K.J. Walker

Endocrinological and clinical aspects of LHRH action (ICI 118630) in hormone dependent breast cancer

The effect of an LHRH agonist, D-Ser (But)6Azgly10-LHRH (Zoladex, ICI 118630) on pituitary gland and ovarian function has been investigated in patients with advanced breast cancer. In both pre and postmenopausal women ICI 118630 produced a substantial rise in circulating concentrations of gonadotrophins within 2 h of the first injection. However, on continued exposure to the drug plasma LH and FSH levels decreased to below pre-treatment values (14-21 days). This was especially evident in postmenopausal women. In premenopausal patients plasma progesterone and estradiol levels were significantly reduced after 2 and 4-6 weeks of therapy respectively, reaching values observed in oophorectomized or postmenopausal patients. No substantial acute or long-term influence of the drug on these hormones was seen in postmenopausal women. Breast tumor remissions were recorded primarily in premenopausal patients with estrogen receptor positive tumors. No responses were seen in patients with estrogen receptor negative disease. Minimal side effects were recorded.

Zoladex® plus tamoxifen versus zoladex® alone in pre- and peri-menopausal metastatic breast cancer

Phase II studies examining the endocrinological and clinical efficacy of Zoladex and Zoladex plus tamoxifen have been examined in pre- and peri-menopausal women with advanced breast cancer. No adverse endocrinological interaction between the drugs have been observed. Although a higher proportion of static disease was observed with the combination of the drugs, which possibly occurred at the expense of partial remissions, the time to disease progression was extended in women who received Zoladex plus tamoxifen. Remissions were primarily restricted to patients whose tumours were ER positive. Only occasional responses were seen in ER negative disease. This was especially evident where the ER negative tumours were EGF-R positive and showed high rates of cell proliferation.

Endocrine effects of combination antioestrogen and LH-RH agonist therapy in premenopausal patients with advanced breast cancer

Thirty-eight premenopausal breast cancer patients were treated for periods up to 12 months with a sustained-release formulation of the luteinizing hormone-releasing hormone agonist goserelin [Zoladex, (D-Ser(But)6Azgly10-LH-RH); 3.6 mg depot every 4 weeks] either alone or in combination with the antioestrogen tamoxifen citrate (Nolvadex 40 mg/day). In both treatment groups serum gonadotrophin concentrations fell durig the first month of therapy and were suppressed on continued treatment. In patients treated with the combination therapy FSH concentrations were significantly reduced in comparison with goserelin alone. Relatively normal ovarian activity was observed during the first few weeks of therapy. Thereafter, oestradiol and progesterone concentrations rapidly declined in both treatment groups. Slightly lower serum oestradiol concentrations were recorded in patients receiving combination therapy. No significant adverse side-effects were recorded in either group of patients.

Review of the endocrine actions of luteinising hormone-releasing hormone analogues in premenopausal women with breast cancer.

The endocrinological actions of the luteinising hormone-releasing hormone (LHRH) analogue, Zoladex (goserelin) in premenopausal women with advanced breast cancer are reviewed. LHRH analogues are an interesting addition to the currently available treatments for hormone-sensitive breast cancer in premenopausal women. Their modest side effects and ease of administration are in contrast to the risks and morbidity of surgical endocrine therapy.

Gn-RH agonists in breast and gynaecologic cancer treatment

The effects of Gn-RH agonists in advanced breast cancer patients have been examined. In both pre- and postmenopausal women they produce pituitary gland desensitisation and a fall in circulating concentrations of LH and FSH. In premenopausal patients plasma progesterone and oestradiol levels fall to the castrate or postmenopausal range within 3-4 weeks. Tumour remissions have been observed in approximately 30% of premenopausal women and approximately 10% of postmenopausal patients. The mechanism of action of Gn-RH agonists is discussed and their use projected to other tumour types.

Preclinical Studies and Antitumor Mechanism of Action of LHRH Analogues

In the last 15 years a new class of pharmacologic agents has emerged—luteinizing hormone-releasing hormone (LHRH) analogues. As their name suggests, they are modified versions of LHRH and can either have agonistic or antagonistic properties. Because LHRH is essential for normal reproductive functions in mammals, it is not surprising that the availability of these drugs has generated much excitement, and they are currently under examination as clinical agents in such diverse areas as the augmentation of fertility [1], contraception [2], and oncology [3,4]. Our own interest in LHRH analogues began in 1977 following an approach by ICI Pharmaceuticals division in the United Kingdom to screen a series of LHRH agonists that they believed might have interesting endocrinologic and antitumor properties. The results obtained at that time clearly showed that in female rats the compounds were able to suppress ovarian activity, reduce circulating levels of estradiol, and cause a decrease in size of estrogen target tissue [5], including an ability to promote extensive regressions in estrogen receptor-positive, dimethylben-zanthracene-induced mammary tumours [6, 7]. Similarly, in male animals, LHRH agonists decreased circulating levels of testosterone and, at least in young animals, promoted an atrophy of the accessory sex organs [8–10].