The selectivty and anti-metastatic activity of oral bioavailable butyric acid prodrugs

Investigational New Drugs
Ada RephaeliA Nudelman

Abstract

Acyloxyalkyl ester prodrugs of histone deacetylase inhibitors, a family of anti-cancer agents, are metabolized intracellularly to acids and aldehyde(s). The purpose of this study was to assess the in vitro and in vivo anticancer activity, selectivity and oral bioavailability of these prodrugs. The prodrugs exhibited a hierarchal potency of AN-193 > or = AN-7 > AN-1 and AN-9 > AN-10 against murine lung carcinoma (3LLD122) and human breast carcinoma (MCF-7) cell lines. AN-9, and to even greater extent AN-7, displayed preferential cytotoxicity against leukemic and glioblastoma cells compared to their normal cellular counterparts-normal mononuclear and astrocytes cells, respectively. In vivo, anti-metastatic activity was evaluated in a metastatic model of lung cancer in which Lewis lung carcinoma (3LLD122) cells are injected intravenously into C57/BL mice and produce lung nodules. The prodrugs administered orally demonstrated a significant inhibition of lung-lesion formation and their hierarchal potency concurred with that observed in vitro, with the exception of AN-193 that was the least active compound. Escalating doses of AN-7 (5-100 mg/kg), administered by oral or intraperitoneal routes and displayed equivalent anti-metastatic ...Continue Reading

References

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Citations

Jul 11, 2006·Journal of Cancer Research and Clinical Oncology·Dikla EngelAda Rephaeli
Mar 22, 2013·BioResearch Open Access·Kosta SteliouDouglas V Faller
Mar 28, 2008·Expert Review of Anticancer Therapy·Walid RasheedH Miles Prince
Feb 24, 2016·Drug Development Research·Walter H MoosKosta Steliou
May 17, 2008·Nanomedicine : Nanotechnology, Biology, and Medicine·Rachela PopovtzerYosi Shacham-Diamand
Oct 11, 2008·Fundamental & Clinical Pharmacology·G Y Perret, M Crépin
Apr 1, 2014·Drug Discovery Today·Fatima el BahhajPhilippe Bertrand
May 31, 2016·Bioorganic Chemistry·Mohammed ManalM J Nanjan
Jun 11, 2016·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Ada RephaeliAbraham Nudelman
Feb 29, 2008·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Andrea BrioschiAlessandro Mauro
Feb 10, 2019·International Journal of Molecular Sciences·Mor DahbashTami Livnat
Nov 15, 2017·Journal of Cellular Biochemistry·Nataly TarasenkoAda Rephaeli
Mar 25, 2017·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Michal Schaap-FoglerTami Livnat

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