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Biomedical subjects

M J Reed

Publications and source records attributed to M J Reed.

262 records · Page 15Linked to original sources
PubMedDate not supplied

Inhibition of superoxide dismutase by 2-methoxyoestradiol analogues and oestrogen derivatives: structure-activity relationships.

Superoxide dismutases catalyse the dismutation of highly reactive superoxide ions to produce hydrogen peroxide and several lines of evidence suggest that these enzymes play important roles in the development and response to treatment of human cancers. For example, Mn-containing superoxide dismutase is frequently overexpressed in various cancer types and can contribute to resistance to apoptosis. 2-Methoxyoestradiol is a naturally occurring metabolic product of 17beta-oestradiol that inhibits tubulin polymerization and possesses growth inhibitory and cytotoxic activity in vitro and in vivo. More recently 2-methoxyoestradiol has also been shown to inhibit superoxide dismutase (SOD) in a tetrazolium salt based enzyme assay, suggesting that oestrogen derivatives might be useful starting points for the development of effective, non-toxic enzyme inhibitors. Here we have tested the SOD inhibiting activity of a range of oestrogen derivatives to determine structural features important for enzyme inhibition.

2-Methoxyestradiol↗
PubMedDate not supplied

The effect of oestrogens and medroxyprogesterone acetate on the uptake of cytotoxic drugs by MCF-7 breast cancer cells.

Previous studies have shown that human breast cancer cells (MCF-7) show an increased response to a number of cytotoxic drugs after 48 h pretreatment with medroxyprogesterone acetate (MPA). As there is evidence that MPA can influence membrane fluidity, we have examined the effect of pre-treatment with MPA on the uptake of methotrexate (MTX) and vincristine (VCR) by MCF-7 cells. The effect of pre-treatment with oestrogen on cytotoxic drug uptake was also examined. After 48 h pre-treatment with MPA (40 or 160 nmol/L), the uptake of MTX was significantly reduced by 14%-44%. Uptake of VCR was also reduced (10%-16%) after pre-treatment of cells with MPA but to a lesser degree than detected for MTX. Pre-treatment with ethinyloestradiol increased the uptake of MTX by up to 45% but enhanced uptake was only detected in cells after exposure to MTX for 1 h. While the results from this study show that oestrogens or MPA can alter the uptake of cytotoxic drugs by MCF-7 breast cancer cells, it is not clear how the MPA dependent decrease in drug uptake enhances the response of MCF-7 to such drugs previously reported.

Antineoplastic Agents↗
PubMedDate not supplied

The role of STS and OATP-B mRNA expression in predicting the clinical outcome in human breast cancer.

