In vivo and in vitro properties of STX2484: a novel non-steroidal anti-cancer compound active in taxane-resistant breast cancer.

BACKGROUND: STX2484 is a novel non-steroidal compound with potent anti-proliferative activity. These studies aimed to identify STX2484's mechanism of action, in vivo efficacy and activity in taxane-resistant breast cancer models. METHODS: Effects of STX2484 and paclitaxel on proliferation, cell cycle and apoptosis were assessed in vitro in drug-resistant (MCF-7(DOX)) and non-resistant cells (MCF-7(WT)). STX2484 efficacy in ßIII tubulin overexpression in MCF-7 cells was also determined. Anti-angiogenic activity was quantified in vitro by a co-culture model and in vivo using a Matrigel plug assay. An MDA-MB-231 xenograft model was used to determine STX2484 efficacy in vivo. RESULTS: STX2484 is a tubulin disruptor, which induces p53 expression, Bcl2 phosphorylation, caspase-3 cleavage, cell cycle arrest and apoptosis. In addition, STX2484 is a potent anti-angiogenic agent in vitro and in vivo. In breast cancer xenografts, STX2484 (20 mg kg(-1) p.o.) suppressed tumour growth by 84% after 35 days of daily dosing, with limited toxicity. In contrast to paclitaxel, STX2484 efficacy was unchanged in two clinically relevant drug-resistant models. CONCLUSIONS: STX2484 is an orally bioavailable microtubule-disrupting agent with in vivo anti-angiogenic activity and excellent in vivo efficacy with no apparent toxicity. Crucially, STX2484 has superior efficacy to paclitaxel in models of clinical drug resistance.

Randomized controlled trial of computerized cognitive behavioural therapy for depressive symptoms: effectiveness and costs of a workplace intervention.

BACKGROUND: Depression and anxiety are major causes of absence from work and underperformance in the workplace. Cognitive behavioural therapy (CBT) can be effective in treating such problems and online versions offer many practical advantages. The aim of the study was to investigate the effectiveness of a computerized CBT intervention (MoodGYM) in a workplace context. METHOD: The study was a phase III two-arm, parallel randomized controlled trial whose main outcome was total score on the Work and Social Adjustment Scale (WSAS). Depression, anxiety, psychological functioning, costs and acceptability of the online process were also measured. Most data were collected online for 637 participants at baseline, 359 at 6 weeks marking the end of the intervention and 251 participants at 12 weeks post-baseline. RESULTS: In both experimental and control groups depression scores improved over 6 weeks but attrition was high. There was no evidence for a difference in the average treatment effect of MoodGYM on the WSAS, nor for a difference in any of the secondary outcomes. CONCLUSIONS: This study found no evidence that MoodGYM was superior to informational websites in terms of psychological outcomes or service use, although improvement to subthreshold levels of depression was seen in nearly half the patients in both groups.

Risk assessment and receiver operating characteristic curves.

Risk assessment is now regarded as a necessary competence in psychiatry. The area under the curve (AUC) statistic of the receiver operating characteristic curve is increasingly offered as the main evidence for accuracy of risk assessment instruments. But, even a highly statistically significant AUC is of limited value in clinical practice.

Anticipated discrimination among people with schizophrenia.

OBJECTIVE: The aim of this study was to evaluate the level of anticipated discrimination in people with schizophrenia (n = 732) from 27 countries in the International Study of Discrimination and Stigma Outcomes (INDIGO). METHOD: Anticipated discrimination was assessed through four questions of Discrimination and Stigma Scale. Twenty-five individuals were identified at each site who were reasonably representative of all such treated cases within the local area. RESULTS: Sixty-four per cent of the participants reported that they had stopped themselves from applying for work, training or education because of anticipated discrimination. Seventy-two per cent of them reported that they felt the need to conceal their diagnosis. Expecting to be avoided by others who know about their diagnosis was highly associated with decisions to conceal their diagnosis. Those who concealed their diagnosis were younger and more educated. The participants who perceived discrimination by others were more likely to stop themselves from looking for a close relationship. Anticipated discrimination in finding and keeping work was more common in the absence than in the presence of experienced discrimination, and the similar findings applied to intimate relationships. CONCLUSION: This study shows that anticipated discrimination among people with schizophrenia is common, but is not necessarily associated with experienced discrimination.

