Search

Breast cancer and carcinoma of the prostate belong to a group of hormone-dependent cancers that would also include tumours of the ovary and endometrium. These cancers comprise a major proportion of the so-called 'Western diseases'. The incidence of and mortality from these cancers are high in the Western world relative to the rates associated with Asian populations such as the Chinese, Japanese, Thai and Filipino, and somewhat higher than those for people in countries surrounding the Mediterranean. Cardiovascular disease and osteoporosis follow a similar pattern and would also be considered 'Western diseases'.Carcinoma of the breast remains the principal cause of death from cancer in women in the developed countries of the West and particularly in the United States of America and Northern Europe. A recent report (Boyle & Maisonneuve 1995) confirms that the highest incidence rates are exclusively within the United States with an annual rate

A common phenotypic consequence of the genetic changes that occur in breast cancer is a loss of steroid hormone growth sensitivity, a feature manifested clinically by primary or acquired resistance to antihormones. Although it appears that the absence of steroid receptor machinery determines the failure of oestrogen receptor (ER) negative tumours to respond to endocrine therapies, the erbB signalling pathway seems far from redundant in these tumours and in vivoevidence suggests that elevated epidermal growth factor receptor (EGFR) and c-erbB-2 proteins are fundamental elements in ER negative disease growth control. In contrast, neither diminished ER nor elevated EGFR expression appears to be essential in determining any primary endocrine insensitivity demonstrated by ER positive tumours, although elevated expression of additional erbB pathway components (e.g. transforming growth factor-α, Fos, Myc and c-erbB-2 protein) may be important. However, none of these factors appears to direct endocrine unresponsive, ER positive cell proliferation. Furthermore, it is unlikely that selective outgrowth of endocrine unresponsive, EGFR membrane positive/ER negative cells constitutes a major event in ER positive tumours during their progression towards endocrine resistance.Endocrine-Related Cancer(1997) 4297-305

The last decade has seen the emergence of a new class of pharmacological agents termed pure antioestrogens (Wakeling 1991, 1993). These compounds, which were originally developed by ICI Pharmaceuticals Division in the UK, bind to the oestrogen receptor (ER) (Wilson et al.1990, Wakeling et al.1991). Figure 1 shows the structures of ICI 164384, the lead compound, and ICI 182780, which are 7α long chain analogues of oestradiol. Both the ER binding affinity and potency of ICI 182780 are greater than those observed for ICI 164384 due to the replacement of the amide function with a sulphoxide group and the fluorination of the terminal chain (Wakeling et al.1991). Such differences, nevertheless, do not alter the intrinsic biological behaviour of the drugs, which are identical to other more recently developed steroidal and non-steroidal pure antioestrogens (Von Angerer et al.1990, Day et al.1991, Claussner et al.1992,

During the last 7 years the Breast Cancer Group within the Tenovus Cancer Research Centre has maintained an involvement in the use of pure antioestrogens in two important areas of breast cancer research. First, their development as clinical agents, where we hoped to induce total oestrogen deprivation and thereby improve the effectiveness of first-line endocrine therapy (Nicholson et al.1992, Nicholson 1993, Nicholson et al.1993a, DeFriend et al.1994, Nicholson et al.1994c). Second, as pharmacological probes to investigate the cellular and molecular actions of oestrogens and tamoxifen (Nicholson et al.1988, Weatherill et al.1988, Wilson et al.1990). Implicit in each of these areas of research are questions associated with the impact which pure antioestrogens might have on the therapy of endocrine-resistant states and whether resistance develops as a consequence of incomplete oestrogen withdrawal, with tumour cells more efficiently utilising either a reduced oestrogenic pool