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Biomedical subjects

A Purohit

Publications and source records attributed to A Purohit.

At least 19 recordsLinked to original sources
PubMed2006

The regulation and inhibition of 17beta-hydroxysteroid dehydrogenase in breast cancer.

17Beta-hydroxysteroid dehydrogenase Type 1 (17beta-HSD1) has a pivotal role in regulating the synthesis of oestradiol (E2) within breast tumours. In whole body studies in postmenopausal women with breast cancer the conversion of oestrone (E1) to E2 (4.4+/-1.1%) was much lower than the inactivation of E2 to E1 (17.3+/-5.0%). In contrast, an examination of in vivo oestrogen metabolism within breast tumours revealed that whereas little metabolism of E2 occurred, E1 was converted to E2 to a much greater extent in malignant (48+/-14%) than in normal (19+/-6%) breast tissue. Findings from these studies originally suggested that oestrogen metabolism within breast tumours may differ from the mainly oxidative direction found in most other body tissues and that the activity of 17beta-HSD1 might be regulated by tumour-derived factors. Several growth factors (e.g. IGF-I, IGF-II) and cytokines (e.g. IL-6, TNFalpha) have now been identified which can markedly stimulate the activity of 17beta-HSD1 and such a mechanism may account for the high concentrations of E2 found in most breast tumours. Cells of the immune system, which can infiltrate breast tumours, are thought to be a major source of the growth factors and cytokines which can modulate 17beta-HSD1 activity. Given the central role that 17beta-HSD1 has in regulating breast tumour E2 concentrations the development of potent inhibitors of this enzyme has recently attracted considerable attention. Our initial studies in this area explored the use of derivatives of E1 as inhibitors, with 2-ethyl- and 2-methoxy E1 being found to inhibit 17beta-HSD1 activity in T-47D breast cancer cells by 96+/-2 and 91+/-1% respectively at 10 microM, but with a lack of specificity. Using the E1 scaffold a number of potent, selective 17beta-HSD1 inhibitors have now been identified including E1- and 2-ethyl-E1 containing a side chain with a m-pyridylmethylamidomethyl functionality extending from the 16beta position of the steroid nucleus. At 10 microM these compounds both inhibited 17beta-HSD1 activity by >90%, however some inhibition of 17beta-HSD2 activity was exhibited by the E1 derivative (25%) but not the 2-ethyl analogue. It is now apparent that 17beta-HSD1 activity contributes to the high E2 concentrations found in most breast tumours. The identification of potent, selective novel 17beta-HSD1 inhibitors will allow their efficacy to be tested in in vitro and in vivo studies.

Breast Neoplasms↗
PubMed2006

Inhaled formaldehyde exposure: effect on bronchial response to mite allergen in sensitized asthma patients.

BACKGROUND: Formaldehyde, an indoor air pollutant, is known to be an irritant and an etiologic factor in occupational asthma. An epidemiologic study suggests that it may also increase the risk of childhood asthma for concentrations above 60 microg/m(3). AIM: To evaluate the influence of pre-exposure to low-dose formaldehyde (100 microg/m(3) in 30 min according to the World Health Organization's recommended maximum value for indoor environments) on bronchial response to Dermatophagoides pteronyssinus. METHOD: Nineteen asthmatic subjects were included. Each subject underwent a mite allergen bronchial challenge test immediately after a standardized exposure in a chamber to formaldehyde or air (random order). Induced sputum were collected 24 h before and after mite challenge. RESULTS: After formaldehyde inhalation, patients developed an immediate bronchial response at a significantly lower dose of mite allergen than after air exposure (the geometric mean PD(20) for Der p 1 was 34.3 ng after formaldehyde and 45.4 ng after placebo, P = 0.05). The late-phase reaction, expressed as the maximum fall in forced expiratory volume in 1 s (FEV(1)) from baseline, was significantly higher after formaldehyde (15%vs 11%, P = 0.046). CONCLUSION: Our study demonstrated that exposure to low levels of formaldehyde significantly enhanced bronchial responsiveness to mite allergen in mite-sensitized subjects with asthma.

Adult↗
PubMed2006

[The bronchial response to inhaled formaldehyde].

