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 language | English |
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Pages (from-to) | 383-392 |
Number of pages | 10 |
Journal | Investigational New Drugs |
Volume | 24 |
Issue number | 5 |
DOIs | |
State | Published - Sep 2006 |
Bibliographical note
Funding Information:Acknowledgments The work was supported in part by grants from: 542/00-4 Israel Science Foundation (A.N and A.R), Israeli Cancer Association (A.R), the Nofar grant from the Chief Scientist at Israel Ministry of Industry and Commerce and Teva Pharmaceuticals (A.R and A.N), Ministry of commerce and industry and Teva Pharmaceutical Industry Ltd (A.N and A.R), The Marcus Center for Pharmaceutical and Medicinal Chemistry at Bar Ilan University (A.N), NIH-PO1 NS-42927-27A2 (D.A.H-K), NIH Brain Tumor SPORE grant P50 CA097257, the Children’s Brain Tumor Foundation, and The Nancy and Stephen Grand Philanthropic Fund. (D.A.H-K).
Funding
Acknowledgments The work was supported in part by grants from: 542/00-4 Israel Science Foundation (A.N and A.R), Israeli Cancer Association (A.R), the Nofar grant from the Chief Scientist at Israel Ministry of Industry and Commerce and Teva Pharmaceuticals (A.R and A.N), Ministry of commerce and industry and Teva Pharmaceutical Industry Ltd (A.N and A.R), The Marcus Center for Pharmaceutical and Medicinal Chemistry at Bar Ilan University (A.N), NIH-PO1 NS-42927-27A2 (D.A.H-K), NIH Brain Tumor SPORE grant P50 CA097257, the Children’s Brain Tumor Foundation, and The Nancy and Stephen Grand Philanthropic Fund. (D.A.H-K).
Funders | Funder number |
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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 Health | P50 CA097257 |
National Institute of Neurological Disorders and Stroke | P01NS042927 |
Israel Science Foundation |
Keywords
- AN-1
- AN-7
- AN-9
- Formaldehyde
- Histone acetylation
- Lewis lung carcinoma