Article (Scientific journals)
Plasmin-activated doxorubicin prodrugs containing a spacer reduce tumor growth and angiogenesis without systemic toxicity
Devy, L.; de Groot, F. M.; Blacher, Silvia et al.
2004In FASEB Journal, 18 (3), p. 565-567
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Keywords :
angiogenesis; proteases; anthracycline prodrugs; anticancer therapy
Abstract :
[en] To generate doxorubicin (Dox) specifically at the tumor site, the chemotherapeutic agent was incorporated into a prodrug by linkage to a peptide specifically recognized by plasmin, which is overproduced in many cancers. ST-9905, which contains an elongated self-elimination spacer, is activated more rapidly in vitro by plasmin than is ST-9802. Prodrug activation in vitro depended on the level of urokinase produced by tumor cells and was inhibited by aprotinin, a plasmin inhibitor. Comparison of equimolar concentrations of ST-9905, ST-9802, and Dox in EF43.fgf-4 and MCF7 models revealed that both prodrugs, in sharp contrast to Dox, displayed antiproliferative and antiangiogenic activities without discernible toxicity. Although MCF7 cells are poor urokinase producers in vitro, prodrug efficacy in this model may be explained by production of plasmin by tumor-infiltrating host cells. Mice treated with equitoxic concentrations (maximum tolerated doses) of prodrugs showed 100% survival and negligible body weight loss, in contrast to results after Dox treatment. ST-9905 was substantially more effective than ST9802 and induced similar tumor growth inhibition as Dox but without apparent toxicity. This finding may be explained by the elongated spacer, which facilitates enzymatic prodrug activation. These data validate both the use of elongated spacers in vivo and the concept of targeting anticancer prodrugs to tumor-associated plasmin.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Devy, L.
de Groot, F. M.
Blacher, Silvia ;  Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Hajitou, A.
Beusker, P. H.
Scheeren, H. W.
Foidart, Jean-Michel ;  Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Noël, Agnès ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Language :
English
Title :
Plasmin-activated doxorubicin prodrugs containing a spacer reduce tumor growth and angiogenesis without systemic toxicity
Publication date :
2004
Journal title :
FASEB Journal
ISSN :
0892-6638
eISSN :
1530-6860
Publisher :
Federation of American Society for Experimental Biology, Bethesda, United States - Maryland
Volume :
18
Issue :
3
Pages :
565-567
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 25 March 2009

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