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In vivo and in vitro antitumor activity of butyroyloxymethyl‐diethyl phosphate (AN‐7), a histone deacetylase inhibitor, in human prostate cancer
Author(s) -
Rephaeli Ada,
BlankPorat Diana,
Tarasenko Nataly,
EntinMeer Michal,
Levovich Inesa,
Cutts Suzanne M.,
Phillips Don R.,
Malik Zvi,
Nudelman Abraham
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21030
Subject(s) - in vivo , apoptosis , metastasis , prostate cancer , cancer , prostate , in vitro , cancer research , medicine , primary tumor , pathology , chemistry , biology , biochemistry , microbiology and biotechnology
AN‐7, a prodrug of butyric acid, induced histone hyperacetylation and differentiation and inhibited proliferation of human prostate 22Rv1 cancer cells in vitro and in vivo. In nude mice implanted with these cells, 50 mg/kg AN‐7 given orally thrice a week led to inhibition of tumor growth and metastasis, tumor regression in >25% of animals and increased survival. Median time to the experimental end point (tumor volume 2 cm 3 or death) in the untreated was 52 days, and average tumor volume was 0.8 ± 0.18 cm 3 . At the same time, 94.4% of AN‐7‐treated mice survived and had average tumor volumes of 0.37 ± 0.1 cm 3 . PSA expression was a useful marker for 22Rv1 lung metastasis detection. Sizeable metastases positively stained for PSA and limited air gaps were found in lungs of untreated mice. In animals treated with AN‐7, lung morphology appeared normal. Primary tumors of treated animals were highly positive for PSA and had an elevated level of p21 and the proapoptotic protein Bax. Sections taken from AN‐7‐treated animals, examined under an electron microscope, exhibited condensed chromatin and apoptotic bodies. PSA serum levels were higher in untreated compared to treated animals and correlated with tumor volume. Since prolonged oral administration with 50 mg/kg or a single oral dose of 1.2 g/kg AN‐7 did not cause adverse effects and the former exhibited significant anticancer activity, AN‐7 is likely to display a high therapeutic index and may be beneficial for prostate cancer patients. © 2005 Wiley‐Liss, Inc.