The selectivty and anti-metastatic activity of oral bioavailable butyric acid prodrugs.
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.
Rephaeli
Ada
A
Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Beilinson Campus, Petach Tikva, 49100, Israel.
Entin-Meer
Michal
M
Angel
Dikla
D
Tarasenko
Nataly
N
Gruss-Fischer
Tal
T
Bruachman
Irena
I
Phillips
Don R
DR
Cutts
Suzanne M
SM
Haas-Kogan
Daphne
D
Nudelman
Abraham
A
D000107:Acetylation; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001682:Biological Availability; D002087:Butyrates / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011355:Prodrugs