INTRODUCTION: Formaldehyde is an ubiquitous indoor chemical polutant. Occupational exposure to high concentrations has revealed its irritant and allergenic potential. Nevertheless, domestic exposure to low concentrations may also have an effect on respiratory health in a non-specific way, just as has been found for other pollutants. STATE OF KNOWLEDGE: Potentiation of the response to allergens has been observed in animals and children. This effect has also been found on respiratory symptoms, with a 39% increase in the risk of asthma for a domiciliary exposure of more than 60 microgrammes.m(-3). We have recently been able to show, in a study with asthmatics sensitised to house dust mite, that the response to allergen provocation was increased following a 30 minutes exposure to 100 microgrammes.m(-3) formaldehyde. VIEWPOINT AND CONCLUSIONS: All the data show that mild exposure to formaldehyde in the home is sufficient to provoke sensitisation and also an aggrevation of symptoms in patients with allergic asthma. Taking into account the published evidence it is advisable that the concentrations of formaldehyde in domestic products should be made known in order to improve domiciliary air quality.

Air Pollution, Indoor↗
PubMed2005

The nature of inhibition of steroid sulphatase activity by tibolone and its metabolites.

Tibolone is used for hormone replacement therapy and acts in a tissue-specific manner being oestrogenic on CNS and bone but not on breast tissues or endometrium. The ability of tibolone and its metabolites to inhibit steroid sulphatase (STS) activity has a crucial role in regulating its tissue-specific effects. In this study, we have examined the ability of tibolone and its non-sulphated and sulphated metabolites to inhibit STS activity in different enzyme preparations and in intact cells. For this, we have used an 'extracellular' method, which measures the amount of product released into culture medium, and an 'intracellular' method, which assesses the extent of product formation within cells. In addition, the nature by which tibolone and some of its metabolites inhibit STS activity was investigated using intact cells and an enzyme kinetic method. In MCF-7 and T47D breast cancer cells and JEG-3 choriocarcinoma cells, which have high STS activity, tibolone and its metabolites were relatively potent inhibitors of STS activity (33-57% inhibition at 10 microM) using the extracellular assay method. In HOS-TE-85 osteoblast-like cells, tibolone and its Delta-4 metabolite were relatively inactive whereas the 3alpha/3beta-hydroxy metabolites and their sulphated conjugates inhibited activity by 39-55%. When STS activity was assessed in HOS-TE-85 cells using an 'intracellular' method tibolone and its 3beta-hydroxy metabolite were inactive. Pre-treatment of breast cancer cells and JEG-3 cells, and removal of drugs prior to assaying for STS activity, revealed that in these cells tibolone and its metabolites were acting mainly as reversible inhibitors. This finding was confirmed in an enzyme kinetic study to measure concentration-dependent STS inhibition. In HOS-TE-85 cells, pre-treatment of cells and removal of compounds before assaying for remaining STS activity indicated that some tibolone metabolites appeared to stimulate STS activity. Possible mechanisms by which this might occur are discussed but, if confirmed, this could contribute to the positive oestrogenic effects that tibolone has on bone.

Enzyme Inhibitors↗
PubMed2005

The effects of 2-methoxyoestrogen sulphamates on the in vitro and in vivo proliferation of breast cancer cells.

