AN-113, a novel prodrug of 4-phenylbutyrate with increased anti-neoplastic activity in glioma cell lines.
Butyroyloxymethyl-4-phenylbutyrate (AN-113) is a novel HDACI that releases potent anti-neoplastic derivatives upon intracellular hydrolysis. The precursor of AN-113, 4-phenylbutyrate has shown promising results in a Phase I study of gliomas, and we hypothesized that AN-113 offers significant advantages over the parent drug. AN-113 demonstrates selective in vitro cytotoxicity against malignant cells while sparing normal astrocytes, effective at doses over 20-fold lower than 4-phenylbutyrate. Combining AN-113 and radiation results in additive therapeutic effects. Enthusiasm is lent to this approach by the ability of AN-113 to efficiently kill glioma cells, its bioavailability and potency when administered orally, its capacity to cross the blood-brain barrier, and its effectiveness in combination with radiation.
Entin-Meer
Michal
M
Department of Radiation Oncology, Neurological Surgery, and Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
Rephaeli
Ada
A
Yang
Xiaodong
X
Nudelman
Abraham
A
Nudelman
Ayelet
A
Haas-Kogan
Daphne Adele
DA
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000528:radiation effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000201:enzymology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005910:Glioma / Q000201:enzymology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D010654:Phenylbutyrates / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; D011355:Prodrugs; C523320:butyroyloxymethyl 4-phenylbutyrate; C075773:4-phenylbutyric acid