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PubMed2006

RANKL-dependent and RANKL-independent mechanisms of macrophage-osteoclast differentiation in breast cancer.

The cellular and humoral mechanisms accounting for tumour osteolysis in metastatic breast cancer are uncertain. Osteoclasts, the specialised multinucleated cells responsible for tumour osteolysis, are derived from monocyte/macrophage precursors. Breast cancer-derived tumour-associated macrophages (TAMs) are capable of osteoclast differentiation but the cellular and humoral mechanisms controlling this activity are uncertain. In this study, TAMs were isolated from primary breast cancers and cultured in the presence and absence of cytokines/growth factors influencing osteoclastogenesis. Extensive TAM-osteoclast differentiation occurred only in the presence of RANKL and M-CSF; this process was inhibited by OPG and RANK:Fc, decoy receptors for RANKL. Breast cancer-derived fibroblasts and human bone stromal cells expressed mRNA for RANKL, OPG and TRAIL, and co-culture of these fibroblasts with human monocytes stimulated osteoclast formation by a RANKL-dependent mechanism. Osteoclast formation and lacunar resorption also occurred by a RANKL-independent mechanism when the conditioned medium from breast cancer cells, MDA-MB-231 and MCF-7, was added (with M-CSF) to monocyte cultures. Our findings indicate that TAMs in breast cancer are capable of osteoclast differentiation and that breast cancer-derived fibroblasts and breast cancer cells contribute to this process by producing soluble factors that influence osteoclast formation by RANKL-dependent and RANKL-independent mechanisms respectively.

Aged↗

PubMed2006

Role of tumor-associated macrophages in tumor progression and invasion.

Tumor-Associated Macrophages (TAM) represent the major inflammatory component of the stroma of many tumors, able to affect different aspects of the neoplastic tissue. Many observations indicate that TAM express several M2-associated protumoral functions, including promotion of angiogenesis, matrix remodelling and suppression of adaptive immunity. The protumoral role of TAM in cancer is further supported by clinical studies that found a correlation between the high macrophage content of tumors and poor patient prognosis and by evidence showing that long-term use of non-steroidal anti-inflammatory drugs reduces the risk of several cancers. Here, we discuss evidence supporting the view that TAM represent a unique and distinct M2-skewed myeloid population and a potential target of anti-cancer therapy.

Animals↗

PubMed2005

Combined efficacy of tamoxifen and coenzyme Q10 on the status of lipid peroxidation and antioxidants in DMBA induced breast cancer.

An increasing amount of experimental and epidemiological evidence implicates the involvement of oxygen derived radicals in the pathogenesis of cancer development. It is well known that chemical carcinogenesis is multistage process. Free radicals arefound to be involved in both initiation and promotion of multistage carcinogenesis. Tamoxifen (TAM) is a potent antioxidant and a non-steroidal antiestrogen drug most used in the chemotherapy and chemoprevention of breast cancer. Besides its anticarcinogenic potential, it also produces some adverse toxic side effects, while taken for a long time. In order to minimise the side effects and to improve the antioxidant efficacy of tamoxifen, coenzyme Q10 (CoQ10) was added. Hence the present study was designed to investigate the combined efficacy of TAM along with CoQ10 in 7, 12 dimethyl benz(a)anthracene (DMBA) induced peroxidative damage in rat mammary carcinoma. The experimental setup comprised of one control and five experimental groups and it was carried out in adult female Sprague-Dawley rats. Mammary carcinoma was induced by oral administration of DMBA (25 mg kg(-1) body wt) and the treatment was started by the oral administration of TAM (10 mg kg(-1) body wt day(-1)) and CoQ10 (40 mg kg(-1) body wt day(-1)) dissolved in olive oil and continued for 28 days. Rats induced with DMBA showed a decline in the thiol capacity of the cell accompanied by high malondialdehyde content levels along with lowered activities of antioxidant status (superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione). In contrast, glutathione metabolising enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase) were increased significantly in chemically induced carcinoma bearing rats. Administration of TAM along with CoQ10 restored the activities to a significant level thereby preventing cancer cell proliferation. This study highlights the increased antioxidant enzyme activities in relation to the susceptibility of cells to carcinogenic agents and the response of tumour cells to the chemotherapeutic agents.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2007

A prospective study of the efficacy of Serenoa repens, tamsulosin, and Serenoa repens plus tamsulosin treatment for patients with benign prostate hyperplasia.

