Document Detail


Two novel nucleoside ester derivatives of chlorambucil as potential antileukemic prodrugs: a preliminary study.
MedLine Citation:
PMID:  17264763     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
2-Chloro-2'-deoxyadenosine (cladribine) and chlorambucil are two drugs used in the treatment of lymphoid malignancies. We have synthesized 5'-O-esters of cladribine and its parental nucleoside 2'-deoxyadenosine with chlorambucil (2-chloro-2'-deoxyadenosine-chlorambucil and 2'-deoxyadenosine-chlorambucil, respectively) and compared some properties of the esters with regard to their potential use as antileukemic prodrugs. The 5'-O-ester bond showed no spontaneous hydrolysis at pH 7.4, but was susceptible to hydrolysis by porcine liver esterase and enzymes present in human lymphocyte lysate and blood plasma. Both 2-chloro-2'-deoxyadenosine-chlorambucil and 2'-deoxyadenosine-chlorambucil were taken up more avidly than their parental nucleosides by normal and malignant human lymphoid cells. 2-Chloro-2'-deoxyadenosine-chlorambucil was by an order of magnitude more toxic than 2'-deoxyadenosine-chlorambucil to human leukemic MOLT4 cells in culture. On the other hand, 2-chloro-2'-deoxyadenosine-chlorambucil cytotoxicity did not exceed that of its parental 2-chloro-2'-deoxyadenosine in MOLT4 cells, whereas 2'-deoxyadenosine-chlorambucil was considerably more cytotoxic than free chlorambucil in a variety of myeloid and lymphoid human malignant cell lines. Moreover, acute toxicity of 2'-deoxyadenosine-chlorambucil was lower than that of chlorambucil in mice. In summary, 2'-deoxyadenosine-chlorambucil, but not 2-chloro-2'-deoxyadenosine-chlorambucil, shows promise for clinical utility as a chlorambucil prodrug and thus warrants a more detailed study in vivo.
Authors:
Tomasz Kryczka; Zygmunt Kazimierczuk; Mariola Kozłowska; Stanisław J Chrapusta; Leena Vilpo; Juhani Vilpo; Krzysztof Stachnik; Monika Janisz; Paweł Grieb
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anti-cancer drugs     Volume:  18     ISSN:  0959-4973     ISO Abbreviation:  Anticancer Drugs     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-01-31     Completed Date:  2007-04-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  England    
Other Details:
Languages:  eng     Pagination:  301-10     Citation Subset:  IM    
Affiliation:
Department of Experimental Pharmacology, Polish Academy of Sciences Medical Research Center, Warsaw, Poland. tkryczka@cmdik.pan.pl
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents, Alkylating / chemical synthesis*,  metabolism,  therapeutic use*
Binding, Competitive
Cell Line, Tumor
Cell Membrane / drug effects
Cell Survival / drug effects
Chlorambucil / analogs & derivatives*,  chemical synthesis,  therapeutic use*
Chromatography, High Pressure Liquid
Diffusion
Esters / chemical synthesis,  therapeutic use
Female
Humans
Hydrolysis
Indicators and Reagents
Leukemia / drug therapy*
Mice
Mice, Inbred BALB C
Monocytes
Nucleosides / therapeutic use*
Prodrugs / therapeutic use*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Esters; 0/Indicators and Reagents; 0/Nucleosides; 0/Prodrugs; 305-03-3/Chlorambucil

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