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PubMed2002

Determination of tamoxifen and metabolites in mouse fetal tissue using nonaqueous capillary electrophoresis.

Tamoxifen (TAM), an antiestrogen, has been approved for use by women at risk for developing hormone-dependent breast cancer. Administration of TAM to pregnant CD-1 mice apparently results in reproductive tract toxicity in female offspring. However, there is little or no data describing potential TAM-induced fetal toxicity to women who may become pregnant while receiving prophylactic TAM treatment. In support of the National Toxicology Program's characterization of reproductive and developmental effects of TAM, the present work describes a capillary electrophoresis (CE)-based analytical technique used for detection of TAM and two major metabolites, N-desmethyltamoxifen (DMT), and 4-hydroxytamoxifen (4-HT) in CD-1 mouse fetal tissue. TAM-derived material was extracted from CD-1 mouse fetuses 2-12 h following TAM administration (100 mg/kg) to dams on gestation day 16. The presence of TAM, DMT, and 4-HT was confirmed in the solvent extracts by nonaqueous CE. The limit of detection of TAM by UV absorption was approximately 675 amol at a signal-to-noise ratio of 2:1. This work demonstrates both transplacental transport of TAM in CD-1 mice and a sensitive analytical technique for detecting low concentrations of TAM and similar compounds in biological tissues.

Animals↗
PubMed2006

Differential response to phytoestrogens in endocrine sensitive and resistant breast cancer cells in vitro.

Women approaching menopause increasingly investigate alternatives to hormone replacement therapy. Plant phytoestrogens are being promoted as "natural" alternatives but there is a lack of substantive data to advocate their safe use in breast cancer patients receiving tamoxifen (TAM), or in those who have relapsed. The aim of our study was to investigate the proliferative effects and mode of action of the phytoestrogens genistein, daidzein and coumestrol on TAM-sensitive (-s) and resistant (-r) breast cancer cells under in vitro conditions designed to mimic the hormonal environment of the pre- and post-menopausal breast. At physiological concentrations (<10 microM) and under reduced estrogen (E2) conditions, genistein was mitogenic to TAM-s cells with TAM-r cells generally refractory. Daidzein and coumestrol were growth stimulatory irrespective of TAM sensitivity. Transcriptional activity was ERE-mediated. Combining phytoestrogens with E2 (simulating the pre-menopausal breast environment) had no effect on growth of TAM-s or TAM-r cells. Addition of 4-HT mimicked the hormonal environment in post-menopausal breast cancer patients receiving TAM. The growth inhibitory effects of 4-HT were abrogated in TAM-s cells when combined with genistein and coumestrol, and to a lesser extent, daidzein, where significant growth stimulatory effects were observed. In TAM-r cells, proliferation did not exceed control values. At phytoestrogen concentrations above 10 microM, growth inhibitory effects were seen, irrespective of estrogenic environment or cell sensitivity to TAM. Our in vitro data suggests that phytoestrogens could have potentially adverse mitogenic effects on tumour cells and should probably be avoided by patients who remain sensitive to TAM or in those with pre-existing and possibly undiagnosed breast tumours.

Antineoplastic Agents, Hormonal↗
PubMed1985

FACS quantitation of leucine aminopeptidase and acid phosphatase on tumor-associated macrophages from metastatic and nonmetastatic mouse mammary tumors.