2-Methoxyoestrogen sulphamates are a new class of compounds, which inhibit breast cancer cell proliferation and are also potent inhibitors of steroid sulphatase (STS) activity. In the present study, we have used two cell proliferation assays (MTS and AB) to identify potent new compounds in this class. Similar IC(50) values were obtained using these assays with two of the most potent compounds identified being 2-methoxyoestradiol-bis-sulphamate (2-MeOE2bisMATE) and 2-methoxyoestradiol-17beta-cyanomethyl-3-O-sulphamate (2-MeOE2CyMATE). Both compounds inhibited the proliferation of MCF-7 (ER+) and MDA-MB-231 (ER-) breast cancer cells. Using the AB assay, which allows repeat measurements of cell proliferation without killing cells, both compounds were shown to inhibit cell proliferation in an irreversible manner. As STS may be involved in the removal of the sulphamoyl moiety of these compounds, which could reduce their potency, their ability to inhibit the proliferation of MCF-7 cells transfected with the cDNA for STS was also examined. Although the STS activity was 20-fold higher in these cells than in non-transfected MCF-7 cells, no decrease in the ability of these compounds to inhibit cell proliferation was detected. To test the efficacy of these compounds in vivo, nude mice were inoculated with MCF-7 cells in Matrigel and stimulated to grow with oestradiol. Three weeks after the oral administration of 2-MeOE2bisMATE or 2-MeOE2CyMATE (20mg/kg/day, 5 days/week) tumour volumes had regressed by 52% and 22%, respectively. Both compounds also inhibited liver and tumour STS activity by >90%. The potent anti-proliferative effects of these compounds, and their ability to inhibit tumour growth and STS activity in vivo, indicates that they are suitable for development as novel therapeutic agents, which should be active against a wide range of cancers.

Breast Neoplasms↗
PubMed2005

Regulation of aromatase activity by cytokines, PGE2 and 2-methoxyoestrone-3-O-sulphamate in fibroblasts derived from normal and malignant breast tissues.

Synthesis of oestrone from androstenedione within tumours, by the aromatase enzyme complex, is an important source of oestrogen that is available to support the growth of hormone-dependent breast tumours. In view of the central role that the aromatase enzyme has in oestrogen synthesis there has been considerable interest in understanding its regulation and developing inhibitors to block its action. In the present study we have derived fibroblasts from breast tumours (TFs), tissue proximal to tumours (PFs) and reduction mammoplasty tissue (RMFs) and used them to investigate the regulation of aromatase activity by PGE(2), IL-6 plus its soluble receptor (SR) or TNFalpha. In addition we have examined the ability of 2-methoxyoestrone sulphamate (2-MeOEMATE), a compound which alters microtubule stability, to block the stimulation of aromatase activity by these factors. Basal aromatase activity in PFs was significantly higher (p<0.001) than in TFs or RMFs. The combination of IL-6 plus SR or TNFalpha produced the greatest stimulation of aromatase activity in TFs (up to 61-fold) while having a much lower stimulatory effects on aromatase activity in PFs (up to 60% increase) or RMFs (up to 192% increase). 2-MeOEMATE reduced basal aromatase activity in TFs by 87% and completely abrogated the ability of PGE(2), IL-6 plus SR or TNFalpha to stimulate aromatase activity in these fibroblasts. Results from these studies indicate that while PFs have the highest level of non-stimulated aromatase activity, aromatase activity in TFs shows the greatest response to cytokines. These findings suggest that intrinsic difference may exist for the different types of fibroblasts in the way in which they respond to regulatory factors. The ability of 2-MeOEMATE to block cytokine stimulated aromatase activity suggests that, in addition to its other anti-cancer properties, this compound may also act to inhibit cytokine-stimulated aromatase activity in breast tumours.

Aromatase↗
PubMed2005

Non-small-cell lung cancer in a French department, (1982-1997): management and outcome.

Addition of chemotherapy to the treatment of non-small-cell lung cancer (NSCLC) resulted in a modest but clear improvement in the survival of selected patients. To ascertain if this translates to improved survival in the whole population of patients, we conducted a retrospective population-based study of a sample of 1738 patients diagnosed with primary NSCLC in a French department between 1982 and 1997. The proportion of women, metastatic cases and adenocarcinoma changed significantly over time, as did their management: use of chemotherapy alone increased from 9.7 to 28.1% (P<0.0001), while the use of radiotherapy alone decreased from 32.2 to 9.4% (P<0.0001). The 5-year survival probability was 15.7 % for all patients and 32.6% for those with resectable disease. The 1- and 2-year survival probabilities were 38.2 and 15.6% in locally advanced disease, and were, respectively, 16.8 and 5.2% in metastatic disease. Disease extent and histological subtype were significant independent prognostic factors. Survival of resectable disease was longer among patients treated with surgery or surgery plus chemotherapy, while better outcomes for locally advanced disease were associated with radiation plus chemotherapy. In metastastic disease, patients treated by classical agent without platin or palliative care only had the shortest survival. Despite changes in treatment in accordance with the state-of-the-art, overall survival did not improve over time. It is not unlikely that more patients with bad PS were diagnosed during the latter end of the study period. This could at least partially explain the absence of detection of an overall improvement in survival.

