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 widel y reported, indicating the potential of this arylalkylamine antiandrog en to stimulate the growth of prostate cancer, Flutamide is known to i nhibit cytochrome P450-mediated testosterone synthesis and metabolism, Our laboratory has shown that arylalkylamine potencies in three in vi tro assays of P450 binding or function correspond to a propensity of t he drugs to enhance tumor growth in vivo. Accordingly, we measured inh ibition by flutamide of (a) histamine binding to cytochrome P450 in ra t liver microsomes, as determined spectrally, (b) P450-mediated demeth ylation of aminopyrine, and (c) DNA synthesis in mouse spleen cells st imulated by concanavalin A, and me compared its potencies in these ass ays with those of other arylalkylamine pharmaceuticals. Flutamide inhi bited histamine binding to P450 (K-i = 31 +/- 7 mu M), aminopyrine dem ethylation (K-i = 39 +/- 2 mu M), and mitogenesis (IC50 = 12 +/- 1 mu M). In overall potency, it ranked with a group of eight drugs, includi ng the antiestrogen tamoxifen, all linked with enhanced tumor growth, In the context of clinical observations that some patients with prosta te cancer benefit from flutamide withdrawal, our findings underline co ncerns 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 re sult 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.