Macrophages were isolated by adherence from tumors produced by a number of murine mammary carcinoma lines and were examined by fluorescence-activated cell sorting for quantitation of leucine aminopeptidase and acid phosphatase. The tumors included three lines, 66, 67, and 168, which were originally derived from a single, spontaneously arising tumor in a BALB/cfC3H mouse and two other lines, D2A1 and D2F2, which were derived from a single tumor arising from the transplantable hyperplastic alveolar nodule line, D2. These five lines differ from one another in a number of characteristics, including the ability to metastasize spontaneously to the lung from subcutaneous implants and to form experimental metastases in lungs following intravenous injection. Line 67 is nonmetastatic under both circumstances, whereas lines 66, D2A1, and D2F2 are metastatic under the same conditions. Intermediate to these is line 168, which is nonmetastatic from the subcutaneous site but capable of colonizing the lung with an efficiency similar to 66 when injected IV. Tumor-associated macrophages (TAM) from lines 66, D2A1, and D2F2 contained the greatest amounts of leucine aminopeptidase (LAP) and those from line 67 the least, with TAM from 168 being intermediate. Conversely, the TAM from line 67 had the greatest amounts of acid phosphatase (APTase) and those from line 168 the least. In addition to differences among tumors in enzyme levels of the adherent TAM, the precentages of TAM that were adherent were also different among the tumors. Only 12% of TAM from line 67 were recovered in the adherent fraction as opposed to 35-38% of TAM from lines 66 and 168. These results confirm and extend our previous findings that TAM from metastatic tumors have increased levels of LAP compared to TAM from nonmetastatic tumors. They also demonstrate noncoordinate expression of LAP and APTase in TAM, and illustrate how a population of TAM can be homogeneous for one enzyme and heterogeneous for another. Furthermore, the difference in the percentage of macrophages that are adherent between metastatic and nonmetastatic tumors is another indication both of the heterogeneous nature of TAM and of the role of a tumor in determining the type of host infiltrate with which it is associated.

Acid Phosphatase↗
PubMed1998

Steroid receptor expression in endometria from women treated with tamoxifen.

Breast cancer patients receiving tamoxifen (Tam) are at an increased risk for developing endometrial carcinomas, possibly due to the partial estrogenic effect of Tam on endometrial cells. Progestational therapy has not routinely been included in Tam regimens. It was our aim to determine the presence of estrogen receptors (ERs) and progesterone receptors (PRs) in normal and abnormal endometria from postmenopausal women with breast cancer who were treated with Tam. Standard immunohistochemical staining of ERs and PRs was performed on paraffin sections from formalin-fixed uterine curettings or hysterectomy specimens from 40 patients who had received 20-40 mg of Tam daily for a minimum of 3 months. For comparison, normal endometria from 20 women who had not received Tam (11 premenopausal, 9 postmenopausal) were also studied for ER and PR expression. Staining was evaluated using semiquantitative immunoreactivity scores (IRS) ranging from 0 (negative) to 12 (strongly positive). In the group of patients receiving Tam, ERs and PRs were detected in the nuclei of glandular cells in 24/24 cases of endometrial atrophy (ER/PR-IRS, 2-12), in 8/8 endometrial polyps (ER-IRS, 6-12; PR-IRS, 4-12), in 4/4 adenomatous endometrial hyperplasias (ER-IRS, 3-8; PR-IRS, 1-12), and in 4/4 well-differentiated endometrioid adenocarcinomas (ER-IRS, 2-12; PR-IRS, 6-8). Of the 11 endometria from premenopausal patients who had not received Tam, 8 were ER+/PR+ (ER-IRS, 1-12; PR-IRS, 1-12), 1 was ER+/PR- (ER-IRS, 3; PR-IRS, 0), 1 was ER-/PR+ (ER-IRS, 0; PR-IRS, 2), and 1 was ER-/PR- (ER/PR-IRS, 0). Among 9 atrophic endometria from women not treated with Tam, 6 were ER+/PR+ (ER-IRS, 4-12; PR-IRS, 3-6), 1 was ER+/PR- (ER-IRS, 4; PR-IRS, 0), and 2 were ER-/PR- (ER/PR-IRS, 0). The consistent finding of ER and PR expression in endometria from postmenopausal women receiving Tam further supports the suspected estrogenic effect exerted by Tam on endometrial cells. Progestational therapy could be beneficial in the prevention of Tam-induced abnormal endometrial proliferations.

Antineoplastic Agents, Hormonal↗
PubMed1996

Ovarian status influences the skeletal effects of tamoxifen in adult rats.