Aged↗
PubMed2005

Poor association between allergen-specific serum immunoglobulin E levels, skin sensitivity and basophil degranulation: a study with recombinant birch pollen allergen Bet v 1 and an immunoglobulin E detection system measuring immunoglobulin E capable of binding to Fc epsilon RI.

BACKGROUND: Results from several studies indicate that the magnitude of immediate symptoms of type I allergy caused by allergen-induced cross-linking of high-affinity Fc epsilon receptors on effector cells (mast cells and basophils) is not always associated with allergen-specific IgE levels. OBJECTIVE: To investigate the association of results from intradermal skin testing, basophil histamine release and allergen-specific IgE, IgG1-4, IgA and IgM antibody levels in a clinical study performed in birch pollen-allergic patients (n = 18). METHODS: rBet v 1-specific IgEs were measured by quantitative CAP measurements and by using purified Fc epsilon RI-derived alpha-chain to quantify IgE capable of binding to effector cells. Bet v 1-specific IgG subclasses, IgA and IgM levels were measured by ELISA, and basophil histamine release was determined in whole blood samples. Intradermal skin testing was performed with the end-point titration method. RESULTS: Our study demonstrates on the molecular level that the concentrations of allergen-specific IgE antibodies capable of binding to Fc epsilon RI and biological sensitivities are not necessarily associated. A moderate association was found between cutaneous and basophil sensitivity. CONCLUSION: Our results highlight the quantitative discrepancies and limitations of the present diagnostic tools in allergy, even when using a single allergenic molecule. The quantity of allergen-specific serum IgE is only one component of far more complex cellular systems (i.e. basophil-based tests, skin tests) used as indirect diagnostic tests for IgE-mediated allergic sensitivity.

Adult↗
PubMed2004

Steroid sulfatase: molecular biology, regulation, and inhibition.

Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and therefore has a pivotal role in regulating the formation of biologically active steroids. The enzyme is widely distributed throughout the body, and its action is implicated in physiological processes and pathological conditions. The crystal structure of the enzyme has been resolved, but relatively little is known about what regulates its expression or activity. Research into the control and inhibition of this enzyme has been stimulated by its important role in supporting the growth of hormone-dependent tumors of the breast and prostate. STS is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be converted to steroids with estrogenic properties (i.e., estradiol and androstenediol) that can stimulate tumor growth. STS expression is increased in breast tumors and has prognostic significance. The role of STS in supporting tumor growth prompted the development of potent STS inhibitors. Several steroidal and nonsteroidal STS inhibitors are now available, with the irreversible type of inhibitor having a phenol sulfamate ester as its active pharmacophore. One such inhibitor, 667 COUMATE, has now entered a phase I trial in postmenopausal women with breast cancer. The skin is also an important site of STS activity, and deficiency of this enzyme is associated with X-linked ichthyosis. STS may also be involved in regulating part of the immune response and some aspects of cognitive function. The development of potent STS inhibitors will allow investigation of the role of this enzyme in physiological and pathological processes.

Animals↗
PubMed2004

Pharmacokinetics of the nonsteroidal steroid sulphatase inhibitor 667 COUMATE and its sequestration into red blood cells in rats.

Breast cancer is a major cause of mortality in Western countries and there is an urgent requirement for novel treatment strategies. The nonsteroidal sulphatase inhibitor 667 COUMATE inhibits hepatic steroid sulphatase and growth of oestrone sulphate stimulated tumours in the nitrosomethylurea-induced rat mammary model. Other compounds that contain an aryl sulphamate moiety, for example, oestrone-3-O-sulphamate, are sequestered into red blood cells (RBCs). The aims of this study were to determine the pharmacokinetics of 667 COUMATE and to investigate its sequestration into RBCs. We administered a single p.o. or i.v. dose (10 mg kg(-1)) of 667 COUMATE to rats and used a high-performance liquid chromatography method to measure the levels of the agent and its putative metabolites in plasma. 667 COUMATE had a bioavailability of 95% and could be detected in plasma for up to 8 h. Using two independent analytical methods, we demonstrated that 667 COUMATE is sequestered by RBCs both ex vivo and in vivo. Previous investigations have revealed that 667 COUMATE is rapidly degraded in plasma ex vivo. In this study, we demonstrate that 667 COUMATE is stabilised due to its sequestration into RBCs. In conclusion, the pharmacological efficacy and high oral bioavailability of 667 COUMATE may be partly a consequence of the ability of RBCs to both protect the agent from metabolic degradation and facilitate its transport to tissues. These data support the further clinical evaluation of this novel endocrine therapeutic agent.