Estimating probability of sustained recovery from mild to moderate depression in primary care: evidence from the THREAD study.

BACKGROUND: It is important for doctors and patients to know what factors help recovery from depression. Our objectives were to predict the probability of sustained recovery for patients presenting with mild to moderate depression in primary care and to devise a means of estimating this probability on an individual basis. METHOD: Participants in a randomized controlled trial were identified through general practitioners (GPs) around three academic centres in England. Participants were aged >18 years, with Hamilton Depression Rating Scale (HAMD) scores 12-19 inclusive, and at least one physical symptom on the Bradford Somatic Inventory (BSI). Baseline assessments included demographics, treatment preference, life events and difficulties and health and social care use. The outcome was sustained recovery, defined as HAMD score <8 at both 12 and 26 week follow-up. We produced a predictive model of outcome using logistic regression clustered by GP and created a probability tree to demonstrate estimated probability of recovery at the individual level. RESULTS: Of 220 participants, 74% provided HAMD scores at 12 and 26 weeks. A total of 39 (24%) achieved sustained recovery, associated with being female, married/cohabiting, having a low BSI score and receiving preferred treatment. A linear predictor gives individual probabilities for sustained recovery given specific characteristics and probability trees illustrate the range of probabilities and their uncertainties for some important combinations of factors. CONCLUSIONS: Sustained recovery from mild to moderate depression in primary care appears more likely for women, people who are married or cohabiting, have few somatic symptoms and receive their preferred treatment.

Antenatal domestic violence, maternal mental health and subsequent child behaviour: a cohort study.

OBJECTIVE: To investigate the long-term impact of antenatal domestic violence on maternal psychiatric morbidity and child behaviour. DESIGN: Cohort study. SETTING: Avon, UK. POPULATION OR SAMPLE: A birth cohort of 13,617 children and mother dyads were followed to 42 months of age. METHODS: Experiences of domestic violence and depressive symptoms were gathered at 18 weeks of gestation and up to 33 months after birth, together with maternal, paternal and child characteristics. MAIN OUTCOME MEASURES: Child behavioural problems were assessed at 42 months using the Revised Rutter Questionnaire. ANALYSIS: Logistic regression with the use of multiple imputation employing chained equations for missing data. RESULTS: Antenatal domestic violence was associated with high levels of maternal antenatal (odds ratio [OR], 4.02; 95% confidence interval [CI], 3.4-4.8) and postnatal (OR, 1.29; 95% CI, 1.02-1.63) depressive symptoms after adjustment for potential confounders. Antenatal domestic violence predicted future behavioural problems at 42 months in the child before adjustment for possible confounding and mediating factors (OR, 1.87; 95% CI, 1.45-2.40); this association was not significant after adjustment for high levels of maternal antenatal depressive symptoms, postnatal depressive symptoms or domestic violence since birth. CONCLUSIONS: Antenatal domestic violence is associated with high levels of both maternal antenatal and postnatal depressive symptoms. It is also associated with postnatal violence, and both are associated with future behavioural problems in the child at 42 months. This is partly mediated by maternal depressive symptoms in the ante- or postnatal period.

In situ measurements of the physical characteristics of Titan's environment.

On the basis of previous ground-based and fly-by information, we knew that Titan's atmosphere was mainly nitrogen, with some methane, but its temperature and pressure profiles were poorly constrained because of uncertainties in the detailed composition. The extent of atmospheric electricity ('lightning') was also hitherto unknown. Here we report the temperature and density profiles, as determined by the Huygens Atmospheric Structure Instrument (HASI), from an altitude of 1,400 km down to the surface. In the upper part of the atmosphere, the temperature and density were both higher than expected. There is a lower ionospheric layer between 140 km and 40 km, with electrical conductivity peaking near 60 km. We may also have seen the signature of lightning. At the surface, the temperature was 93.65 +/- 0.25 K, and the pressure was 1,467 +/- 1 hPa.

