Prevention of the Transient Adverse Effects of a Gonadotropin-Releasing Hormone Analogue (Buserelin) in Metastatic Prostatic Carcinoma by Administration of an Antiandrogen (Nilutamide)

Abstract

Gonadotropin-releasing hormone (GnRH) analogues administered for the treatment of advanced prostatic cancer induce a transient increase in plasma testosterone levels during the first week of treatment, often with a secondary rise in plasma levels of prostatic acid phosphatase and a flareup of disease. To determine whether the antiandrogen nilutamide (Anandron) blocks these effects, we carried out a multicenter, placebo-controlled study of nilutamide in men with prostatic cancer treated with the GnRH analogue buserelin. Thirty-six men with disseminated prostatic cancer and elevated plasma levels of prostatic acid phosphatase were randomly assigned to two groups. Group 1 included 17 men who received buserelin (500 micrograms daily subcutaneously) and nilutamide (300 mg daily by mouth); group 2 included 19 men treated with buserelin and placebo. Symptoms were assessed, and plasma was collected before treatment, daily for 14 days, and on days 18, 22, and 29 after the initiation of treatment. Bone pain appeared or worsened in 5 of the 17 men in group 1 and in 12 of the 19 men in group 2 (P less than 0.05). Acute urinary obstruction occurred in one man in group 2. Despite similar changes in the plasma testosterone levels in both groups, the median concentration of plasma prostatic acid phosphatase decreased almost immediately in group 1, but increased transiently, then decreased on day 14 in group 2. Median levels of prostate-specific antigen decreased immediately in group 1 and decreased on day 8 in group 2. We conclude that nilutamide can prevent the adverse consequences of the buserelin-induced transient rise in plasma testosterone levels in men with advanced prostate cancer treated with a GnRH analogue.

Câncer de próstata e testosterona: riscos e controvérsias

“…Contudo, as discrepâncias na frequência e na severidade dos eventos clínicos e o fato de que os estudos falharam em detectar um aumento no PSA durante o flare nos levam a questionar tal hipótese (30,31). Os detalhes relacionados ao tratamento foram pesquisados, incluindo se a braquiterapia foi usada isoladamente ou em combinação com a radioterapia externa ou bloqueio androgênico.…”

Therapeutic use and Perspectives of Synthetic Peptides in Oncology

“…The initial and transitory stimulation (lasting for about 7 days) of testicular androgen secretion (flare-up reaction) may result in a transitory tumoural growth effect. The addition of an antiandrogen, prescribed at the beginning of the treatment with a GnRH agonist, can prevent this reaction (18). The continuation of treatment by the antiandrogen for more than a month, remains controversial ( 17).…”

Synthesis and Pharmacological Evaluation of Novel Arylpiperazine Derivatives as Nonsteroidal Androgen Receptor Antagonists

“…A number of nonsteroidal AR antagonists have been reported in the literature [23][24][25][26][27][28][29][30] and three of these, flutamide (2), nilutamide (3), and bicalutamide (4), are used clinically in conjunction with gonadotropin-releasing hormone (GnRH) agonists. 31) These nonsteroidal AR antagonists exhibit some adverse effects such as mastodynia, gynaecomastia and hepatotoxicity [15][16][17][18][19][20][21][22] ; therefore potent AR antagonists with less adverse effects are highly desirable.To identify novel AR antagonists, we conducted an HTS of the Yamanouchi chemical library using a reporter assay, which measured the inhibitory activity of test compounds on androgen-induced activation of AR. Compound 5 was discovered as an HTS hit with an associated IC 50 value of 3.1 mM.…”

“…7) Thus compounds that block the action or synthesis of androgens have been proven useful in the treatment of diseases such as prostate cancer, benign prostatic hypertrophy, hirsutism, and acne. [8][9][10][11] AR antagonists, 12,13) including cyproterone acetate (1), 14) flutamide (2), [15][16][17] nilutamide (3), 18) and bicalutamide (4), [19][20][21][22] have been used clinically for the treatment of prostate cancer (Fig. 1).…”