Tamoxifen (TAM), an antiestrogen used in adjuvant therapy for breast cancer, is currently being evaluated for prevention of breast cancer in premenopausal and postmenopausal disease-free women. In light of this clinical application in young women, the skeleton's potential predisposition for osteoporosis following long-term treatment with an antiestrogen is a concern. In postmenopausal women being treated for breast cancer TAM was shown to prevent bone loss. There is little information, however, about the skeletal effects of TAM in premenopausal women. Previous animal studies in ovariectomized (OVX'd) rats have consistently reported TAM to prevent cancellous and cortical bone loss. The effects of TAM on ovary-intact animals, however, are not well established. We have performed a histomorphometric analysis in order to evaluate the influence of ovarian function on the skeletal effects of long-term TAM treatment in the laboratory animal model. Six-month-old rats were implanted subcutaneously with pellets designed for the controlled release of TAM at a dose (5 mg/3 wks) previously shown to be effective at antagonizing short-term bone loss in OVX'd growing rats. TAM acted as an estrogen agonist on cortical bone measurements in tibia of ovary-intact as well as OVX'd rats. In cancellous bone of OVX'd rats, TAM reduced indices of bone formation and resorption and reduced the bone loss from over 90 percent to less than 50 percent. In ovary-intact rats, however, TAM produced a 31 percent loss of cancellous bone, a deficit associated with a 26 percent reduction in the trabecular number. These results clearly demonstrate an interaction between TAM and ovarian status whereby TAM partially prevents estrogen-deficient bone loss in OVX'd animals but antagonizes selective actions of estrogen on the skeleton of ovary-intact animals.

Analysis of Variance↗
PubMed2003

Combined antitumor activity of 7-hydroxystaurosporine (UCN-01) and tamoxifen against human breast carcinoma in vitro and in vivo.

BACKGROUND: 7-Hydroxystaurosporine (UCN-01) was originally isolated as a protein kinase C inhibitor and has shown antitumor activity against several human cancer cell lines. UCN-01 inhibits cell cycle progression from the G1 to the S phase and is associated with inhibition of cyclin-dependent kinase (CDK) activity and induction of intrinsic CDK inhibitor p21, leading to dephosphorylation of retinoblastoma (Rb) protein. Tamoxifen (TAM) traps cancer cells in the G1 phase, suggesting that the mechanism of action of TAM is similar to that of UCN-01. The present study was conducted to assess the antitumor activity of UCN-01 combined with TAM against human breast carcinoma cells in vitro and in vivo. MATERIALS AND METHODS: MCF-7 cells were treated with UCN-01, TAM, or UCN-01 combined with TAM at various concentrations in vitro. The antitumor effect was evaluated as the inhibition rate (I.R.%) by MTT assay. Two human breast carcinoma xenografts in nude mice, MCF-7 and Br-10, were treated with UCN-01, TAM or both agents together. The expression of p21 and the phosphorylation status of Rb protein in MCF-7 cells were detected by Western blotting. RESULTS: UCN-01 or TAM alone inhibited the proliferation of MCF-7 cells in a concentration-dependent manner. Combined treatment with UCN-01 followed by TAM inhibited the growth of MCF-7 cells synergistically and no significant differences in cytotoxicity were observed between the different sequences of UCN-01/TAM and TAM/UCN-01. Combination treatment with UCN-01 and TAM against MCF-7 and Br-10 in vivo exhibited superior antitumor effects compared with either agent treatment alone. Although 0.1 microg UCN-01 per ml (I.R.: 48.1%) or 2 microM TAM (I.R.: 31%) induced p21 expression, phosphorylation of Rb protein was not inhibited. However, combination treatment with UCN-01 and TAM at the same concentrations resulted in an I.R. of 67% and dephosphorylation of Rb protein. CONCLUSION: The present study suggests that combining UCN-01 and TAM could result in augmented cytotoxicity because of their similar mechanism of action. This combination may have potential clinical applications for breast cancer treatment, by reducing the toxicity of UCN-01.

Animals↗
PubMed2006

Cost-utility of adjuvant hormone therapies for breast cancer in post-menopausal women: sequential tamoxifen-exemestane and upfront anastrozole.

BACKGROUND: Adjuvant Anastrozole (ANA) for 5 years and Tamoxifen followed by Exemestane (TAM-EXE) for 2.5 years each have become acceptable alternatives to 5 years of Tamoxifen (TAM) for post-menopausal women with breast cancer. As these newer options are associated with higher drug costs as well as improved outcomes, an economic evaluation was undertaken to compare the cost-utility of ANA and TAM-EXE relative to TAM alone and to each other in terms of cost per quality-adjusted life year (QALY) gained. METHODS: A Markov model was developed to calculate monthly costs and outcomes in a hypothetical cohort of post-menopausal women with early-stage breast cancer. Baseline rates of cancer recurrence and adverse effects with TAM, and hazard ratios associated with ANA and EXE, were derived from the ATAC and IES trials. Patients received hormonal therapy for 5 years and benefit was modeled to persist 5 years beyond treatment. The analysis took a direct payer perspective with a 20-year time horizon. Costs and outcomes were discounted by 3%. Costs are in 2005 Canadian dollars. RESULTS: ANA and TAM-EXE were associated with increased costs and QALYs, though the cost-utility of both relative to TAM alone was strongly favourable (<$50,000/QALY). Based on an indirect comparison of ANA and TAM-EXE, using TAM alone as a common comparator, the cost-utility of ANA relative to TAM-EXE appears unfavourable. CONCLUSIONS: Both upfront and sequential AI options were cost-effective alternatives to TAM alone, but TAM-EXE appears to be the economically preferred AI option based on its more favourable cost-utility versus ANA.

