Abraham Nudelman

In vivo and in vitro antitumor activity of butyroyloxymethyl-diethyl phosphate (AN-7), a histone deacetylase inhibitor, in human prostate cancer

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.

CHAPTER 4:The Story of ALA Photodynamic Therapy: A Cancer Enigma

ALA photodynamic therapy (PDT) is an established clinical method of proven efficacy and safety using ALA as a prodrug applied for 4–24 hours prior to photosensitization. The intracellular levels of protoporphyrin IX (PpIX) produced during ALA treatment are dependent on the overall activity of the heme synthesis pathway, specifically the third enzyme porphobilinogen deaminase (PBGD), which is activated during the synthesis of porphobilinogen, and on the activity of the last enzyme ferrochelatase. The characteristic phenomenon of anomalous energy metabolism in tumors, using mostly glycolysis for ATP production, is further correlated with disturbed heme synthesis as manifested by PpIX production. In the future, improved ALA administration protocols adjusted in order to preactivate the key enzyme PBGD prior to photoactivation may improve PpIX accumulation in cancers and their corresponding stem cells. Furthermore, the use of multifunctional ALA prodrugs that maximize photosensitizer biosynthesis, targeting multiple subcellular targets, may increase PDT anticancer efficacy in additional disease settings. In conclusion, improved ALA delivery protocols, light irradiation regimes and novel ALA prodrugs may boost anticancer actions and drive ALA-PDT into becoming a front-line cancer therapy.