Class III beta-tubulin expression and in vitro resistance to microtubule targeting agents.

BACKGROUND: Class III beta-tubulin overexpression is a marker of resistance to microtubule disruptors in vitro, in vivo and in the clinic for many cancers, including breast cancer. The aims of this study were to develop a new model of class III beta-tubulin expression, avoiding the toxicity associated with chronic overexpression of class III beta-tubulin, and study the efficacy of a panel of clinical and pre-clinical drugs in this model. METHODS: MCF-7 (ER+ve) and MDA-MB-231 (ER-ve) were either transfected with pALTER-TUBB3 or siRNA-tubb3 and 24 h later exposed to test compounds for a further 96 h for proliferation studies. RT-PCR and immunoblotting were used to monitor the changes in class III beta-tubulin mRNA and protein expression. RESULTS: The model allowed for subtle changes in class III beta-tubulin expression to be achieved, which had no direct effect on the viability of the cells. Class III beta-tubulin overexpression conferred resistance to paclitaxel and vinorelbine, whereas downregulation of class III beta-tubulin rendered cells more sensitive to these two drugs. The efficacy of the colchicine-site binding agents, 2-MeOE2, colchicine, STX140, ENMD1198 and STX243 was unaffected by the changes in class III beta-tubulin expression. CONCLUSION: These data indicate that the effect of class III beta-tubulin overexpression may depend on where the drug's binding site is located on the tubulin. Therefore, this study highlights for the first time the potential key role of targeting the colchicine-binding site, to develop new treatment modalities for taxane-refractory breast cancer.

Development and responsiveness of a scale to measure clinicians' attitudes to people with mental illness (medical student version).

OBJECTIVE: We report the rationale, reliability, validity and responsiveness studies of the Mental Illness: Clinicians' Attitudes (MICA) Scale, a 16-item scale designed to measure attitudes of health care professionals towards people with mental illness. METHOD: Items were generated through focus groups with service users, carers, medical students and trainee psychiatrists. Psychometric testing was completed in a number of student samples. The responsiveness of the scale was tested after a 1.5 h mental illness stigma related intervention with medical students. RESULTS: The MICA scale showed good internal consistency, alpha = 0.79. The test-retest reliability (concordance) was 0.80 (95% CI: 0.68-0.91). The standardised response mean for the scale was 0.4 (95% CI 0.02-0.8) after a mental illness related stigma intervention. CONCLUSION: The MICA scale is a responsive, reliable and valid tool, which can be used in medical education and mental health promotion settings and studies.

Alternatives to standard acute in-patient care in England: short-term clinical outcomes and cost-effectiveness.

BACKGROUND: Outcomes following admission to residential alternatives to standard in-patient mental health services are underresearched. AIMS: To explore short-term outcomes and costs of admission to alternative and standard services. METHOD: Health of the Nation Outcome Scales (HoNOS), Threshold Assessment Grid (TAG), Global Assessment of Functioning (GAF) and admission cost data were collected for six alternative services and six standard services. RESULTS: All outcomes improved during admission for both types of service (n = 433). Adjusted improvement was greater for standard services in scores on HoNOS (difference 1.99, 95% CI 1.12-2.86), TAG (difference 1.40, 95% CI 0.39-2.51) and GAF functioning (difference 4.15, 95% CI 1.08-7.22) but not GAF symptoms. Admissions to alternatives were 20.6 days shorter, and hence cheaper (UK pound3832 v. pound9850). Standard services cost an additional pound2939 per unit HoNOS improvement. CONCLUSIONS: The absence of clear-cut advantage for either type of service highlights the importance of the subjective experience and longer-term costs.

Effectiveness and cost-effectiveness of admissions to women's crisis houses compared with traditional psychiatric wards: pilot patient-preference randomised controlled trial.