Aged↗
PubMed1988

In vitro growth regulation of endometrial carcinoma cells by tamoxifen and medroxyprogesterone acetate.

The growth inhibitory effects of medroxyprogesterone acetate (MPA) and tamoxifen (TAM) were tested on three long-established endometrial carcinoma cell lines (HEC-1, KLE, and RL95-2) and on UM-EC-1, a new endometrial carcinoma cell line established in our laboratory. MPA and TAM were used in growth experiments either alone, simultaneously, or sequentially. The MCF-7 breast cancer cell line was used as a control. None of the endometrial carcinoma cell lines showed significant sensitivity to 0.1-10 microM MPA. In contrast, 10 days exposure to 5 microM TAM induced 83 and 70% growth inhibition in HEC-1 and KLE cultures, whereas the growth of UM-EC-1 was inhibited by 99.7% and RL95-2 cultures by 100%. TAM-induced growth inhibition was reversible since all cell lines resumed logarithmic growth when TAM was removed from the culture medium. Addition of 17 beta-estradiol (E2) to the culture medium did not accelerate recovery, and reversal of TAM-induced growth inhibition was not seen when TAM and E2 were added simultaneously. This is consistent with our finding that, except for MCF-7, these cell lines did not show detectable estrogen receptor (ER) activity in assays performed at the time of these experiments. When treated sequentially with TAM and MPA, all cell lines resumed logarithmic growth when medium containing TAM was replaced with medium containing MPA. Simultaneous exposure to 5 microM MPA and 5 microM TAM resulted in a slight additive growth inhibitory effects only in KLE cultures. Our results show that MPA does not have growth inhibitory effects in these endometrial carcinoma cell cultures, whereas TAM exerts a potent inhibitory effect that is not reversed by estrogen and may thus be mediated through a mechanism different from blockade of ER. In vitro results with the UM-EC-1 cell line correlated with the clinical response of the cell line donor. Her disease progressed during postoperative MPA therapy, but subsequently she responded to TAM therapy.

Aged↗
PubMed1995

In vivo formation of DNA-adducts in mouse skin DNA by tamoxifen.

Tamoxifen (TAM)-induced DNA adduct formation in mouse skin was determined by a nuclease P1-enhanced 32P-postlabelling technique. Topical application of TAM significantly induced a number of DNA-adducts in mouse skin in a dose- and time-dependent manner. When SENCAR mice were topically treated with different doses of TAM for 6 h, total DNA adduct levels in skin were increased by 2.5- (1 mumol TAM), 4.5- (5 mumol TAM) and 4.8-fold (10 mumol TAM), respectively. In addition, at least four novel DNA adducts were observed. Time-course studies showed that TAM-induced DNA adducts reach a peak at 6 h post-treatment. However, the pattern of TAM-induced DNA adducts was different from that induced by DMBA (a potent skin carcinogen). TAM has been found to form DNA-adducts in the liver and kidney of rodents. Our work confirms the genotoxic effects observed by other investigators by showing that TAM also causes DNA-adducts formation in mouse skin. Since TAM is widely used for the treatment of breast cancer and currently for chemo-prevention trials, further studies should be conducted to assess the potential risk of long-term use of TAM in humans.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Tamoxifen resistance in breast cancer.