BACKGROUND: Steroid sulfatase (STS) is the enzyme responsible for hydrolysing biologically inactive estrogen sulfates to active estrogens. Therefore it plays a significant role in supporting the growth of hormone-dependent tumours of the breast, endometrium and prostate. OATP-B is a member of a family of membrane transporter proteins that regulates the uptake of steroid sulfates through cell membranes. Our objective was to determine, using quantitative PCRA whether the mRNA expression levels from these genes were positively correlated with clinical outcome in human breast cancer. This is the first study in the literature to examine the relationship between STS and OATP-B in human breast cancer and to investigate the potential prognostic value of OATP-B. MATERIALS AND METHODS: A total of 153 samples (120 tumour tissues and 33 normal breast tissues) were analysed. The levels of transcription of STS and OATP-B were determined using real-time quantitative PCR and normalized against cytokeratin 19. The levels of expression were analysed against tumour's stage, grade, nodal status, local relapse, distant metastasis, ERalpha, ERbeta and HER1-4 receptor status and survival over a 10 year follow up period. RESULTS: The levels of STS mRNA were significantly higher in malignant samples (p=0.031) and in node positive disease (p=0.0222). STS mRNA expression increased with increasing tumour grade but this did not reach statistical significance. A significant increase was also noted in levels correlating with tumour stage when stages TNM1 and TNM2, TNM2 and TNM3, and TNM3 and TNM4 (p=0.00001, 0.0017 and 0.02, respectively) were compared. Furthermore, STS expression levels positively correlated with progression of disease, as levels were significantly higher in samples from patients who developed metastasis, local recurrence, or died of breast cancer when compared to those who were disease free for >10 years (p=0.0036). No significant correlation was found between the levels of STS expression and ERalpha/ERbeta/ status. The levels positively correlated with HER1 and HER3 receptors. The levels of mRNA expression of OATP-B were higher in malignant tissue compared to normal tissue; this, however, did not reach statistical significance (p=0.4045). Levels were also higher in node positive disease (p=0.0672). Expression levels increased with increasing tumour grade and this became statistically significant when comparing grade 1 to 2, and grade 2 to 3 (p=0.0271 and 0.0289, respectively). An increase in levels correlating with TNM tumour staging was also observed; this, however, did not reach statistical significance. There was no significant correlation between OATP-B expression levels and clinical progression of breast cancer. No correlation was found between STS and OATP-B expression levels. CONCLUSION: This study demonstrates a compelling trend for STS transcription levels to be higher in cancer tissues and in patients who developed progressive disease. OATP-B expression levels correlated with the grade and stage of the disease, but not with the clinical outcome. These results suggest that STS mRNA has a significant potential as an important predictor of clinical outcome in patients with breast cancer.

Breast Neoplasms↗
PubMedDate not supplied

Oestradiol and epidermal growth factor in breast cyst fluid.

Gross cystic breast disease may be categorised into 2 groups according to the intracystic cation ratios (Na+/K+ less than 3 and Na+/K+ greater than 3). It has been suggested that women in the low electrolyte ratio group may be at higher risk of developing breast cancer. Epidermal growth factor concentrations in breast cyst fluid were significantly higher in the low than in the high electrolyte ratio group but there was no significant difference in oestradiol concentrations between the two groups of breast cysts. A negative correlation was obtained between intracystic concentrations of epidermal growth factor and Na+/K+ (rs = -0.617, p less than 0.001). No evidence was found to support the hypothesis that concentrations of epidermal growth factor may be modulated by oestradiol. The higher concentrations of epidermal growth factor in the low electrolyte ratio group may provide an explanation for the higher risk of breast cancer observed in this group.

Biomarkers↗
PubMedDate not supplied

The effect of ethynyloestradiol and medroxyprogesterone acetate on the in vivo uptake and metabolism of 3H-oestradiol by breast tumour tissue in postmenopausal women.

The uptake and metabolism of 3H-oestradiol by breast tumour tissue was studied in three postmenopausal women before, after 1 week of treatment with ethynyl-oestradiol (EE, 10 micrograms/day) and again two weeks later after treatment with medroxyprogesterone acetate (MPA, 500mg/day, i.m.). Treatment with EE reduced the tissue: plasma gradients for both 3H-oestradiol and 3H-oestrone and little further change in these ratios occurred after MPA treatment. The proportion of oestrogen present as 3H-oestrone increased in tumours from 2/3 women after treatment with MPA but not EE, although no increase in the activity of oestradiol 17 beta-hydroxysteroid dehydrogenase (E2DH) was detected. Plasma and tissue concentrations of 5-androstenediol, dehydroepiandrosterone and dehydroepiandrosterone sulphate were all reduced after MPA treatment. The results from this study show that treatment with EE and MPA can reduce the uptake of oestradiol by breast tumours. No increase in E2DH activity was detected but it is possible that MPA influences other enzymes involved in oestradiol metabolism.

17-Hydroxysteroid Dehydrogenases↗
PubMedDate not supplied

The effect of cortisol or ACTH on plasma concentrations of free fatty acids.