INTRODUCTION: Increasing attention has been focused on the use of phytotherapeutic agents to alleviate the symptoms of benign prostatic hyperplasia (BPH) in recent times. The best described and studied phytotherapeutic agent is Serenoa repens (SR). MATERIALS AND METHODS: This prospective study was designed to have 3 arms including SR 320 mg per day (N = 20), Tamsulosin (TAM) 0.4 mg per day (N = 20) and SR + TAM (N = 20) to reveal the superiority or equivalence between these treatment regimens in BPH. RESULTS: The groups were not statistically different with regard to increase in maximal urinary flow rate (Q (max)) and decrease in International Prostate Symptom Score (I-PSS) (P > 0.05). No adverse effect was detected in SR therapy group. CONCLUSION: Treatment of BPH by both SR and TAM seems to be effective alone. None of them had superiority to another and additionally, combined therapy (SR + TAM) does not provide extra benefits. Furthermore SR is a well-tolerated agent that can be used alternatively in the treatment of LUTS due to BPH.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1983

Regulation of cytochrome P-450-dependent catechol estrogen formation in rat liver microsomes. Evidence for involvement of estrogen receptors.

Experiments were conducted to evaluate whether estrogen 2-hydroxylase activity in liver microsomes, the main pathway for oxidative metabolism of estrogens in the rat, is regulated by administration of synthetic estrogens. Ovariectomized rats were treated with ethinylestradiol (EE), 100 micrograms s.c. for 3 days. Liver microsomes from EE-treated animals showed a 2-fold increase over control in estrogen 2-hydroxylase activity measured over a substrate concentration range of 0.5 to 50 microM. Double-reciprocal plots of enzyme activity as a function of substrate concentration were linear; apparent Vmax values were 2-fold greater in microsomes from EE-treated animals while apparent Km values for control and EE preparations were not different. Administration of the triphenylethylene antiestrogen tamoxifen (TAM), 100 micrograms s.c. for 3 days, did not affect microsomal catechol estrogen formation activity, and apparent Km and Vmax values were comparable with controls. When EE and TAM were co-administered, no increase in microsomal estrogen 2-hydroxylase was observed, and apparent Km and Vmax values were not different from either control of TAM-treated preparations. Thus, acute administration of EE was associated with a specific increase in the apparent Vmax of estrogen 2-OHase activity, and this effect was not observed when TAM was co-administered with the estrogen.

Animals↗

PubMed1984

Influence of tamoxifen and its N-desmethyl and 4-hydroxy metabolites on rat liver microsomal enzymes.

Tamoxifen (Nolvadex; TAM) and its major metabolites, N-desmethyl- (DMT) and 4-hydroxy-tamoxifen (HT), were shown to be potent inhibitors of hepatic cytochrome P-450-dependent mixed function oxidations. From in vitro experiments, all three were found to be potent inhibitors of oxidation of Type-I substrates (ethylmorphine and aminopyrine) and less potent, non-competitive inhibitors of Type-II substrates (aniline and dimethylnitrosamine). TAM, DMT and HT were of essentially equal potency and had a much more pronounced effect on Type-I substrates than on Type-II compounds studied. Their action appears to parallel SKF-525A in type and potency of inhibition produced. Spectral binding studies suggest that TAM and its metabolites exert their effects by occupying the Type-I binding site of cytochrome P-450 and thus limiting the accessibility of other substrates to the active site of the enzyme. TAM (and its metabolites) also inhibits its own metabolism, altering the distribution and elimination half-lives of tamoxifen-derived species. In addition, tamoxifen metabolism was found to be sensitive to the presence of other drugs. These results raise concern regarding the role that continued administration of tamoxifen plays in changing its own disposition as well as in the detoxification of drugs administered with it.