Tamoxifen (TAM) resistance is the underlying cause of treatment failure in many breast cancer patients receiving TAM. The mechanism(s) involved in TAM resistance are poorly understood. A variety of mechanisms have been proposed but only limited evidence exists to substantiate them. Studies have now shown that in many patients TAM resistance is not related to the down regulation or loss of estrogen receptors (ER). Variant ER have been identified, but their significance clinically remains to be proven. Since breast cancer cells secrete several estrogen-regulated growth factors and growth inhibitors that may have autocrine or paracrine activity, altered growth factor production is another possible mechanism for TAM resistance. Tissue-specific transcription activating factors that may alter how the signal induced by TAM binding to the receptor is interpreted by the cell also require further investigation. An increase in antiestrogen binding sites (AEBS), which could effectively partition TAM and reduce its concentration at the ER has also been proposed as a potential mechanism. Pharmacologic mechanisms, such as a shift in metabolism toward the accumulation of estrogenic metabolites, are supported by recent data demonstrating metabolite E and bisphenol in tumors from TAM-resistant patients. Furthermore, a decrease in tumor TAM accumulation and an altered metabolite profile have been reported in TAM-resistant breast tumors grown in nude mice. These and other studies suggest that TAM resistance may be multifactorial in nature, but definitive identification of mechanisms that are operative in clinical TAM resistance requires further study.

Animals↗
PubMed1997

Effects of cytochrome P450 inducers on tamoxifen genotoxicity in female mice in vivo.

We recently reported that administration of the antiestrogen tamoxifen (TAM) gives rise to two groups of DNA adducts in female mouse liver in vivo, as measured by 32P-postlabeling, and provided evidence that 4-hydroxytamoxifen and alpha-hydroxytamoxifen are proximate carcinogenic metabolites leading to group I and group II adducts, respectively (Randerath et al., Carcinogenesis 15: 2087-2094, 1994). Because cytochrome P450 (CYP) enzymes play an important role in TAM metabolism, in this investigation we tested the hypothesis that induction of liver CYP enzymes may affect TAM metabolism profoundly, resulting in increased or decreased TAM-DNA adduct formation in vivo. To this end, we treated female ICR mice with TAM either alone or in combination with one of several classic CYP inducers, i.e. phenobarbital (PB), beta-naphthoflavone (BNF), and pregnenolone-16 alpha-carbonitrile (PCN), and determined the levels of 32P-postlabeled TAM-DNA adducts and the activities of several CYP-dependent enzymes. Each of the inducers greatly diminished levels of group II, but did not affect group I adducts. TAM elicited induction of benzphetamine N-demethylase activity in liver, while activities of other enzymes were not affected. TAM, when given in combination with BNF, elicited a synergistic induction of ethoxyresorufin O-deethylase (EROD) (CYP1A1) and methoxyresorufin O-demethylase (MROD) (CYP1A2) activities. Likewise, PCN given along with TAM caused synergistic induction of EROD and ethylmorphine N-demethylase activities. There was no synergism between PB and TAM, however. Overall, the results further support the existence of two pathways of TAM metabolism to DNA-reactive electrophiles and strongly suggest that the classic CYP inducers tested enhance detoxication of TAM to non-genotoxic metabolites.

Animals↗
PubMed2000

High dose tamoxifen and radiotherapy in patients with glioblastoma multiforme: a phase IB study.

PURPOSE: To assess the feasibility and the toxicity of adjuvant high dose tamoxifen (TAM) and postoperative brain irradiation for patients with newly-diagnosed glioblastoma multiforme (GBM). MATERIAL AND METHODS: Twelve patients with histopathologically confirmed GBM entered the study. There were nine males and three females, with median age of 48.8 years (range 30-75 years). Karnofsky performance status (KPS) was 60-70% for four patients and 80-100% for eight patients. Based on the Radiation Therapy Oncology Group recursive partition analysis, there were three class III patients, six class IV, one class V, and two class VI. Eleven patients underwent partial surgical tumor resection and one patient had a near complete resection. Two weeks post surgery, the patients were started on high dose TAM (120 mg/m2 P.O. BID for three months). Two weeks from date of starting TAM, external beam radiotherapy (RT) was given at a dose of 59.4 Gy/33 qd fractions/6.5 weeks. Patients were assessed weekly for toxicity during treatment. Imaging studies were done at the end of two weeks of TAM, then monthly. RESULTS: Median follow-up was 40 weeks (range 22-84 weeks). In one patient, TAM was associated with significant vomiting, necessitating the TAM dose to be decreased at three weeks and then stopped at two months. One other patient had bilateral deep venous thrombosis after 52 weeks on TAM, although the relationship to TAM was not firmly established. There were no radiological responses after two weeks of TAM or at the end of RT. The median time to progression was 17.7 weeks (range 5.1-43.8 weeks). Median survival time was 33.4 weeks (range 10-79.7). Actuarial survival at 48 and 74 weeks was 40% and 15%, respectively. CONCLUSION: Our study shows that adjuvant high dose TAM is feasible and relatively well-tolerated. Furthermore, the combined use of high dose TAM and RT postoperatively was not associated with any significant increase in radiation-induced neurological toxicity. However, high dose TAM does not appear to improve treatment results.

