Sununary The effect of anastrozole ('Arimidex', ZD1033), a new, selective, non-steroidal aromatase inhibitor on in vivo aromatisation and plasma oestrogen levels was evaluated in post-menopausal women with breast cancer. Twelve patients progressing after treatment with tamoxifen were randomised to receive anastrozole 1 mg or 10 mg once daily for a 28 day period in a double-blinded crossover design. In vivo aromatisation and plasma oestrogen levels were determined before commencing treatment and at the end of each 4-week period. Breast cancer is the most common malignancy among women in the western hemisphere. Many of these patients develop metastatic disease, for which no cure is currently available. Because endocrine treatment causes fewer side-effects than chemotherapy, such therapy is first-line treatment in patients with metastatic disease and hormone receptor-positive tumours. While the anti-oestrogen tamoxifen is first choice of therapy in post-menopausal patients with metastatic breast cancer. increasing use of tamoxifen as adjuvant therapy focuses on the need for alternative endocrine treatment options on relapse in breast cancer patients.While ovarian oestrogen synthesis ceases at the menopause, oestrogens are synthesised in peripheral tissue from circulating androgens by the process called aromatisation (Grodin et al., 1973). The main pathway is conversion of androstenedione (A) into oestrone (El), with a minor contribution from conversion of testosterone into oestradiol (E2) (L0nning et al., 1990).Aromatase inhibitors are drugs that inhibit the peripheral conversion of androgens to oestrogens (Santen et al., 1982a), thereby suppressing plasma oestrogen levels in postmenopausal women. The first-generation aromatase inhibitor, aminoglutethimide, was implemented in breast cancer treatment more than 20 years ago (Cash et al., 1967). While the drug is effective in hormone-sensitive breast cancer, lack of specificity (inhibition of adrenal steroid-synthesising enzymes) and side-effects (such as skin rash and lethargy) provoked the development of new aromatase inhibitors (Coombes et al., 1984;Evans et al., 1992;Johnston et al., 1994;Lipton et al., 1995; Santen et al., 1989).Anastrozole (Arimidex; 2,2'[5-(1H-1 ,2,4-triazol-1-ylmethyl) -1,3-phenylene]bis-(2-methylpropiononitrile, Figure 1) is a new, potent and selective aromatase inhibitor belonging to the triazole class. Pilot studies in post-menopausal women have shown the drug to suppress plasma E2 by > 80% (Plourde et al., 1994), and preclinical studies as well as observations in women suggest the drug to be highly specific with no influence on adrenal steroid synthesis (Plourde et al., 1995). A major problem in evaluating the biochemical efficacy of aromatase inhibitors has been the lack of internal consistency between the percentage aromatase inhibition and degree of plasma oestrogen suppression. While aminoglutethimide as well as the second-generation aromatase inhibitor formestane and the third-generation inhibitor fadrozole (L0nning et al., 1991) ...

Summary We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-' and during the sixth month was 12.6 ng ml-l. The AUCs were 140.5 and 206.8 ng day ml-' on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Sideeffects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed 'no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer.

Transglutaminase activity and subcellular distribution have been examined in both normal and tumour tissue. Subcellular fractionation of rat liver demonstrated a bimodial distribution for transglutaminase between the particulate (approximately 40%) and cytosol (approximately 60%) fractions. Isolation of enriched plasma membrane fractions indicated the presence of membrane associated transglutaminase activity which co-distributed with that of 5'-nucleotidase and Na+/K+-ATPase. Induction of hepatocellular carcinomas in rats by treatment with either diethylnitrosamine or 6-p-dimethylaminophenylazobenzothiazole resulted in a reduction in transglutaminase activity which was accompanied by redistribution of the enzyme to the particulate fraction of the cell. The tumour bearing liver appeared to represent an intermediate stage between the hepatocellular carcinoma and control liver when assayed for content and distribution of transglutaminase activity. The transglutaminase activity of four transplantable rat sarcomas (P7, P8, MC3 and CC5) was found to be greatly reduced when compared with the normal tissues of rat liver, lung and spleen. A further reduction in this activity occurred in the primary growths of the sarcomas P7 and P8 following detection of metastases. Our data suggest that such changes in the distribution and content of transglutaminase may be a feature of tumour tissue and may be of value in both monitoring and investigating the carcinogenic process.

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