt, is able to restore tamoxifen response in tamoxifen-resistant breast cancer cells. Given that Akt and mTOR phosphorylation also is frequently detected in ovarian and endometrial cancer, we intended to find out to what extent mTOR inhibitor RAD001 (everolimus) and tamoxifen add to each other's effects on growth and apoptosis of cancer cell lines derived from these tissues when given concomitantly. METHODS: OVCAR-3 and SK-OV-3 ovarian cancer cells, HEC-1A endometrial adenocarcinoma cells and MCF-7 breast cancer cells were treated with different concentrations of mTOR inhibitor RAD001 alone or in combination with 4-OH tamoxifen. Relative numbers of viable cells were assessed by means of the resazurin-based Cell Titer Blue assay, cellular apoptosis was examined by measurement of activated caspases 3 and 7 by means of the luminometric Caspase-Glo assay. RESULTS: Treatment with RAD001 resulted in growth inhibition of all employed cancer cell lines in a dose-dependent manner, and SK-OV-3 ovarian cancer cells proved to be most sensitive to this drug. Moreover, we report the observation of additive, but not synergistical growth inhibitory effects of a combination treatment with RAD001 and 4-OH TAM on SK-OV-3 and OVCAR-3 ovarian cancer cells and MCF-7 breast cancer cells in vitro, whereas no such effect was observed in HEC-1A endometrial adenocarcinoma cells. Combination treatment with both drugs was demonstrated to be superior to single treatment with lower concentrations (0.1 and 1 nM) of RAD001 or standard concentrations of 4-OH TAM. Furthermore, RAD001 increased the apoptotic effect triggered by high 4-OH TAM concentrations in SK-OV-3 ovarian cancer cells. CONCLUSION: Combination treatment with RAD001 and 4-OH TAM in vitro exerts an additive antitumoral effect on ovarian cancer cells and MCF-7 breast cancer cells. The significance of these data in the clinical situation has to be evaluated in further studies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Mechanisms of 4-hydroxytamoxifen anti-growth factor activity in breast cancer cells: alterations of growth factor receptor binding sites and tyrosine kinase activity.

We previously demonstrated that antiestrogen 4-hydroxytamoxifen (OH-Tam) blocks the mitogenic activity of growth factors in breast cancer. We now investigate this mechanism by evaluating how OH-Tam affects growth factor binding and receptor tyrosine kinase activity. We show here that OH-Tam has an opposite effect on epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1) binding in estrogen receptor (ER) positive cells. A decrease in IGF-1 binding sites may explain the reduced IGF-I mitogenic effect, whereas an increase in high affinity EGF binding associated with a decrease in in vitro receptor autophosphorylation rather favors the possibility of an alteration in EGF receptor tyrosine kinase activity. We conclude that OH-Tam may prevent growth factor action in ER+ cells both by modulating the concentration of growth factor binding sites and by altering growth factor receptor functionality.

Breast Neoplasms↗
PubMedDate not supplied

Tamoxifen and toremifene cause impairment of learning and memory function in mice.

Tamoxifen (TAM) and toremifene (TOR) are two antiestrogen agents frequently used in the treatment of breast cancer. They are currently being assessed as the prophylactic for patients at high risk of developing tumors. However, the side effects of these drugs on memory function have drawn attention in clinical usage. In the present study, it is demonstrated in mice that TAM and TOR significantly shortened the escaping latency or increased the number of errors, respectively, by using the step-down and step-through passive avoidance tests. By using an appetitively motivated task in T-maze, it is demonstrated that TAM and TOR significantly delayed the latency of finding food in well-trained mice. TAM appeared to impair memory consolidation and retrieval processes, rather than acquisition of memory, whereas TOR appeared to impair acquisition, consolidation, and retrieval processes. These results provide experimental support for the clinical findings that have shown that these drugs impaired memory function in patients routinely taking the drugs and suggest that caution should be taken for using these drugs as the prophylactics for those at risk of developing tumors.

Animals↗