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

Ada Rephaeli*, Michal Entin-Meer, Dikla Angel, Nataly Tarasenko, Tal Gruss-Fischer, Irena Bruachman, Don R. Phillips, Suzanne M. Cutts, Daphne Haas-Kogan, Abraham Nudelman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 ≥ 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 activities, confirmed the good oral bioavailability of AN-7. Consistent with these findings, a time course study of histone acetylation in subcutaneously implanted 3LL122 tumors showed 2-4 fold increases in histone acetylation within 0.5 h of intravenous, intraperitoneal, or oral administration of AN-7 (100 mg/kg). Relative contributions of the prodrug metabolites to the anti-neoplastic activity and the best candidate for clinical studies are discussed.

Original languageEnglish
Pages (from-to)383-392
Number of pages10
JournalInvestigational New Drugs
Volume24
Issue number5
DOIs
StatePublished - Sep 2006
Externally publishedYes

Funding

FundersFunder number
Chief Scientist at Israel Ministry of Industry and Commerce
Children’s Brain Tumor Foundation
Israeli Cancer Association
Marcus Center for Pharmaceutical and Medicinal Chemistry at Bar Ilan University
Ministry of commerce and industry and Teva Pharmaceutical Industry Ltd
NIH-PO1 NS-42927-27A2
Teva Pharmaceuticals
National Institutes of HealthP50 CA097257
National Institute of Neurological Disorders and StrokeP01NS042927
Israel Science Foundation

    Keywords

    • AN-1
    • AN-7
    • AN-9
    • Formaldehyde
    • Histone acetylation
    • Lewis lung carcinoma

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