Administration, Oral↗
PubMed2004

Vaccination with genetically engineered allergens prevents progression of allergic disease.

IgE-mediated allergy affects >25% of the population in industrialized countries. Repeated contact with the disease-eliciting allergens induces rises of allergen-specific IgE Abs and progression of the disease to more severe manifestations. Our study uses a type of vaccine that is based on genetically modified allergen derivatives to treat allergic patients. We developed hypoallergenic derivatives of the major birch pollen allergen, Bet v 1, by genetic engineering and vaccinated birch pollen-allergic patients (n = 124) in a double-blind, placebo-controlled study. Active treatment induced protective IgG Abs that inhibited allergen-induced release of inflammatory mediators. We also observed a reduction of cutaneous sensitivity as well as an improvement of symptoms in actively treated patients. Most important, rises of allergen-specific IgE induced by seasonal birch pollen exposure were significantly reduced in vaccinated patients. Vaccination with genetically engineered allergen derivatives is a therapy for allergy that not only ameliorates allergic reactions but also reduces the IgE production underlying the disease.

Allergens↗
PubMed2004

Pharmacokinetics and efficacy of 2-methoxyoestradiol and 2-methoxyoestradiol-bis-sulphamate in vivo in rodents.

2-Methoxyoestradiol (2-MeOE2) is an endogenous oestrogen metabolite that inhibits the proliferation of cancer cells in vitro, and it is also antiangiogenic. In vivo 2-MeOE2, when administered at relatively high doses, inhibits the growth of tumours derived from breast cancer cells, sarcomas and melanomas. Sulphamoylated derivatives of 2-MeOE2 are more potent inhibitors of in vitro breast cancer cell growth than 2-MeOE2. In the present study, we have compared the pharmacokinetic profiles and metabolism of 2-MeOE2 and its sulphamoylated derivative, 2-methoxyoestradiol-bis-sulphamate (2-MeOE2bisMATE), in adult female rats. Their ability to inhibit tumour growth was compared in nude mice bearing xenografts derived from MDA-MB-435 (oestrogen receptor negative) melanoma cancer cells. After a single oral 10 mg kg(-1) dose of 2-MeOE2bisMATE, significant concentrations of this compound were still detectable at 24 h. In contrast, no 2-MeOE2 or metabolites were detected in plasma at any time after a 10 mg kg(-1) oral dose. Thus, the bioavailability of 2-MeOE2 is very low, whereas for 2-MeOE2bisMATE it was 85%. No significant metabolites of 2-MeOE2bisMATE were detected in plasma after oral or intravenous dosing, showing that this drug is resistant to metabolism. In the tumour efficacy model, oral administration of 2-MeOE2bisMATE, at 20 mg kg(-1) day(-1) daily for 28 days, almost completely inhibited tumour growth. Inhibition of tumour growth was maintained for a further 28 days after the cessation of dosing. At this dose level, 2-MeOE2 did not inhibit tumour growth. The resistance to metabolism shown by 2-MeOE2bisMATE and its ability to inhibit tumour growth in vivo suggest that this compound should have considerable potential for development as a novel anticancer drug.

2-Methoxyestradiol↗
PubMed2004

2-MeOE2bisMATE induces caspase-dependent apoptosis in CAL51 breast cancer cells and overcomes resistance to TRAIL via cooperative activation of caspases.

