BUTYRATE ANALOG, ISOBUTYRAMIDE, INHIBITS TUMOR-GROWTH AND TIME TO ANDROGEN-INDEPENDENT PROGRESSION IN THE HUMAN PROSTATE LNCAP TUMOR-MODEL

Progression to androgen independence remains the main obstacle to impr oving survival and quality of life in patients with advanced prostate cancer. Induction of differentiation may serve as a rational basis for prevention of progression to androgen independence by modulating gene expression activated by castration or upregulated during androgen-ind ependent progression. The objectives of this study were to characteriz e the in vitro effects of sodium butyrate on human prostate cancer cel l growth, PSA gene expression, and differentiation in the LNCaP tumor model and to determine whether tumor progression in vivo is delayed by isobutyramide an orally bioavailable butyrate analogue with a longer half-life. The effects of isobutyramide on LNCaP tumor growth and seru m PSA levels in both intact and castrate male mice were compared to co ntrols. At concentrations >1 mM, butyrate induced dose-dependent chang es rewards a more differentiated phenotype, G1 cell cycle arrest, and an 80% decrease in LNCaP cell growth rates. PSA gene expression was in creased threefold by butyrate, indicative of differentiation-enhanced gene expression. The half-life of isobutyramide in athymic mice was de termined by gas chromatography to be 4 h. During a 4 week period in in tact-placebo mice, tumor volume and serum PSA increased 4.1- and 6.6-f old, respectively, compared to twofold and 2.7-fold increases in tumor volume and serum PSA in intact-treated mice. During a 7 week period i n castrate-placebo mice, tumor volume and serum PSA levels increased 2 .4-fold and fourfold, respectively, compared to a 50% reduction in tum or volume and a twofold increase in serum PSA above nadir levels in ca strate mice treated with adjuvant isobutyramide. Isobutyramide treatme nt induced pronouced morphological changes in LNCaP tumor cells, with loss of defined nucleoli and dispersion of chromatin distribution. LNC aP tumor PSA mRNA levels actually increased threefold, indicative of d ifferentiation-enhanced gene expression. This study demonstrates that butyrate causes LNCaP cell cycle arrest and increased PSA gene express ion, both indicative of differentiation. The combination of castration and adjuvant isobutyramide was synergistic in delaying tumor progress ion. Decreased tumor cell proliferation and increased PSA gene express ion induced by isobutyramide results in disconcordant changes in serum PSA and tumor volume and reduces the utility of serum PSA as a marker of response to therapy. (C) 1998 Wiley-Liss, Inc.