Comparison of in vitro effects of the pure antiandrogens OH-flutamide, Casodex, and nilutamide on androgen-sensitive parameters.
OBJECTIVE
A combination of flutamide (Eulexin) or nilutamide (Anandron) with a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy is the only therapy demonstrated to prolong life in prostate cancer. Recently, the low 50-mg daily dose of Casodex, an analogue of the pure antiandrogen flutamide, was chosen for clinical studies on the basis that the compound was 5 to 10 times more potent than flutamide, as suggested by data obtained in the inappropriate intact rat model. The present study was designed to compare the in vitro antiandrogenic activity of OH-flutamide (OH-FLU), the active metabolite of flutamide, Casodex, and nilutamide.


METHODS
The effect of the antiandrogens was tested on two androgen-sensitive parameters, namely proliferation of the SEM-107 clone of Shionogi mouse mammary tumor cells and secretion of the GCDFP-15 (gross cystic disease fluid protein 15 kDa) in T-47D and ZR-75-1 human breast cancer cells.


RESULTS
The twofold stimulation of Shionogi cell proliferation caused by a 10-day exposure to 1 nM testosterone was competitively reversed by incubation with OH-FLU, Casodex, or nilutamide, at the respective IC50 values of 72, 243, and 412 nM. Moreover, the marked increase in GCDFP-15 release induced by 1 nM testosterone was blocked by OH-FLU. Casodex, or nilutamide at respective IC50 values of 29, 180, and 87 nM in T-47D cells and at 35, 142, and 75 nM in ZR-75-1 cells. Similar data were detected in 4-androstenedione-induced Shionogi cell proliferation and in dihydrotestosterone-induced GCDFP-15 secretion in T-47D cells.


CONCLUSIONS
OH-FLU is 3.1- to 7.8-fold more potent than Casodex, as measured on two in vitro androgen-sensitive parameters, in agreement with our recent in vivo data obtained in the model of castrated rats supplemented with 4-androstenedione implants, in which threefold greater potency of flutamide was observed. The present data, as well as other data from the literature, strongly indicate the need to choose a more appropriate dose of Casodex for the treatment of prostate cancer.
Simard
J
J
Laboratory of Molecular Endocrinology, CHUL Research Center, Quebec, Canada.
Singh
S M
SM
Labrie
F
F
D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001053:Apolipoproteins; D053399:Apolipoproteins D; D001943:Breast Neoplasms / Q000473:pathology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005485:Flutamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D006023:Glycoproteins; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D026901:Membrane Transport Proteins; D051379:Mice; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles; D014105:Tosyl Compounds; D014407:Tumor Cells, Cultured
C024328:APOD protein, human; D000726:Androgen Antagonists; D000813:Anilides; D001053:Apolipoproteins; D053399:Apolipoproteins D; D002352:Carrier Proteins; D006023:Glycoproteins; D007093:Imidazoles; D048289:Imidazolidines; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D009570:Nitriles; C488892:PIP protein, human; D014105:Tosyl Compounds; C014290:hydroxyflutamide; C021277:nilutamide; D005485:Flutamide; C053541:bicalutamide