Aminopyrine N-Demethylase↗

PubMed1992

Antiestrogen binding sites in brain and pituitary of ovariectomized rats.

In addition to interacting with estrogen binding sites in a number of tissues, antiestrogens have recently been shown to interact with a separate, estrogen-non-compatible, antiestrogen-specific binding site (AEBS). In order to better understand possible mechanisms by which the antiestrogens may effect behavioral and physiological changes, we have examined AEBS in several areas of the brain and pituitary in adult, ovariectomized rats. Single point binding assays with 2 nM [3H]tamoxifen (TAM) in the presence of saturating amounts (1 microM) E and +/- 1 microM TAM indicated the existence of specific binding to AEBS throughout the brain and pituitary. In most areas of the brain (cortex, cerebellum, amygdala, area postrema/nucleus of the solitary tract region) as well as pituitary. Scatchard analyses revealed the presence of a single AEBS with a dissociation constant (Kd = 1-4 x 10(-9) M) similar to that previously reported for other tissues. However, in both hypothalamus and preoptic area, an additional, higher affinity site (Kd = 6-9 x 10(-11) M) was found. Competitive inhibition studies revealed that there was little competition by the potent estrogen agonist, diethylstilbesterol, for AEBS binding. Antiestrogens competed in the following order: tamoxifen greater than or equal to nafoxidine much greater than keoxifene. Additional competitive inhibition studies were run using neurotransmitter antagonists. The phenothiazines, chlorpromazine and fluphenazine, bind to both D1 and D2 dopamine receptors and effectively compete with [3H]TAM for binding at the AEBS. Other pharmacological substances, including specific antagonists of the D2 sites, as well as antagonists of the norepinephrine, opiate, histamine, GABA and acetylcholine systems, were ineffective competitors for [3H]TAM binding.

Animals↗

PubMed1987

Activation of the IL-1 pathway during amplification of immune responses in tumor-bearing mice.

Previous work identified certain components of the immunological network that had been activated following the adoptive immunotherapy of tumor-bearing mice. The present report shows that part of the activation process involves the IL-1 pathway. Tumor-associated macrophages (TAM) from C57BL/6J mice bearing the immunogenic sarcoma, MCA/76-9, and tumor-bearers injected with cyclophosphamide (CY) or CY plus the intravenous transfer of tumor-sensitized lymphocytes showed relatively high levels of intracellular (IC) IL-1, as demonstrated in the mitogenic and comitogenic assays. Gel chromatography of IC IL-1 and extracellular (EC) IL-1 from TAM induced to secrete IL-1 by stimulation with lipopolysaccharide indicated a single peak of activity of similar molecular size. The active fractions of the EC IL-1 were found to increase in activity as they were diluted to a maximum of 1/64, beyond which IL-1 activity declined. Fractions of the IC IL-1 showed no increased activity on dilution. Filtrates (less than 10 kDa) obtained on concentration of the IC and EC IL-1 samples prior to fractionation were shown to contain an activity (3-5 kDa) that inhibited the uptake of [3H]TdR by thymocytes in the mitogenic and comitogenic assays. Membrane-bound IL-1 activity also was expressed by TAM and this coincided with the previously reported peak Ia expression by these cells. TAM were also shown to induce strong proliferative responses by allogeneic lymphocyte. Systemic amplification of antitumor responses was detected in mice bearing progressing tumors and in those that had received combination therapy as measured both by increases in free IL-1 in the peritoneal cavity and IL-1 within the peritoneal macrophages. These observations indicate that in addition to enhancement of Ia expression, the IL-1 pathway also is activated and amplified systemically in this model system of tumor progression and rejection.

Animals↗

PubMed1988

Growth inhibitory effect of 4-hydroxy-tamoxifen on the BT-20 mammary cancer cell line.