BACKGROUND: Women's crisis houses have been developed in the UK as a less stigmatising and less institutional alternative to traditional psychiatric wards. AIMS: To examine the effectiveness and cost-effectiveness of women's crisis houses by first examining the feasibility of a pilot patient-preference randomised controlled trial (PP-RCT) design (ISRCTN20804014). METHOD: We used a PP-RCT study design to investigate women presenting in crisis needing informal admission. The four study arms were the patient preference arms of women's crisis house or hospital admission, and randomised arms of women's crisis house or hospital admission. RESULTS: Forty-one women entered the randomised arms of the trial (crisis house n = 19, wards n = 22) and 61 entered the patient-preference arms (crisis house n = 37, ward n = 24). There was no significant difference in outcomes (symptoms, functioning, perceived coercion, stigma, unmet needs or quality of life) or costs for any of the groups (randomised or preference arms), but women who obtained their preferred intervention were more satisfied with treatment. CONCLUSIONS: Although the sample sizes were too small to allow definite conclusions, the results suggest that when services are able to provide interventions preferred by patients, those patients are more likely to be satisfied with treatment. This pilot study provides some evidence that women's crisis houses are as effective as traditional psychiatric wards, and may be more cost-effective.

Alternatives to standard acute in-patient care in England: differences in content of care and staff-patient contact.

BACKGROUND: Differences in the content of care provided by acute in-patient mental health wards and residential crisis services such as crisis houses have not been researched. AIMS: To compare planned and actual care provided at alternative and standard acute wards and to investigate the relationship between care received and patient satisfaction. METHOD: Perspectives of stakeholders, including local service managers, clinicians and commissioners, were obtained from 23 qualitative interviews. Quantitative investigation of the care provided at four alternative and four standard services was undertaken using three instruments developed for this study. The relationship of care received to patient satisfaction was explored. RESULTS: No significant difference was found in intensity of staff-patient contact between alternative and standard services. Alternative services provided more psychological and less physical and pharmacological care than standard wards. Care provision may be more collaborative and informal in alternative services. All measured types of care were positively associated with patient satisfaction. Measured differences in the care provided did not explain the greater acceptability of community alternatives. CONCLUSIONS: Similarities in care may be more marked than differences at alternative and standard services. Staff-patient contact is an important determinant of patient satisfaction, so increasing it should be a priority for all acute in-patient services.

Alternatives to standard acute in-patient care in England: roles and populations served.

BACKGROUND: Key questions regarding residential alternatives to standard acute psychiatric care, such as crisis houses and short-stay in-patient units, concern the role that they fulfil within local acute care systems, and whether they manage people with needs and illnesses of comparable severity to those admitted to standard acute wards. AIMS: To study the extent to which people admitted to residential alternatives and to standard acute services are similar, and the role within local acute care systems of admission to an alternative service. METHOD: Our approach combined quantitative and qualitative methods. Consecutive cohorts of patients in six residential alternatives across England and six standard acute wards in the same areas were identified, and clinical and demographic characteristics, severity of symptoms, impairments and risks compared. Semi-structured interviews with key stakeholders in each local service system were used to explore the role and functioning of each alternative. RESULTS: Being already known to services (OR = 2.6, 95% CI 1.3-5.2), posing a lower risk to others (OR = 0.49, 95% CI 0.31-0.78) and having initiated help-seeking in the current crisis (OR = 2.2, 95% CI 1.2-4.3) were associated with being admitted to an alternative rather than a standard service. Stakeholder interviews suggested that alternatives have a role that is similar but not identical to standard hospital services. They can divert some, but not all, patients from acute admission. CONCLUSIONS: Residential alternatives are integrated into catchment area mental health systems. They serve similar, but not identical, clinical populations to standard acute wards and provide some, but not all, of the functions of these wards.

BCRP expression does not result in resistance to STX140 in vivo, despite the increased expression of BCRP in A2780 cells in vitro after long-term STX140 exposure.

