Salutary clinical response of prostate cancer to antiandrogen withdrawal: assessment of flutamide in an in vitro paradigm predictive of tumor growth enhancement.
Salutary clinical responses to withdrawal of flutamide have been widely reported, indicating the potential of this arylalkylamine antiandrogen to stimulate the growth of prostate cancer. Flutamide is known to inhibit cytochrome P450-mediated testosterone synthesis and metabolism. Our laboratory has shown that arylalkylamine potencies in three in vitro assays of P450 binding or function correspond to a propensity of the drugs to enhance tumor growth in vivo. Accordingly, we measured inhibition by flutamide of (a) histamine binding to cytochrome P450 in rat liver microsomes, as determined spectrally, (b) P450-mediated demethylation of aminopyrine, and (c) DNA synthesis in mouse spleen cells stimulated by concanavalin A, and we compared its potencies in these assays with those of other arylalkylamine pharmaceuticals. Flutamide inhibited histamine binding to P450 (Ki = 31 +/- 7 microM), aminopyrine demethylation (Ki = 39 +/- 2 microM), and mitogenesis (IC50 = 12 +/- 1 microM). In overall potency, it ranked with a group of eight drugs, including the antiestrogen tamoxifen, all linked with enhanced tumor growth. In the context of clinical observations that some patients with prostate cancer benefit from flutamide withdrawal, our findings underline concerns that many arylalkylamine drugs have the potential to stimulate the growth or development of malignancies, including prostate cancer. Tumor growth enhancement by flutamide and other arylalkylamines may result from drug perturbation and/or induction of histamine-binding P450 enzymes involved in the synthesis of steroid and eicosanoid mediators that regulate gene function and cell growth.
Brandes
L J
LJ
Departments of Medicine, Faculty of Medicine, University of Manitoba, 100 Olivia Street, Winnipeg, R3E 0V9, Manitoba, Canada.
Queen
G M
GM
LaBella
F S
FS
D000633:Aminopyrine N-Demethylase / Q000378:metabolism*; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004334:Drug Administration Schedule; D005485:Flutamide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000201:enzymology*; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000166:cytology
D000726:Androgen Antagonists; D005485:Flutamide; D006632:Histamine; D003577:Cytochrome P-450 Enzyme System; D000633:Aminopyrine N-Demethylase