The power and potential of doxorubicin-DNA adducts

被引:138
作者
Cutts, SM
Nudelman, A
Rephaeli, A
Phillips, DR [1 ]
机构
[1] La Trobe Univ, Dept Biochem, Bundoora, Vic 3086, Australia
[2] Bar Ilan Univ, Dept Chem, Ramat Gan, Israel
[3] Tel Aviv Univ, Felsenstein Med Res Ctr, Petah Tiqwa, Israel
关键词
doxorubicin; anthracyclines; doxorubicin-DNA adducts; formaldehyde; formaldehyde-releasing prodrugs; anticancer drugs;
D O I
10.1080/15216540500079093
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Doxorubicin ( trade name Adriamycin) is a widely used anticancer agent which exhibits good activity against a wide range of tumors. Although the major mode of action appears to be normally as a topoisomerase II poison, it also exhibits a number of other cellular responses, one of which is the ability to form adducts with DNA. For adduct formation doxorubicin must react with cellular formaldehyde to form an activated Schiff base which is then able to form an aminal (N-C-N) linkage to the exocyclic amino group of guanine residues. The mono-adducts form primarily at G of 5'-GCN-3' sequences where the chromophore of the drug is intercalated between the C and N base pair. The structure of the adducts has have been well defined by 2D NMR, mass spectrometry and X-ray crystallography. The formation of these anthracycline adducts in cells grown in culture has been unequivocally demonstrated. The source of formaldehyde in cells can be endogenous, provided by coadministration of prodrugs that release formaldehyde or by prior complexation of anthracyclines with formaldehyde. Since the adducts appear to be more cytotoxic than doxorubicin alone, and also less susceptible to drug-efflux forms of resistance, they offer new approaches to improving the anticancer activity of the anthracyclines.
引用
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页码:73 / 81
页数:9
相关论文
共 57 条
[1]  
[Anonymous], [No title captured]
[2]  
Arcamone F., 1982, DOXORUBICIN ANTICANC
[3]   Design, synthesis, and biological evaluation of doxorubicin - Formaldehyde conjugates targeted to breast cancer cells [J].
Burke, PJ ;
Koch, TH .
JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (05) :1193-1206
[4]  
Burke PJ, 2001, ANTICANCER RES, V21, P2753
[5]   Structure-based design fill of a new bisintercalating anthracycline antibiotic [J].
Chaires, JB ;
Leng, FF ;
Przewloka, T ;
Fokt, I ;
Ling, YH ;
PerezSoler, R ;
Priebe, W .
JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (03) :261-266
[6]   Rational design and synthesis of androgen receptor-targeted nonsteroidal anti-androgen ligands for the tumor-specific delivery of a doxorubicin-formaldehyde conjugate [J].
Cogan, PS ;
Koch, TH .
JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (24) :5258-5270
[7]   Interstrand cross-linking by Adriamycin in nuclear and mitochondrial DNA of MCF-7 cells [J].
Cullinane, C ;
Cutts, SM ;
Panousis, C ;
Phillips, DR .
NUCLEIC ACIDS RESEARCH, 2000, 28 (04) :1019-1025
[8]   DOES ADRIAMYCIN INDUCE INTERSTRAND CROSS-LINKS IN DNA [J].
CULLINANE, C ;
VANROSMALEN, A ;
PHILLIPS, DR .
BIOCHEMISTRY, 1994, 33 (15) :4632-4638
[9]   INDUCTION OF STABLE TRANSCRIPTIONAL BLOCKAGE SITES BY ADRIAMYCIN - GPC SPECIFICITY OF APPARENT ADRIAMYCIN DNA ADDUCTS AND DEPENDENCE ON IRON(III) IONS [J].
CULLINANE, C ;
PHILLIPS, DR .
BIOCHEMISTRY, 1990, 29 (23) :5638-5646
[10]   FORMATION OF ADRIAMYCIN - DNA-ADDUCTS IN-VITRO [J].
CULLINANE, C ;
CUTTS, SM ;
VANROSMALEN, A ;
PHILLIPS, DR .
NUCLEIC ACIDS RESEARCH, 1994, 22 (12) :2296-2303