title: Propionate and butyrate esters of camptothecin and 9-nitrocamptothecin as antileukemia prodrugs in vitro.
abstract: Six camptothecin (CPT) alkyl esters and four 9-nitrocamptothecin (9NC) alkyl esters were assayed for ability to inhibit proliferation and induce programmed cell death (apoptosis) in human leukemia HL-60 and U-937 cells, which exhibit differential sensitivity to CPT and 9NC. In general, CPT-propionate and CPT-butyrate demonstrated activities, while the other esters were practically inactive. Similarly, 9NC-propionate and 9NC-butyrate were active, while the other 9NC esters exhibited little or no activity. The biologically active esters required metabolic conversion (i.e., de-esterification) to their parental compounds as demonstrated by the conversion of CPT-propionate to CPT in mouse liver homogenate, and the topoisomerase I-inhibition assay. In conclusion, the propionate and butyrate esters of CPT and 9NC are CPT and 9NC prodrugs, that can develop to important chemotherapeutic agents for the effective treatment of human leukemias and other malignancies.
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Han
authors.forename: Z
authors.initials: Z
authors.lastname: Cao
authors.forename: D
authors.initials: D
authors.lastname: Chatterjee
authors.forename: J
authors.initials: J
authors.lastname: Wyche
authors.forename: P
authors.initials: P
authors.lastname: Pantazis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001711:Biotransformation; D002087:Butyrates; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D011355:Prodrugs / Q000633:toxicity*; D011422:Propionates; D013329:Structure-Activity Relationship; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D002087:Butyrates; D011355:Prodrugs; D011422:Propionates; C079905:rubitecan; D002166:Camptothecin