The antiestrogenic activities of Tamoxifen have been well documented and this molecule has been successfully used in the treatment of hormone dependent breast cancer. In the present experiments we demonstrate that 4-hydroxy-Tamoxifen (OH-TAM) is able to reduce the growth of the BT-20 cell line which is devoid of estrogen and progesterone receptors. Various parameters have been investigated in growth studies under control conditions and in the presence of OH-TAM. Cell numerations, [3H]thymidine incorporation per cell or per microgram of DNA have shown that OH-TAM reduces the growth rate in proportion to its concentration from 10(-9) M to 10(-6) M. This activity is not reversed by estradiol addition. It is unaffected by the presence or the absence of Phenol Red in the medium. Analysis by flow cytometry suggests that it takes place before the S phase of the cycle. Examination of control and treated cells by Electron Microscopy shows no sign of toxicity. The growth inhibitory activity of OH-TAM on these cell lines appears therefore unrelated to its antiestrogenic properties.

Breast Neoplasms↗

PubMed1988

Effects of two different medical treatments on dihydrotestosterone content and androgen receptors in human benign prostatic hyperplasia.

In order to evaluate the biochemical modifications induced by hormonal treatments on human prostatic tissue, the intracellular distribution of tissue DHT and AR were investigated in BPH patients untreated and treated (25-30 days before surgery) with the association of cyproterone acetate (CPA), 100 mg p.o./day plus tamoxifen (TAM), 100 mg p.o./day, or with flutamide (FLU) alone, 750 mg p.o./day. Dextran-coated charcoal and exchange assay in the presence of sodium molybdates (0.2 M) were used for AR determination, employing methyltrienolone as radioligand in the presence of triamcinolone acetonide. Endogenous DHT was measured by RIA, after ether extraction and purification on celite microcolumns. The treatment with CPA plus TAM led to a detection of cytosol AR (ARc) in 50% of the specimens, while nuclear AR (ARn) were never measurable. The FLU treatment did not modify the incidence of ARc, while ARn was not detectable. The cytosolic and nuclear compartmentalization of DHT was scarcely affected by the combined CPA plus TAM treatment, while FLU treatment induced a prevalent cytosolic localization of DHT (DHTc = 283.2 +/- 24.6 S.E. and DHTn = 1138.4 +/- 98.7 S.E. pg/mg DNA in untreated patients; DHTc = 350.4 +/- 97.7 S.E. and DHTn = 589.7 +/- 154.4 S.E. pg/mg DNA in CPA plus TAM treated patients; DHTc = 1101.7 +/- 165.7 S.E. and DHTn = 733.0 +/- 93.9 S.E. pg/mg DNA in FLU treated patients). Both medical treatments, therefore, were able to reduce prostatic growth on account of the reduced value of nuclear DHT content.

Androgen Antagonists↗

PubMed1996

Hypothalamic obese, functionally castrated hens are hypersensitive to estrogenic modulation of lipid metabolism.

Estradiol benzoate (E2) increases plasma lipids in hypothalamic obese, functionally castrated (OFC), obese laying (OL), and control laying hens (CONT). However, E2 reduces fattiness in OFC but not in OL or CONT hens. Antiestrogen, such as tamoxifen (TAM), reduces plasma lipids in OL and CONT, but not in OFC, hens and has no effect on fattiness in any of them. Apolipoprotein VLDL-II (apo-VLDL-II), lipoprotein lipase (LPL), and rate of lipolysis may mediate these estrogenic effects. In the present study, effects of E2 and TAM on fattiness, plasma apo-VLDL-II, in vitro lipolysis, and LPL activity in postheparin plasma and abdominal adipose tissue (AAT) were determined in OFC, OL, and CONT hens. Basomedial hypothalamic lesions were performed in 3-month-old White Leghorn hens. At the static phase, 10 months later, OFC OL, and CONT hens were divided into three subgroups and injected IM on alternate days, with either 2 mg E2/kg b.wt., 10 mg TAM/kg, or vehicle corn oil, for 5 weeks. In OL and OFC hens, body and AAT weights were higher than in CONT poullets. Food intake and ovarian weight were similar in OL and CONT, higher than in OFC hens. Plasma LPL activity was higher, whereas plasma apo-VLDL-II and stimulated lipolysis were lower in OFC than in OL and CONT hens. In OFC hens LPL activity per unit of AAT was half than in OL and CONT. Total LPL activity in AAT was similar in OFC and CONT and higher in OL hens. Levels of basal lipolysis were similar in all experimental hens. TAM did not affect any of the measured parameters in OFC hens. In OL and CONT hens, TAM depressed apo-VLDL-II, increased plasma LPL activity, but had no effects on AAT LPL activity, on stimulated lipolysis, or fattiness. E2 increased apo-VLDL-II to similar levels in all groups and reduced LPL activity in plasma and AAT of obese hens. Only in OFC hens did E2 enhance basal and stimulate lipolysis and reduce FI and fattiness. We conclude that in adult laying hens, unlike in cockerels and juvenile hens, estrogen reduces lipid incorporation in fat depots by enhancing apo-VLDL-II production that reduces plasma and AAT LPL activity. This may increase lipoprotein available for incorporation into developing yolks. The lack of estrogen in OFC hens reduces circulating apo-VLDL-II and thus increases LPL activity and amount of fat depots.