The anti-proliferative and anti-angiogenic properties of the endogenous oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2), are enhanced in a series of sulphamoylated derivatives of 2-MeOE2. To investigate possible mechanisms of resistance to these compounds, a cell line, A2780.140, eightfold less sensitive to the 3,17-O,O-bis-sulphamoylated derivative, STX140, was derived from the A2780 ovarian cancer cell line by dose escalation. Other cell lines tested did not develop STX140 resistance. RT-PCR and immunoblot analysis demonstrated that breast cancer resistance protein (BCRP) expression is dramatically increased in A2780.140 cells. The cells are cross-resistant to the most structurally similar bis-sulphamates, and to BCRP substrates, mitoxantrone and doxorubicin; but they remain sensitive to taxol, an MDR1 substrate, and to all other sulphamates tested. Sensitivity can be restored using a BCRP inhibitor, and this pattern of resistance is also seen in a BCRP-expressing MCF-7-derived cell line, MCF-7.MR. In mice bearing wild-type (wt) and BCRP-expressing tumours on either flank, both STX140 and mitoxantrone inhibited the growth of the MCF-7wt xenografts, but only STX140 inhibited growth of the MCF-7.MR tumours. In conclusion, STX140, a promising orally bioavailable anti-cancer agent in pre-clinical development, is highly efficacious in BCRP-expressing xenografts. This is despite an increase in BCRP expression in A2780 cells in vitro after chronic dosing with STX140.

Developing a user-generated measure of continuity of care: brief report.

OBJECTIVE: This paper describes a measure of continuity of care, establishes its reliability and tests it in a field trial sample for evidence of its validity. In contrast to others, this measure has been generated from the perspectives of service users. As continuity of care is a concern particularly for those with severe mental illness, we have confined our work to this population group. METHOD: Service users in focus groups and expert panels generated the measure. The researchers were themselves service users. Test-retest reliability was assessed with an independent sample. The measure was administered to a final independent field trial sample to determine their experiences of continuity of care and for further psychometric testing. RESULTS: The measure generated by service users has satisfactory psychometric properties. Service users in the field trial sample were more satisfied when continuity, as assessed by this measure, was in place. CONCLUSION: It is possible and valid to construct outcome measures in mental health entirely from the user perspective. This has not been done before.

The transfer of unsterilized material from Mars to Phobos: Laboratory tests, modelling and statistical evaluation.

Sample return missions to Phobos are the subject of future exploration plans. Given the proximity of Phobos to Mars, Mars' potential to have supported life, and the possibility of material transfer from Mars to Phobos, careful consideration of planetary protection is required. If life exists, or ever existed, on Mars, there is a possibility that material carrying organisms could be present on Phobos and be collected by a sample return mission such as the Japanese Martian Moons eXplorer (MMX). Here we describe laboratory experiments, theoretical modelling and statistical analysis undertaken to quantify whether the likelihood of a sample from Phobos material containing unsterilized material transferred from Mars is less than 10-6, the threshold to transition between restricted and unrestricted sample return classification for planetary protection. We have created heat, impact and radiation sterilization models based on the Phobos environment, and through statistical analyses investigated the level of sterilization expected for martian material transferred to Phobos. These analyses indicate that radiation is the major sterilization factor, sterilizing the Phobos surface over timescales of millions of years. The specific events of most relevance in the Phobos sample return context are the 'young' cratering events on Mars that result in Zunil-sized craters, which can emplace a large mass of martian material on Phobos, in a short period of time, thus inhibiting the effects of radiation sterilization. Major unknowns that cannot yet be constrained accurately enough are found to drive the results - the most critical being the determination of exact crater ages to statistical certainty, and the initial biological loading on Mars prior to transfer. We find that, when taking a conservative perspective and assuming the best-case scenario for organism survival, for a 100 g sample of the Phobos regolith to be below the planetary protection requirement for unrestricted sample return, the initial biological loading on Mars must be <8.2 × 103cfu kg-1. For the planned MMX mission, a ∼10 g sample to be obtained from a 25-30 mm diameter core as planned would require an initial martian biological loading to be <1.6 × 104cfu kg-1, in order to remain compliant with the planetary protection threshold.

2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer.