Adult↗
PubMed1996

Influence of polyethylene glycol and acetone on the in vitro biotransformation of tamoxifen and alprazolam by human liver microsomes.

The use of in vitro hepatic microsomal models as a method of studying the biotransformation of xenobiotics can be complicated by the insolubility of a lipophilic substrate. Addition of solvent to an in vitro system is an approach used to increase solubility of such substrates, but solvents may interact with the microsomal enzymes and cause changes in the kinetic parameters. This study focused on the solvents polyethylene glycol-400 (PEG) and acetone and their influence on the human microsomal in vitro biotransformation of the antineoplastic agent tamoxifen (TAM). The antianxiety agent alprazolam (ALP), a verified P450 3A substrate, was also studied. TAM is a nonpolar drug that is metabolized to two oxidative metabolites, N-desmethyltamoxifen (DMT) and 4-hydroxytamoxifen (4-OH-TAM), by cytochrome P450 isoforms. DMT is formed primarily by 3A isoforms, and the pathway(s) responsible for 4-OH-TAM formation are unknown. Biotransformation of ALP is mediated by P450 3A isoforms, which form alpha-hydroxyalprazolam (alpha-OH-ALP) and 4-hydroxyalprazolam (4-OH-ALP). Both PEG and acetone at 5% of the total microsomal incubation volume were found to solubilize TAM in the in vitro system. However, both solvents had an effect on the P450 mediated metabolism of ALP and TAM. For ALP, PEG was a noncompetitive inhibitor of alpha-OH-ALP (mean Ki = 2.06%) and 4-OH-ALP (mean Ki = 2.37%) formation. Acetone stimulated the production of alpha-OH-ALP, but had no apparent influence on 4-OH-ALP formation. The solvent's influence on TAM metabolism varied. PEG decreased the amount of DMT formed by the microsomes as compared to the system containing no solvent (control); however, 4-OH-TAM formation in the presence of PEG was 146-226% of controls. Samples containing acetone produced smaller quantities of both DMT (39-63%) and 4-OH-TAM (45-69%) as compared to controls. Since PEG and acetone increased the solubility of TAM in the incubation buffer but inhibited or accelerated enzymatic reactions compared to buffer alone, actual solubility in buffer was not a determinant of the rate of TAM metabolism. TAM appeared to be taken up into the microsomal fraction, making it available for biotransformation by the P450 isoforms. Although solvents may increase the solubility of nonpolar agents in aqueous systems, careful evaluation of the effects of solvent on metabolite formation, as compared to buffer controls, is needed in order to properly evaluate an in vitro metabolic model.

Acetone↗
PubMed2003

Three-dimensional assessment of two-dimensional technique for evaluation of right ventricular function by tricuspid annulus motion.

BACKGROUND: Measurement of tricuspid annulus motion (TAM) is an easy way to estimate right ventricular ejection fraction (RVEF). However the accuracy of two-dimensional (2-D) methods for analyzing the three-dimensional (3-D) structure of the tricuspid annulus has not been evaluated. OBJECTIVE: This study evaluated the accuracy with which 2-D measurements of TAM reflect RVEF using 3-D reconstructions of the heart at end diastole (ED) and end systole (ES). METHODS: 2-D echocardiographic studies were performed on 12 subjects and used to reconstruct the RV and tricuspid annulus in 3-D at ED and ES. Measurements of TAM from medial and lateral positions on the annulus were selected from the standard echocardiographic apical four-chamber view. The minimum and maximum possible TAM values, RV volumes, and movement of the apex of the heart along the trajectory of TAM were calculated from the 3-D reconstructions. RESULTS: TAM correlated highly with RVEF (r > or = 0.90). Values found by 2-D and 3-D techniques were not significantly different. Correcting TAM for apex motion did not improve correlation. Summation of medial and lateral TAM data increased correlation values slightly relative to lateral TAM alone. Regional aberrant contractility degraded the predictive value of TAM. CONCLUSION: Estimation of RVEF from 2-D echo measurement of TAM is accurate, especially when medial and lateral TAM are summed, except in patients with severe apical RV dysfunction.

