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R C Coombes, C Harper-Wynne, and M Dowsett

Over the past decade several novel aromatase inhibitors have been introduced into clinical practice. The discovery of these drugs followed on from the observation that the main mechanism of action of aminogluthemide was via inhibition of the enzyme aromatase thereby reducing peripheral levels of oestradiol in postmenopausal patients. The second-generation drug, 4-hydroxyandrostenedione (formestane), was introduced in 1990 and although its use was limited by its need to be given parenterally it was found to be a well-tolerated form of endocrine therapy. Third-generation inhibitors include vorozole, letrozole, anastrozole and exemestane, the former three being non-steroidal inhibitors, the latter being a steroidal inhibitor. All are capable of inhibiting aromatase action by >95% compared with 80% in the case of 4-hydroxyandrostenedione. The sequential use of different generations of aromatase inhibitors in the same patients is discussed. Studies suggest that an optimal sequence of these compounds may well result in longer remission in patients with hormone receptor positive tumours.

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R C Coombes, L Buluwela, and J J Gomm

Abstract

We have studied separated human breast epithelial and myoepithelial cells for the presence of basic fibroblast growth factor (FGF2) and its receptors and for the effects of FGF2 on the proliferation of both cell types. We have also studied the role of activin and its receptor in controlling cell proliferation.

Our results indicated that these cell types differ markedly in synthesis and response to FGF2 and activin and in their receptor content. FGF2 had no effect on the proliferation of myoepithelial cells but promoted the survival of the separated epithelial cells. Immunostainable FGF receptors 1 and 4 were present in epithelial cells and to a lesser extent in myoepithelial cells. These results indicated that myoepithelial-derived FGF2 may be important in controlling epithelial cell survival and that differential receptor expression could control FGF2 action in these different cell types.

We found that activin β-a and activin type II receptor are expressed by myoepithelial cells, whereas no expression was detected in other breast cell types. In examining 15 breast cell lines, we found only four (HBL-100, MCF-10A, PMC-42 and BT-20) to be positive for activin β-a mRNA, whereas all expressed the activin type II receptor. Furthermore, we have found activin A to be a potent growth inhibitor of MCF-7 cells where it causes an arrest in G1. Activin A does not appear to have an effect on the cell cycle of primary myoepithelial or luminal cells. However, we have demonstrated that activin is an inhibitor of tubule formation by human mammary organoids in vitro.

Endocrine-Related Cancer (1997) 4 35-43

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A G Mackay, E A Ofori-Kuragu, A Lansdown, R C Coombes, L Binderup, and K W Colston

Abstract

The anti-tumour effect of EB 1089, a novel vitamin D analogue with reduced calcaemic activity, was examined in vivo using the N-methyl-nitrosourea-induced rat mammary tumour model. The vitamin D compound was given orally at a dose of 1 pg/kg body weight alone and in combination with tamoxifen (1 mg/kg). Effects were compared with oral tamoxifen treatment alone. EB 1089 significantly inhibited tumour progression compared with controls with a response rate of 58% and a regression rate of 92% As expected, tamoxifen at the dose given also caused significant inhibition of tumour progression with a response rate of 73%. Combination of these two compounds did not lead to a marked increase in their effectiveness. Histological examination of tumours from EB 1089-treated rats showed a marked reduction in cellularity and mitotic activity.

At the dose given, EB 1089 produced a significant rise in serum calcium concentration and urinary calcium excretion. Tamoxifen treatment alone did not significantly alter serum calcium levels. However, combined treatment with tamoxifen and EB 1089 led to a significant reduction in hypercalcaemia compared with EB 1089 alone. It is suggested that vitamin D analogues with reduced calcaemic activity may provide a new therapeutic strategy for certain malignancies, either alone or in combination with established treatment regimens.

Endocrine-Related Cancer (1996) 3 327-335

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C Palmieri, G J Cheng, S Saji, M Zelada-Hedman, A Wärri, Z Weihua, S Van Noorden, T Wahlstrom, R C Coombes, M Warner, and J-A Gustafsson

Estrogen is essential for normal growth and differentiation in the mammary gland. It also supports growth of approximately 50% of primary breast cancers. For this reason, removal of estrogen or blocking of its action with the anti-estrogen, tamoxifen, is the main treatment for estrogen receptor alpha (ERalpha)-positive tumors. In 1996, when oncologists became aware of a second ER, ERbeta, there was some doubt as to whether this receptor would be of importance in breast cancer because the clinical consensus was that responsiveness to tamoxifen is related to the presence of ERalpha in breast cancer. Today we know that ERalpha and ERbeta have distinct cellular distributions, regulate separate sets of genes and can oppose each other's actions on some genes. We also know that ERbeta is widely expressed in both the normal and malignant breast and that there are proliferating cells in the breast which express ERbeta. In this review we summarize what is known about ERbeta in breast cancer and examine the possibility that ERbeta-selective ligands may well represent a useful class of pharmacological tools with a novel target, namely proliferating cells expressing ERbeta.

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N Sarwar, J-S Kim, J Jiang, D Peston, H D Sinnett, P Madden, J M Gee, R I Nicholson, A E Lykkesfeldt, S Shousha, R C Coombes, and S Ali

Oestrogen receptor-α (ERα) is an important prognostic marker in breast cancer and endocrine therapies are designed to inhibit or prevent ERα activity. In vitro studies have indicated that phosphorylation of ERα, in particular on serine 118 (S118), can result in activation in a ligand-independent manner, thereby potentially contributing to resistance to endocrine agents, such as tamoxifen and aromatase inhibitors. Here we report the immunohistochemistry (IHC) of S118 phosphorylation in 301 primary breast tumour biopsies. Surprisingly, this analysis shows that S118 phosphorylation is higher in more differentiated tumours, suggesting that phosphorylation at this site is associated with a good prognosis in patients not previously treated with endocrine agents. However, we also report that S118 phosphorylation was elevated in tumour biopsies taken from patients who had relapsed following tamoxifen treatment, when compared to pre-treatment biopsies. Taken together, these data are consistent with the view that S118 phosphorylation is a feature of normal ERα function and that increases in levels of phosphorylation at this site may play a key role in the emergence of endocrine resistance in breast cancer.