2-Methoxyoestradiol (2-MeOE2) is an endogenous oestrogen metabolite which inhibits tubulin polymerisation and has anti-tumour and anti-angiogenic activity. 2-MeOE2 induces apoptosis in a wide range of cancer cell types and has recently been demonstrated to cooperate with TRAIL to induce apoptosis in breast cancer cells. 2-Methoxyoestradiol-3,17-bis-O,O-sulphamate (2-MeOE2bisMATE) is a sulfamoylated derivative of 2-MeOE2 with enhanced activity and improved pharmacokinetic properties, and 2-MeOE2bisMATE is a promising candidate for early clinical trials. It is important, therefore, to understand the mechanisms by which 2-MeOE2bisMATE acts, and whether it retains the ability to cooperate with TRAIL. We demonstrate that 2-MeOE2bisMATE-induced apoptosis of CAL51 breast cancer cells was associated with rapid activation of caspase 3 and 9, but not caspase 8 (as measured by BID cleavage) and was completely prevented by the caspase inhibitor zVADfmk. Interfering with Fas- or TRAIL-receptor function did not prevent 2-MeOE2bisMATE-induced apoptosis. Whereas CAL51 cells were resistant to TRAIL-induced apoptosis, 2-MeOE2bisMATE and TRAIL cooperated to induce cell death. This apoptosis was associated with enhanced activation of caspases, but not increased expression of the DR5 TRAIL receptor, previously demonstrated to be induced by 2-MeOE2. Therefore, 2-MeOE2bisMATE-induced apoptosis is dependent on caspases and like 2-MeOE2, 2-MeOE2bisMATE can overcome resistance to TRAIL by stimulating activation of downstream caspases. Our results suggest that 2-MeOE2bisMATE and TRAIL might be a particularly effective combination of anti-cancer agents.

2-Methoxyestradiol↗
PubMed2003

Inhibition of carbonic anhydrase II by steroidal and non-steroidal sulphamates.

Carbonic anhydrases (CAs) are expressed by many solid tumours where they may act to confer a growth advantage on malignant tissues. In this study we have examined the ability of a series of steroidal and non-steroidal sulphamates (originally developed as steroid sulphatase inhibitors) and related compounds to inhibit human CAII (hCAII) activity in vitro. Using a 96-well plate assay, oestrone-3-O-sulphamate (EMATE) and two coumarin-based sulphamate drugs (667 COUMATE and STX 118) were found to have IC(50) values of 25-59 nM for the inhibition of hCAII activity. These compounds therefore have a similar CAII inhibitory potency to that of acetazolamide (IC(50)=25 nM), a known hCAII inhibitor. Docking studies have been performed with selected compounds to the crystal structure of hCAII and excellent correlation of scores with biological activity was observed. This agrees with our recent observations when we were the first to report the inhibition of hCAII by STS inhibitors. These studies and initial results with docking to the crystal structure of the extracellular domain of hCAXII indicate that the STS sulphamate ester inhibitors should also be interesting candidates to pursue as inhibitors of CA isozymes that are over-expressed in human tumours.

Antineoplastic Agents↗
PubMed2003

Inhibition of IL-6+IL-6 soluble receptor-stimulated aromatase activity by the IL-6 antagonist, Sant 7, in breast tissue-derived fibroblasts.

Interleukin 6 (IL-6) and its soluble receptor (IL-6sR) can markedly stimulate aromatase activity in cultured fibroblasts derived from normal or malignant breast tissues. IL-6 acts by binding to a low-affinity membrane-spanning receptor (IL-6R), which must associate with a high-affinity receptor (gp130) for signal transduction to occur. Sant 7 is a mutated form of IL-6 that can bind to the IL-6R, but inhibits its ability to interact with the gp130 signal transducing protein. In this study, we have used Sant 7 to examine its ability to inhibit IL-6+IL-6 soluble receptor (IL-6sR)-stimulated aromatase activity in breast tissue-derived fibroblasts. As previously observed, IL-6+IL-6sR markedly stimulated aromatase activity (7.7-20.8-fold) in fibroblasts derived from reduction mammoplasty tissue, tissue proximal to tumours and breast tumours. Sant 7 inhibited basal aromatase activity in some fibroblasts by 25-30% that had a high basal activity, but almost completely blocked the ability of IL-6+IL-6sR to stimulate aromatase activity. The IC(50) for the inhibition of IL-6+IL-6sR-stimulated aromatase activity by Sant 7 was 60 ng ml(-1). A comparison of the effects of prostaglandin E(2) (PGE(2)), which can also regulate aromatase activity, and IL-6+IL-6sR revealed a greater degree of aromatase stimulation by IL-6+IL-6sR. Sant 7, however, inhibited PGE(2)-stimulated aromatase activity by 70% suggesting that PGE(2) acts, in part, by stimulating IL-6 production. Much of the IL-6 and IL-6sR available to stimulate breast tumour aromatase activity may originate from infiltrating macrophages and lymphocytes. The ability to block aromatase stimulation by these factors may offer a novel therapeutic strategy for reducing oestrogen synthesis in breast tumours.