Adult↗
PubMed2000

Induction of p21WAF1 expression via Sp1-binding sites by tamoxifen in estrogen receptor-negative lung cancer cells.

Although originally synthesized as an anti-estrogen, tamoxifen (Tam) was found to be able to inhibit proliferation of estrogen receptor (ER)-negative cancer cells in vitro. However, the molecular basis of such ER-independent growth inhibition is largely unknown. We have previously demonstrated that Tam induces p21WAF1 and p27KIP1 expression in human lung cancer cells which lack ER-alpha and -beta. We found that Tam induced p21WAF1 expression via transcriptional activation. In order to determine the molecular mechanism responsible for p21WAF1 induction by Tam, we performed a deletion analysis on the p21WAF1 promoter. The minimal region in the p21WAF1 promoter required for Tam-activated induction was mapped to a contiguous stretch of 10 bp located 83 bases upstream of the transcription initiation site. Our results showed that transcription factor Sp1 and Sp3 bound to this GC-rich region and mutation of Sp1-binding sites dramatically attenuated Tam-induced p21WAF1 promoter activity. We also tried to elucidate the signaling pathway that mediated the activation of p21WAF1 by Tam. Inhibition of mitogen-activated protein kinase pathways did not block Tam-induced p21WAF1. Similarly, protein kinase C inhibitor calphostin C could not suppress Tam-induced p21WAF1. Conversely, pretreatment of a specific protein kinase A inhibitor H89 significantly attenuated the induction of p21WAF1 by Tam. Furthermore, PKA activators forskolin and dibutyryl-cAMP activated p21WAFI promoter activity and increased p21wAF1 protein level in lung cancer cells. Taken together, these results demonstrate that Tam activates the p21WAF1 promoter via Sp1-binding sites and suggest that PKA may be involved in the induction of p21wAF1 by Tam in ER-negative lung cancer cells.

Antineoplastic Agents, Hormonal↗
PubMed2002

Differences and relationships of thymidine phosphorylase expression in tumor-associated macrophages and cancer cells in squamous cell carcinoma of the esophagus.

Thymidine phosphorylase (TP), which has been shown to be identical to platelet-derived endothelial cell growth factor, is expressed in tumor-associated macrophages (TAMs) as well as cancer cells. The aim of this study was to clarify the differences or relationships of TP expression in TAMs and cancer cells in esophageal squamous cell carcinoma (SCC). Tissues samples were taken from 56 patients with esophageal SCC after curative surgery. The expression of TP in TAMs or SCC cells was examined using a monoclonal antibody to TP (clone 654-1). Microvessels in SCC that stained positively for Factor VIII-related antigen were counted (microvessel density, MVD). Macrophages in SCC that stained positively for CD68 antigen were counted (monocytic count). Ki-67 antigen was immunostained with MIB-1, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling was performed, and Ki-67 labeling index (LI) and apoptotic index were calculated. The expression of TP in stromal cells and cancer cells was observed in 43 (76.8%) and 33 patients (58.9%), respectively. There were significant correlations between TP expression in stromal cells (TAMs) as well as in cancer cells and venous invasion, distant metastasis, or MVD. There was a correlation between TP expression in cancer cells and lymph node metastasis, and there were correlations between TP expression in TAMs and monocytic count or Ki-67 LI; however, there was no correlation between TP expression in TAMs and lymph node metastasis. On the other hand, in SCCs with TP expression in both TAMs and cancer cells, higher frequencies of venous invasion and distant metastasis, higher MVD and lower apoptotic index were observed than in other SCCs. The 5-year survival rate in patients with TP expression in both TAMs and cancer cells was poorer than that in patients with TP expression in neither TAMs and cancer cell. In conclusion, these results suggest that co-expression of TP in TAMs and cancer cells is strongly associated with angiogenic promotion and distant metastasis. However, other effects of TP, such as promotion of tumor growth and lymph node metastasis, may be different depending on whether these are expressed in TAMs or cancer cells in esophageal SCCs. Patients with coexpression of TP in TAMs and cancer cells may be associated with a poor prognosis.

