Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo

Purpose: Trichostatin A (TSA), an antifungal antibiotic with cytostatic and differentiating properties in mammalian cell culture, is a potent and spec ific inhibitor of histone deacetylase (HDAC) activity. The purpose of this study was to evaluate the antiproliferative and HDAC inhibitory activity of TSA in vitro in human breast cancer cell lines and to assess its antitumor efficacy and toxicity in vivo in a carcinogen-induced rat mammary cancer m odel. Experimental Design and Results: TSA inhibited proliferation of eight breas t carcinoma cell lines with mean +/- SD IC50 of 124.4 +/- 120.4 nM (range, 26.4-308.1 nw). HDAC inhibitory activity of TSA was similar in all cell lin es with mean +/- SD IC50 of 2.4 +/- 0.5 nM (range, 1.5-2.9 nM), and TSA tre atment resulted in pronounced histone H4 hyperacetylation, In randomized co ntrolled efficacy studies using the N-methyl-N-nitrosourea carcinogen-induc ed rat mammary carcinoma model, TSA had pronounced antitumor activity in vi vo when administered to 16 animals at a dose of 500 mug/kg by s.c. injectio n daily for 4 weeks compared with 14 control animals. Furthermore, TSA did not cause any measurable toxicity in doses of up to 5 mg/kg by s.c. injecti on, Forty-one tumors from 26 animals were examined by histology, Six tumors from 3 rats treated with TSA and 14 tumors from 9 control animals were ade nocarcinomas. In contrast, 19 tumors from 12 TSA-treated rats had a benign phenotype, either fibroadenoma or tubular adenoma, suggesting that the anti tumor activity of TSA may be attributable to induction of differentiation. Two control rats each had tumors with benign histology. Conclusions: The present studies confirm the potent dose-dependent antitumo r activity of TSA against breast cancer in vitro and in vivo, strongly supp orting HDAC as a molecular target for anticancer therapy in breast cancer.