Direct evidence for bimodal DNA damage induced by tirapazamine.
The ability of tirapazamine (1, 3-amino-1,2,4-benzotriazine 1, 4-dioxide, SR4233) to fix DNA radical lesions is demonstrated by studying the reaction between the antitumor drug and an oligonucleotide radical that is independently produced at a defined site within a biopolymer. Using beta-mercaptoethanol as a competitor, it was determined that tirapazamine traps a C1'-nucleotide radical with a rate constant of approximately 2 x 10(8) M-1 s-1. Product and isotopic labeling studies suggest that tirapazamine reacts with the radical via covalent adduct formation, resulting primarily from reaction at the N-oxide oxygen. Intermediate covalent adducts could not be observed, but are postulated to decompose to the alkaline labile 2'-deoxyribonolactone lesion. These experiments affirm recent proposals suggesting that tirapazamine can serve as a surrogate for O2 in converting DNA radicals into toxic strand damage events.
Daniels
J S
JS
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA.
Gates
K S
KS
Tronche
C
C
Greenberg
M M
MM
D000693:Anaerobiosis; D000970:Antineoplastic Agents / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D005609:Free Radicals; D008623:Mercaptoethanol / Q000737:chemistry; D010782:Photolysis; D000077704:Tirapazamine; D014227:Triazines / Q000633:toxicity*
D000970:Antineoplastic Agents; D005609:Free Radicals; D014227:Triazines; D000077704:Tirapazamine; D008623:Mercaptoethanol