Drug combination therapy is a key strategy to improve treatment efficacy and survival of cancer patients. In this study the effects of combining 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140), a microtubule disruptor, with 2-deoxy-D-glucose (2DG) were assessed in MCF-7 (breast) and LNCaP (prostate) xenograft models in vivo. In mice bearing MCF-7 xenografts, daily p.o. administration of STX140 (5 mg kg(-1)) resulted in a 46% (P<0.05) reduction of tumour volume. However, the combination of STX140 (5 mg kg(-1) p.o.) and 2DG (2 g kg(-1) i.p.) reduced tumour volume by 76% (P<0.001). 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate also reduced tumour vessel density. 2-Deoxy-D-glucose alone had no significant effect on tumour volume or vessel density. A similar benefit of the combination treatment was observed in the LNCaP prostate xenograft model. In vitro the degree of inhibition of cell proliferation by STX140 was unaffected by oxygen concentrations. In contrast, the inhibition of proliferation by 2DG was enhanced under hypoxia by 20 and 25% in MCF-7 and LNCaP cells, respectively. The combination of STX140 and 2DG in LNCaP cells under normoxia or hypoxia inhibited proliferation to a greater extent than either compound alone. These results suggest that the antiangiogenic and microtubule disruption activities of STX140 may make tumours more susceptible to inhibition of glycolysis by 2DG. This is the first study to show the benefit of combining a microtubule disruptor with 2DG in the two most common solid tumours.

The in vivo properties of STX243: a potent angiogenesis inhibitor in breast cancer.

The steroidal-based drug 2-ethyloestradiol-3,17-O,O-bis-sulphamate (STX243) has been developed as a potent antiangiogenic and antitumour compound. The objective of this study was to ascertain whether STX243 is more active in vivo than the clinically relevant drug 2-methoxyoestradiol (2-MeOE2) and the structurally similar compound 2-MeOE2-3,17-O,O-bis-sulphamate (STX140). The tumour growth inhibition efficacy, antiangiogenic potential and pharmacokinetics of STX243 were examined using four in vivo models. Both STX243 and STX140 were capable of retarding the growth of MDA-MB-231 xenograft tumours (72 and 63%, respectively), whereas no inhibition was observed for animals treated with 2-MeOE2. Further tumour inhibition studies showed that STX243 was also active against MCF-7 paclitaxel-resistant tumours. Using a Matrigel plug-based model, in vivo angiogenesis was restricted with STX243 and STX140 (50 and 72%, respectively, using a 10 mg kg(-1) oral dose), thereby showing the antiangiogenic activity of both compounds. The pharmacokinetics of STX243 were examined at two different doses using adult female rats. The compound was orally bioavailable (31% after a single 10 mg kg(-1) dose) and resistant to metabolism. These results show that STX243 is a potent in vivo drug and could be clinically effective at treating a number of oncological conditions.

Assessing the needs of pregnant women and mothers with severe mental illness: the psychometric properties of the Camberwell Assessment of Need - Mothers (CAN-M).

There is an absence of standardized validated instruments to assess the complex needs of pregnant women and mothers with severe mental illness. We aimed to develop a standardized assessment of need for pregnant women and mothers with severe mental illness. Staff and service users were asked to identify relevant domains of need. Professional experts and service users were then surveyed and asked to rate the importance of the domains of the Camberwell Assessment of Need - Mothers version (CAN-M). Reliability was established using 36 service user-staff pairs. Concurrent validity was assessed with the Global Assessment of Functioning. Inter-rater reliability (concordance) coefficients for unmet needs were 0.93 (95% confidence interval 0.89 to 0.98) (service users) and 0.83 (95% confidence interval 0.73 to 0.94) (staff); test-retest reliability coefficients were 0.91 (95% confidence interval 0.86 to 0.97) and 0.85 (95% confidence interval 0.73 to 0.96), respectively. Relevant CAN-M domains correlated with the Global Assessment of Functioning-symptom (Spearman's r correlation coefficient = -0.36, 95% confidence interval = -0.62 to -0.04, p = 0.05) and Global Assessment of Functioning-disability subscales (Spearman's r correlation coefficient = -0.52, confidence interval = -0.73 to -0.23, p < 0.01). We conclude that the CAN-M is a reliable and valid instrument for assessing the needs of pregnant women and mothers with severe mental illness.

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.