Adipocytes↗

PubMed1989

Biotransformation, estrogenicity, and steroid structure as determinants of dysmorphogenic and generalized embryotoxic effects of steroidal and nonsteroidal estrogens.

A series of nine chemicals of varying structure and estrogenicity was investigated for biochemical determinants of their relative capacities to alter normal embryonic growth and developmental patterns during organogenesis in rats. In order to circumvent the potentially confounding influences of maternal factors, the direct effects of steroidal and nonsteroidal estrogens on cultured whole embryos were compared at concentrations producing readily measurable embryotoxicity but low embryolethality (2-20%). Nonsteroidal estrogens included were diethylstilbestrol (DES), hexestrol (HES), E,E-dienestrol (alpha-DIES), and tamoxifen (TAM). Steroidal estrogens were estradiol 17 beta (E2), estrone (E1), and 17 alpha-ethinylestradiol 17 beta (EE). For comparative purposes, the effects of two essentially nonestrogenic phenols, Z,Z-dienestrol (beta-DIES) and phenol, were also studied. TAM, a weak estrogen which also exhibits antiestrogenic properties, was studied for possible interactive effects with potent estrogens. Prosencephalic hypoplasia was the abnormality most consistently observed and was elicited by each of the chemicals investigated. Embryotoxicity was neither attenuated by TAM nor related to estrogenic potency or steroidal structure, but was strongly and unpredictably influenced by biotransformational determinants. Presence of a cytochrome P450-dependent oxidizing system in the culture medium resulted in marked increases in embryotoxicity of E1, E2, and phenol, only minor increases for beta-DIES and alpha-DIES, but in strikingly decreased effects of EE, TAM, and HES. It produced no statistically significant differences in effects of DES. The results obtained were compatible with the concept that effects of these agents on growth and development during the earlier stages of organogenesis are independent of steroid structure or estrogenic activity but strongly dependent upon pathways and rates of biotransformation of some (but not all) of the parent chemicals.

Abnormalities, Drug-Induced↗

PubMed1984

The antiproliferative effect of tamoxifen in breast cancer cells: mediation by the estrogen receptor.

The effects of tamoxifen (Tam) and its 4-hydroxylated metabolite (OH-Tam) on the growth of two human breast cancer cell lines ( MCF7 and BT20 ) were evaluated by fluorometric DNA assay. The effects of the antiestrogens were dependent upon their concentrations and the nature of the cells. At concentrations below 4 microM, the degree of inhibition was related to their relative affinities for the estrogen receptor and was totally reversed by estradiol in MCF7 cells. No inhibition was observed in the estrogen receptor negative cell line BT20 . This supports and extends the idea that the antiproliferative effect of Tam at these concentrations is mediated by the estrogen receptor even in the absence of measurable estradiol concentration. At concentrations greater than 4 microM, Tam was cytotoxic on MCF7 and BT20 mammary cell lines within 2 days of treatment. The cytotoxic effect was irreversible and was not prevented by occupation of the estrogen receptor with estradiol, suggesting that it was not mediated by the estrogen receptor. The cytotoxicity of the triphenylethylene drugs, however, has some specificity since it was not observed in a fibroblast rat cell line ( 49F ) or in the two mammary cell lines with similar high concentrations of estradiol and diethylstilbestrol.

