title: In vivo and in vitro antitumor activity of butyroyloxymethyl-diethyl phosphate (AN-7), a histone deacetylase inhibitor, in human prostate cancer.
abstract: 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 cm3 or death) in the untreated was 52 days, and average tumor volume was 0.8 +/- 0.18 cm3. At the same time, 94.4% of AN-7-treated mice survived and had average tumor volumes of 0.37 +/- 0.1 cm3. 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.
authors.affiliation: Faculty of Medicine, Felsenstein Center for Medical Research, Tel Aviv University Beilinson Campus, Petach Tikva, Israel. adarep@past.tau.ac.il
authors.forename: Ada
authors.initials: A
authors.lastname: Rephaeli
authors.forename: Diana
authors.initials: D
authors.lastname: Blank-Porat
authors.forename: Nataly
authors.initials: N
authors.lastname: Tarasenko
authors.forename: Michal
authors.initials: M
authors.lastname: Entin-Meer
authors.forename: Inesa
authors.initials: I
authors.lastname: Levovich
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cutts
authors.forename: Don R
authors.initials: DR
authors.lastname: Phillips
authors.forename: Zvi
authors.initials: Z
authors.lastname: Malik
authors.forename: Abraham
authors.initials: A
authors.lastname: Nudelman
mesh_terms: D000107:Acetylation; D000284:Administration, Oral; D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011355:Prodrugs; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000473:pathology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009943:Organophosphorus Compounds; D011355:Prodrugs; C502471:diethoxyphosphoryloxymethyl butanoate; D017430:Prostate-Specific Antigen