Antigens, CD↗
PubMed2004

Genotoxic mechanism of tamoxifen in developing endometrial cancer.

Increased risk of developing endometrial cancers has been observed in women treated with tamoxifen (TAM), a widely used drug for breast cancer therapy and chemoprevention. The carcinogenic effect may be due to genotoxic DNA damage induced by TAM. In fact, TAM-DNA adducts were detected in the endometrium of women treated with this drug. TAM is alpha-hydroxylated by cytochrome P450 3A4 followed by O-sulfonation by hydroxysteroid sulfotransferase, and reacts with guanine residues in DNA, resulting in the formation of alpha-(N2-deoxyguanosinyl)tamoxifen adducts. During this metabolic process, short-lived carbocations are produced at the ethyl moiety of TAM as reactive intermediates. TAM-DNA adducts promote primarily G -->T transversions in mammalian cells. The same mutations have been frequently detected at codon 12 of the K-ras gene in the endometrial tissue of women treated with this drug. TAM-DNA adducts, if not readily repaired, may act as initiators, leading to development of endometrial cancers. The reactivity of TAM metabolites with DNA is inhibited in toremifene, where the hydrogen atom has been replaced by a chlorine atom at the ethyl moiety. Therefore, toremifene may be a safer alternative to TAM. This article describes an overview of the mechanism of TAM-DNA adduct formation, mutagenic events of this adduct, and detection of TAM-DNA adducts in the endometrium of women treated with TAM.

Adult↗
PubMed2000

Identification of hepatic tamoxifen-DNA adducts in mice: alpha-(N(2)-deoxyguanosinyl)tamoxifen and alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide.

Tamoxifen-DNA adducts detected in the liver of mice treated with tamoxifen have not yet been identified. In the present study a new type of tamoxifen-DNA adduct, four stereoisomers of alpha-(N:(2)-deoxyguanosinyl)tamoxifen N:-oxide 3'-monophosphate (dG(3'P)-N:(2)-TAM N:-oxide) were prepared as standard DNA adducts by reacting 2'-deoxyguanosine 3'-monophosphate with trans-alpha-acetoxytamoxifen N:-oxide in addition to four stereoisomers of alpha-(N:(2)-deoxyguano- sinyl)tamoxifen 3'-monophosphate (dG(3'P)-N:(2)-TAM) that was reported previously. Liquid chromatography-electrospray ionization-mass spectrometry of the reaction products gave the most abundant ion at m/z 731 ([M - H](-)), which corresponded to dG(3'P)-N:(2)-TAM N:-oxide. The modified products digested by alkaline phosphatase corresponded to the isomers of dG-N:(2)-TAM N:-oxide whose structures were identified previously by mass spectrometry and nuclear magnetic resonance. Using these standard markers, we analyzed the hepatic DNA adducts of female DBA/2 mice treated with tamoxifen at a dosage of 120 mg/kg/day for 7 days by (32)P-post-labeling coupled with an HPLC/radioactive detector. Mixtures of eight isomers of dG(3'P)-N:(2)-TAM and dG(3'P)-N:(2)-TAM N-oxide were separated into six peaks, since each of the cis epimers were not separated under the present HPLC conditions. Nine adducts were detected in all liver samples of mice. An epimer of trans-dG(3'P)-N:(2)-TAM was detected as the principal DNA adduct at a level of 29.0 adducts/10(8) nucleotides, which accounted for 53.3% of the total tamoxifen-DNA adducts. Lesser amounts of cis-dG(3'P)-N:(2)-TAM (2.8%) were also observed. An epimer of the trans-dG(3'P)-N:(2)-TAM N:-oxide (3.9 adducts/10(8) nucleotides) was detected as the third biggest adduct (7.2% of the total). The cis-dG(3'P)-N:(2)-TAM N:-oxide (0.4 adducts/10(8) nucleotides) accounted for 0.7% of the total. Thus, dG(3'P)-N:(2)-TAM and dG(3'P)-N:(2)-TAM N:-oxide were identified in tamoxifen-treated mouse liver.

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