diethoxyphosphoryloxymethyl-butanoate and Prostatic-Neoplasms

The antiangiogenic and antineoplastic activities of the butyric acid prodrugs AN-7 and AN-9 were demonstrated in vitro with HUVEC by inhibition of proliferation and vascular tubes formation, enhanced apoptosis, and inhibition of 22Rv-1 cells migration. In the sc implanted human prostate tumors (22Rv-1) in nude mice, AN-7 significantly inhibited Ki-67, HIF-1alpha, HER-2/neu, bFGF and increased PTEN level. AN-7 and AN-9 reduced hemoglobin accumulation in matrigel plugs implanted sc in Balb-c mice. Herein, we show that the anticancer activity of AN-7 and AN-9 can be attributed in part to their antiangiogenic activities suggesting potential therapeutic benefits for prostate cancer patients.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Butyrates; Cell Proliferation; Endothelium, Vascular; Fibroblast Growth Factor 2; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Ki-67 Antigen; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Organophosphorus Compounds; Prodrugs; Prostatic Neoplasms; PTEN Phosphohydrolase; Receptor, ErbB-2; Tumor Cells, Cultured; Umbilical Veins

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.

Topics: Acetylation; Administration, Oral; Animals; Butyrates; Cell Differentiation; Cell Proliferation; Histone Deacetylase Inhibitors; Histones; Humans; Male; Mice; Mice, Nude; Neoplasm Metastasis; Organophosphorus Compounds; Prodrugs; Prostate-Specific Antigen; Prostatic Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured