The selectivty and anti-metastatic activity of oral bioavailable butyric acid prodrugs
| Autor: | Dikla Angel, Tal-A.-L. Gruss-Fischer, Nataly Tarasenko, Daphne A. Haas-Kogan, Don R. Phillips, Michal Entin-Meer, Abraham Nudelman, Irena Bruachman, Suzanne M. Cutts, Ada-D.-A. Rephaeli |
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| Rok vydání: | 2006 |
| Předmět: |
Administration
Oral Biological Availability Antineoplastic Agents Pharmacology Histones Carcinoma Lewis Lung Mice Oral administration In vivo Cell Line Tumor medicine Animals Humans Prodrugs Pharmacology (medical) Enzyme Inhibitors Lung cancer Lung Cell Proliferation Chemistry Lewis lung carcinoma Acetylation Prodrug medicine.disease In vitro Bioavailability Histone Deacetylase Inhibitors Mice Inbred C57BL Butyrates Oncology Leukocytes Mononuclear Female Histone deacetylase Injections Intraperitoneal Neoplasm Transplantation |
| Zdroj: | Investigational New Drugs. 24:383-392 |
| ISSN: | 1573-0646 0167-6997 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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