Aromatase↗
PubMed2003

Growth inhibition of multi-drug-resistant breast cancer cells by 2-methoxyoestradiol-bis-sulphamate and 2-ethyloestradiol-bis-sulphamate.

There is currently considerable interest in the use of the endogenous oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2) for the treatment and prevention of breast cancer. We have previously shown that sulphamoylation of 2-MeOE2 and related derivatives greatly enhances their ability to inhibit the proliferation of ER+ and ER- breast cancer cells. In this study, we have compared the abilities of 2-methoxyoestradiol-bis-sulphamate (2-MeOE2bisMATE) and 2-ethyloestradiol-bis-sulphamate (2-EtE2bisMATE) with that of 2-MeOE2 to inhibit the proliferation of breast cancer cells when grown on three different substrata: plastic, collagen I and Matrigel. The human breast cell line MCF-7 was utilised for these studies together with its doxorubicin resistant variant, MCF-7 DOX40 and mitoxantrone resistant variant, MCF-7 MR, as a longitudinal model of in vitro drug resistance. On a plastic substratum all three cell lines were sensitive to the effects of 2-MeOE2bisMATE and 2-EtE2bisMATE whereas MCF-7 cells and the MCF-MR variant cells were resistant to the effects of 2-MeOE2 at 1 microM. The sensitivity of the cell lines to those compounds also remained significant when grown on more physiological substrata. All of the drugs tested arrested cells in the G2/M phase of the cell cycle. The finding that breast cancer cells that are resistant to conventional chemotherapeutic agents remain sensitive to 2-substituted oestrogen sulphamates offers considerable potential for the treatment of women with drug-resistant breast cancer.

2-Methoxyestradiol↗
PubMed2003

The effects of 2-methoxy oestrogens and their sulphamoylated derivatives in conjunction with TNF-alpha on endothelial and fibroblast cell growth, morphology and apoptosis.

2-methoxyoestradiol (2-MeOE2) is a potent anti-angiogenic agent. Its 3- and 17-sulphamoylated derivatives have been demonstrated to induce G2-M cell cycle arrest and apoptosis in breast cancer cells in vitro as well as tumour regression in rats in vivo with greater potency than the parent oestrogen. To determine whether the anti-cancer properties of these derivatives can be synergistically enhanced with low-dose TNF-alpha co-treatment, we investigated the effects of these treatments in adult human fibroblasts and human umbilical vein endothelial cells (HUVECs). Treatment of fibroblasts with 0.1 microM 2-methoxyoestradiol-3,17-bis sulphamate (2-MeOE2bisMATE) but not 2-MeOE2 caused a reversible morphology change and induced G2-M arrest (from 12 to 33%) but not subsequent apoptosis. In contrast, treatment of HUVECs did not induce morphology change or G2-M arrest. Using a nucleosomal ELISA assay, we showed that TNF-alpha (20 ng/ml) combination treatment synergistically increases 0.1 microM 2-MeOE2bisMATE-induced but not 0.1 microM 2-MeOE2-induced apoptosis in HUVECs. These results suggest that TNF-alpha co-treatment may be a beneficial method of increasing the potency of 2-substituted oestrogens as anti-angiogenic agents through synergistic induction of apoptosis in endothelial cells while maintaining low cytotoxicity to fibroblasts.

2-Methoxyestradiol↗