Breast Neoplasms↗

PubMed1993

Influence of hormones on tumor growth, cell kinetics, estrogen receptor and insulin-like growth factor-I-related protein of human breast cancer (MCF-7) cells transplanted in nude mice.

The influence of estrogens and tamoxifen on estrogen receptor (ER)-positive human breast cancer (MCF-7) cells transplanted into athymic nude mice was investigated. The mice were divided into the following three groups: (1) an E2 group with mice receiving 17 beta-estradiol dipropionate; (2) a TAM group with mice receiving tamoxifen; (3) a control group with mice given no hormone. (1) Tumor growth was significantly increased in the E2 group, but significantly decreased in the TAM group compared to control; (2) the tumor contents of insulin-like growth factor-I (IGF-I) and the rate of IGF-I-positive cells were significantly lower in the E2 group, but significantly higher in the TAM groups compared to control; (3) the IGF-I-positive cell rates were in significant inverse correlation with the [3H]thymidine-labeled cell rates in the E2, TAM and control groups. Thus, the tumor contents of IGF-I and the rate of IGF-I-positive cells were inversely correlated to the tumor growth and the [3H]thymidine-labeled cell rate in this in vivo study, although IGF-I is known to be a mitogen for breast cancer cells in vitro. Further studies are necessary to answer the questions as to the in vivo roles of immunoreactive IGF-I in ER-positive breast cancer.

Animals↗

PubMed1995

The biological action of cDNAs from mutated estrogen receptors transfected into breast cancer cells.

While tamoxifen may inhibit breast cancer proliferation, mutations in the estrogen receptor could potentially result in breast cancer cells which can circumvent the tamoxifen blockade. Previously, we identified a mutation at codon 351 in the estrogen receptor from a tamoxifen-stimulated human breast cancer. This receptor was stably transfected into the estrogen receptor-negative human breast cancer cell line MDA-MB-231 (clone 10A). Clones were compared to stably transfected cell lines containing either the wild type or codon 400 mutant estrogen receptor to study the effect of either estradiol or the tamoxifen analogue, fixed-ring 4-hydroxytamoxifen ((fr)4-OH TAM), on cell growth and reporter gene activation. (fr)4-OH TAM reduced the growth rate in cell lines containing mutant estrogen receptors, while the cell line containing the wild type estrogen receptor is minimally influenced by (fr)4-OH TAM. We then needed to show that the ligand-estrogen receptor interaction resulted in estrogen receptor activation. As a ligand-dependent transcription factor, estrogen receptor activation is measured by its ability to stimulate reporter gene (luciferase) transcription when bound to an estrogenic ligand. We found that the wild type estrogen receptor is activated by estradiol but not by the tamoxifen analogue, while the codon 351 estrogen receptor is activated by both (fr)4-OH TAM and estradiol.

Amino Acid Sequence↗

PubMed1996

Promotion potential of tamoxifen on hepatocarcinogenesis in female SD or F344 rats initiated with diethylnitrosamine.

The liver promotion potential of tamoxifen (TAM), which has been widely used in the treatment of hormone-dependent breast cancers, was investigated using female SD or F344 rat initiated with diethylnitrosamine (DEN). In Experiment 1, 45 newborn female SD rats were administered DEN (100 mg/kg, i.p.) (Groups 1 and 2) or saline (Group 3) 24 h after birth. After weaning at week 3, Groups 1 and 3 were subcutaneously injected with TAM citrate (1 mg/rat per day), suspended in corn oil, in the subscapular region, while Group 2 was given the vehicle alone (s.c.) daily for 9 weeks, and killed at week 12. In Experiment 2, 70 female F344 rats at 7 weeks of age were divided into five groups. All animals were initially given DEN (200 mg/kg i.p.) for initiation. Two weeks later Groups 1-4 were given diets containing 100, 250, 500 ppm TAM, or 500 ppm PB for 6 weeks, respectively, while Group 5 was administered basal diet as a control for the same period. The rats were subjected to two-thirds partial hepatectomy (PH) at week 3 and were killed at week 8. The enhanced development of glutathione S-transferase-placental form (GST-P)-positive liver cell foci after DEN exposure in both newborn SD and adult F344 rat medium-term liver bioassay models (Experiments 1 and 2). This suggests that TAM exerts promotion potential for hepatocarcinogenesis in female rats.