The effect of infusion of cortisol (14 mumol) or ACTH (Synacthen, 250 micrograms) injection on plasma levels of free fatty acids has been examined in normal men. The increment in plasma cortisol levels after infusion of cortisol (+182%) was much less than after ACTH injection (up to 262%). Mean plasma levels of free fatty acids were only significantly increased after ACTH injection. However, some inter-subject variation occurred and a small but significant increment in plasma levels of free fatty acids was seen for one control subject and for a subject who received an infusion of cortisol. It is possible that the reported diurnal variations in plasma levels of free fatty acids may be related to changes in plasma levels of ACTH or cortisol throughout a 24h period.

Adult↗
PubMedDate not supplied

Identification of Bacteroides gingivalis by fluorescent antibody staining.

Reactivity with the conjugates to the 4 serogroups A, B, C and C-1 of the former taxon Bacteroides melaninogenicus and with antisera to B. gingivalis and to oral strains of B. melaninogenicus subsp. intermedius, was studied by fluorescent antibody staining (FAS) on strains representative of the black-pigmented Bacteroides: B. asaccharolyticus, B. melaningogenicus subsp. intermedius, B. melaninogenicus subsp. melaninogenicus, B. melaninogenicus subsp. levii, B. melaninogenicus subsp. macacae and B. gingivalis. The strains of B. gingivalis only reacted with the homologous antiserum and failed to react with any of the other immunoreagents tested indicating that the oral strains of asaccharolytic black- pigmented Bacteroides belong to a serogroup distinct from those currently serogrouped. This serological characteristic corroborates the definition of the new species B. gingivalis which has been proposed on the basis of phenotypic and genetic characteristics different from that of B. asaccharolyticus and can be used for their discrimination. FAS appears to be a reliable method for identification of B. gingivalis, a suspected major periodontopathic organism.

Bacteroides↗
PubMedDate not supplied

Oestrone sulphatase activity in normal and malignant breast tissues: relationship with tumour location.

The hydrolysis of oestrone sulphate to oestrone, by oestrone sulphatase, is thought to be the major source of the high oestrogen concentrations which are present in breast tumours. In this study, the possibility that the location of the tumour within the breast or the size of the tumour might influence oestrone sulphatase activity has been examined. Normal and malignant breast tissues were obtained from 2 pre- and 9 post-menopausal women after mastectomy. Oestrone sulphatase activity was measured in microsomes prepared from these tissues and related to the location and size of the tumour. Of the 11 mastectomy specimens examined, 4 of the 11 (36%) quadrants bearing the tumour had the highest oestrone sulphatase activity. No significant difference in oestrone sulphatase activity was detected between normal and malignant tissues. No significant relationships were found between tumour sulphatase activity and activity in the quadrant bearing the tumour or tumour size and tumour oestrone sulphatase activity. The detection of the highest oestrone sulphatase activity in 36% of the breast quadrants bearing a tumour, or on which a tumour impinged, which a tumour impinges, while lending some support to the concept that breast tumours produce factors which are able to influence the activity of this enzyme, suggests that it is to a lesser extent than previously reported for the aromatase.

Adult↗
PubMedDate not supplied

The effect of treatment with 4-hydroxyandrostenedione or medroxyprogesterone acetate on human breast tumour regression.

We have assessed cell deletion in breast tumours removed surgically from postmenopausal women by measuring the distribution ratio of acid phosphatase activity between the bound (in the lysosome) and free (in the phagosome) states. In benign breast tumours the acid phosphatase distribution ratio was much higher than that found in untreated malignant breast tumours. The acid phosphatase distribution ratio was also measured before and after treatment in malignant breast tumours removed from eight patients treated with 4-hydroxyandrostenedione (4-OH A) and in six patients treated with medroxyprogesterone acetate (MPA). Elevated acid phosphatase distribution ratios in benign compared with malignant tumours, and in malignant tumours after treatment from four of eight patients treated with 4-OH A and from three of six patients treated with MPA, may suggest higher cell deletion in these patients.

Acid Phosphatase↗