Therapeutic significance and the mechanism of action of the LH-RH agonist ICI 118630 in breast and prostate cancer

Nicholson, Robert Ian; Walker, Kate; Turkes, A.; Dyas, J; Blamey, R. W.; Campbell, F. C.; Robinson, M.R.G.; Griffiths, K.

doi:10.1016/0022-4731(84)90199-7

Cited by 45 publications

(20 citation statements)

References 22 publications

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“…The pattern of suppression of oestradiol was similar to that found previously when leuprorelin was given by daily subcutaneous injections (Harvey et al, 1985). There was no indication of an early surge in LH, FSH or oestradiol levels as has been seen in some studies with LHRH agonists (Nicholson et al, 1984(Nicholson et al, , 1987 Weeks treatment Weeks treatment Figure 1 Mean hormone levels before and during treatment with 4-weekly injections of 3.75 mg (0) and 7.5 mg (*) leuprorelin.…”

Section: Discussionsupporting

confidence: 85%

A dose-comparative endocrine-clinical study of leuprorelin in premenopausal breast cancer patients

Dowsett

Mehta²,

Mansi³

et al. 1990

Br J Cancer

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Summary Twelve premenopausal patients with advanced breast cancer were randomised to receive 3.75 or 7.5 mg of a slow release formulation of the luteinising hormone releasing hormone agonist leuprorelin once every 4 weeks. All patients were oestrogen receptor positive or unknown. Serum (Jacobi et al., 1987;Smith et al., 1985; Donnelly & Milstead, 1987) and breast cancer (Harvey et al., 1985;Klijn, 1984;Williams et al., 1986). This is due to the 'down-regulation' of LHRH receptors by the drugs, which results in a fall in gonadotrophin levels and a consequent reduction in the level of gonadal steroid production (Sandow, 1983). The response rate is higher in premenopausal patients in breast cancer as might be expected for a drug with this action. The small number of responses in postmenopausal patients may be due to reduced ovarian androgen secretion with a consequent fall in circulating oestrogen levels (Dowsett et al., 1988;Crighton et al., 1989).Leuprorelin is a synthetic nonapeptide LHRHa (D-Leu6 DES Gly NH2iO GnRH ethylamide) which lacks the aminoacid glycine at position 10 and has leucine substituted for glycine at position 6 of natural LHRH. Earlier clinical studies required daily administration in aqueous solution (Harvey et al., 1985), but a more convenient sustained release formulation has now been developed, in which the agonist is microencapsulated in polylactic and polyglycolic acid. It has been found that the compound is equally effective endocrinologically in prostatic cancer as once monthly doses of either 7.5 or 3.75 mg (Isurugi et al., 1988). This is the first report of the use of the slow-release formulation in premenopausal women. A detailed endocrine study was conducted to compare the doses of 3.75 and 7.5 mg in 12 patients, to determine whether there was any contraindication to further study of the lower dose in a larger group of patients. Blood samples were drawn from patients prior to treatment and 1, 2, 3, 4, 6, 8, 10 and 12 weeks after starting treatment. The samples were allowed to clot and the resultant serum was stored at -20°C until analysis. The following analyses were performed by previously described immunoassays: luteinising hormone (LH) and follicle stimulating hormone (FSH) (Ferguson et al., 1982); oestradiol (Dowsett et al., 1987), oestrone (Harris et al., 1983). Serum levels of androstenedione were measured using the Biogenesis kit. This is a direct assay employing an iodinated tracer in which the only cross-reactions of greater than 0.1 % were to 11-deoxycortisol (1.2%) and isoandrosterone (0.3%). Withinand between-assay coefficients of variation were 7.5% and 8.6%, respectively. Serum levels of testosterone were measured using the St Thomas Hospital Testosterone kit (Wheeler et al., 1983). In this assay, the serum is first extracted with ether and this extract is subject to immunoassay using an iodinated tracer. The antiserum cross-reacts 20% with 5adihydrotestosterone. All other cross-reactions were less than 0.1%. Within-and between-assay coefficients of variation were ...

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Section: Discussionsupporting

confidence: 85%

A dose-comparative endocrine-clinical study of leuprorelin in premenopausal breast cancer patients

Dowsett

Mehta²,

Mansi³

et al. 1990

Br J Cancer

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“…This surgical approach suffers many disadvantages in that treatment is palliative and the majority of patients will not respond, thus exposing many to unnecessary and irreversible morbidity (Kennedy et al, 1964). 7, 7 +, 8, 8 +, 9, 9, 9, 11, 14 +, 14, 14, 15 +, 16 +, 16, 18, 18 +, 22 +, 36 (median 14 +) SD 11 (15%) 6,7,8,9,9, 10+, 10, 16+, 18,37,45+, (median 10 +) PD 39 (52%) Administration of the LH-RH agonist goserelin to premenopausal advanced breast cancer patients produces a rapid desensitisation of the pituitary gland to endogenous LH-RH, with resultant falls in the circulating levels of LH and FSH (Nicholson et al, 1984(Nicholson et al, , 1985Williams et al, 1986;. Castrate levels of oestradiol and progesterone are produced within 3-4 weeks although a small group of patients will shown recurrent suppressed peaks of oestradiol .…”

Section: Discussionmentioning

confidence: 99%

“…No patient had received previous endocrine or cytotoxic therapies: all gave written informed consent to the administration of the drug. The median age of the patients on commencing therapy was 44 years (range 31-55), with the sites of disease as shown in (Nicholson et al, 1981). Patients were assessed for response according to UICC criteria (Hayward et al, 1977).…”

Section: Methodsmentioning

confidence: 99%

“…The endocrine effects and clinical efficacy of the luteinising hormone-releasing hormone (LH-RH) agonist goserelin (Zoladex, ICI plc) as initial hormone therapy for premenopausal advanced breast cancer patients have been previously reported (Nicholson et al, 1984(Nicholson et al, , 1985Williams et al, 1986;Walker et al, 1986). In a study of 53 premenopausal patients we reported a response rate to goserelin of 31%; comparable to our previous experience of surgical oophorectomy Buchanan et al, 1986).…”

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confidence: 99%

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Goserelin (Zoladex) in premenopausal advanced breast cancer: duration of response and survival

Dixon

Robertson²,

Jackson³

et al. 1990

Br J Cancer

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“…Leutinising hormone releasing hormone (LHRH) analogues such as goserelin inhibit gondadotrophin release from the pituitary when administered repeatedly (Dutta et al, 1978). In premenopausal women they have the effect of suppressing ovarian oestrogen synthesis, and have been used as an alternative to surgical oophorectomy in the treatment of advanced breast cancer (Klijn et al, 1982;Nicholson et al, 1984;Williams et al, 1986 We report here on the endocrine and therapeutic effects of 40HA on its own, and in combination with goserelin in premenopausal women with advanced breast cancer.…”

mentioning

confidence: 99%

The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer

Stein

Dowsett²,

Hedley³

et al. 1990

Br J Cancer

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Therapeutic significance and the mechanism of action of the LH-RH agonist ICI 118630 in breast and prostate cancer

Cited by 45 publications

References 22 publications

A dose-comparative endocrine-clinical study of leuprorelin in premenopausal breast cancer patients

A dose-comparative endocrine-clinical study of leuprorelin in premenopausal breast cancer patients

Goserelin (Zoladex) in premenopausal advanced breast cancer: duration of response and survival

The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer

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