Animals↗

PubMed1996

Solid-phase extraction and high-performance liquid chromatographic determination of tamoxifen and its major metabolites in plasma.

Tamoxifen (TAM) is a triphenylethylene anti-oestrogen, commonly used in the treatment of breast cancer. Patients receiving tamoxifen therapy may experience both de novo and acquired resistance. As one of the mechanisms for this may be extensive peripheral bio-transformation of tamoxifen, there has been considerable interest in the pharmacokinetics and metabolism of tamoxifen. A reversed-phase high-performance liquid chromatography separation has been developed to determine the levels of tamoxifen and its major metabolites in human plasma. The method is highly sensitive (2 ng/ml) and selective for tamoxifen, cis-tamoxifen (CIS), 4-hydroxytamoxifen (4-OH) and desmethyltamoxifen (DMT). A micro Bondapak C18 10 microns column (30 cm x 3.9 mm I.D.) was used, with a mobile phase of methanol-1% triethylamine at pH 8 (89:11, v/v). Sample preparation was carried out using a C2 (500 mg sorbent, 3 ml reservoirs) solid phase extraction method, and extraction efficiencies were approximately 60% for TAM and its metabolites. Accuracy and precision, as determined by spiking plasma samples with a mixture of tamoxifen and its metabolites, ranged from 85-110% (+/- 5-10%) at 1 microgram/ml, 101-118% (+/- 8-20%) at 0.1 microgram/ml and 111-168% (+/- 43-63%) at 0.01 microgram/ml. Results from 59 patients show mean values of 54 ng/ml for 4-OH; 190 ng/ml for DMT; 93 ng/ml for TAM and 30 ng/ml for CIS (detected in three patients only). This methodology can be applied routinely to the determination of TAM and its metabolites in plasma from patients undergoing therapy.

Antineoplastic Agents, Hormonal↗

PubMed1990

Anti-steroidal and anti-growth factor activities of anti-estrogens.

Both steroid hormones, such as estrogens and progestins acting via nuclear receptors, and growth factors, such as EGF, IGF-I and IGF-II acting via transmembrane receptors, are able to modulate the growth of human breast cancer cells. In addition to its anti-estrogenic action requiring estrogen receptor (ER) and leading to growth arrest, we have previously shown that the anti-hormone tamoxifen (Tam) is able to block EGF, insulin and IGF-I mitogenic activities in total absence of estrogens (BBRC, 146,1502,1987). This anti-growth factor activity is observed exclusively in ER + cells and is rescued by estradiol addition, thus suggesting that it is mediated by accessible ER sites. In the same culture conditions, progestins and anti-progestins do not display such an inhibition, whereas retinoic acid does, thus indicating that this anti-growth factor effect is not restricted to ER ligands. To progress in the understanding of this inhibition, we first analyzed how Tam could affect EGF and IGF-I binding in responsive cells. We have shown that Tam neither affects EGF and IGF-I binding to their respective receptors by direct competition nor modulates their affinities. However, our recent data suggest that Tam pretreatment (6 days) of MCF7 cells, which similarly prevents EGF and IGF-I mitogenic activities, results in opposite effects on the concentrations of their binding sites. In conclusion, we propose that some steroid antagonists can inhibit not only the action of agonist ligands of the receptors they are binding to, but can also modulate the action of growth factors by decreasing their receptor concentrations or altering their functionalities.

Antineoplastic Agents↗