Implications of enzymatic, acidic and thermal hydrolysis of DNA on the occurrence of cross-linked melphalan DNA adducts.
Calf thymus DNA was treated with melphalan, a nitrogen mustard, and the formation of melphalan cross-linked DNA adducts was investigated. These cross-linked adducts could not be detected either in the enzymatically or in the thermally generated DNA hydrolysates. However, a search for DNA cross-linked adducts in the hydrolysates obtained under acidic conditions revealed the presence of different types of cross-links, mainly containing an adenine moiety. These results are very important because they show that the detection of cross-links is dependent on the hydrolytic procedure used and that these cross-linked adducts are formed under totally different reaction conditions from those in in vivo situations. This can explain the very low abundance or even the absence of cross-linked adducts in nitrogen mustard treated animals. The generally accepted theory that the anti-cancer activity of bifunctional mustards such as melphalan is due to cross-linking of DNA strands remains therefore from our point of view questionable.
Van den Driessche
Bart
B
Nucleoside Research and Mass Spectrometry Unit & Centre for Proteomics and Mass Spectrometry (CEPROMA), University of Antwerp, Department of Chemistry, Groenenborgerlaan 171, B-2020 Antwerp, Belgium.
Lemière
Filip
F
Witters
Erwin
E
Van Dongen
Walter
W
Esmans
Eddy L
EL
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000378:metabolism; D002417:Cattle; D003432:Cross-Linking Reagents / Q000737:chemistry* / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D006358:Hot Temperature; D006868:Hydrolysis; D008558:Melphalan / Q000737:chemistry* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004247:DNA; D008558:Melphalan