DNA guanine-guanine crosslinking sequence specificity of isophosphoramide mustard, the alkylating metabolite of the clinical antitumor agent ifosfamide.
OBJECTIVE
The purpose of this investigation was to determine the base sequence specificity of isophosphoramide mustard (IPM), the alkylating metabolite of ifosfamide, by crosslinking of designed DNA oligomers in comparison with the clinical alkylating agents mechlorethamine (ME) (nitrogen mustard) and phosphoramide mustard (PM), the alkylating metabolite of cyclophosphamide.


METHODS
IPM, as well as PM and ME were each reacted with three dodecameric duplexes, which were designed to detect interstrand crosslinking between guanines in 5'-GC-3' (I), 5'-GNC-3' (II) or 5'-GNNC-3' (III) sequences (N = A or T).


RESULTS
All three agents preferentially react with 5'-GNC-3' target sequences. The 5'-GNNC-3' target sequence is less reactive by a factor of approximately 2.5- to 10-fold, while 5'-GC-3' is of even lower reactivity.


CONCLUSIONS
These results indicate that all three agents show approximately equal preference for reaction with a 5'-GNC-3' target sequence in spite of the fact that IPM yields a 7-atom crosslink, while the other two agents yield 5-atom crosslinks.
Struck
R F
RF
Southern Research Institute, Birmingham, AL 35255-5305, USA.
Davis
R L
RL
Berardini
M D
MD
Loechler
E L
EL
D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism*; D001483:Base Sequence; D003432:Cross-Linking Reagents / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D006147:Guanine / Q000378:metabolism*; D006801:Humans; D007069:Ifosfamide / Q000378:metabolism*; D010752:Phosphoramide Mustards / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D010752:Phosphoramide Mustards; D006147:Guanine; C027061:isophosphamide mustard; D004247:DNA; D007069:Ifosfamide