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Experimental Therapeutics, Preclinical Pharmacology |
Department of Cancer Medicine, Cancer Research Campaign Laboratories, Imperial College of Science, Technology, and Medicine, Hammersmith Hospital, London W12 0NN [D. M. V., S. A., P. E. P., N. M., R. C. C.], and Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College of Science, Technology, and Medicine, London SW3 6LY [K. I., I. A.], United Kingdom
Purpose: Trichostatin A (TSA), an antifungal antibiotic with cytostatic and differentiating properties in mammalian cell culture, is a potent and specific 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 model.
Experimental Design and Results: TSA inhibited proliferation of eight breast carcinoma cell lines with mean ± SD IC50 of 124.4 ± 120.4 nM (range, 26.4–308.1 nM). HDAC inhibitory activity of TSA was similar in all cell lines with mean ± SD IC50 of 2.4 ± 0.5 nM (range, 1.5–2.9 nM), and TSA treatment resulted in pronounced histone H4 hyperacetylation. In randomized controlled efficacy studies using the N-methyl-N-nitrosourea carcinogen-induced rat mammary carcinoma model, TSA had pronounced antitumor activity in vivo when administered to 16 animals at a dose of 500 µg/kg by s.c. injection 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. injection. 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 adenocarcinomas. In contrast, 19 tumors from 12 TSA-treated rats had a benign phenotype, either fibroadenoma or tubular adenoma, suggesting that the antitumor 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 antitumor activity of TSA against breast cancer in vitro and in vivo, strongly supporting HDAC as a molecular target for anticancer therapy in breast cancer.
Commentary
Clin. Cancer Res. 2001 7: 759-760.
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