Mechanism of action of antitumor 3-(2-haloethyl) aryltriazenes on deoxyribonucleic acid.
A series of novel 3-(2-haloethyl)aryltriazenes, many of which exhibit marked antileukemic activity in animal test neoplasms, react readily with DNA under physiological conditions. With regard to a single strand scission (SSS), in contrast to the related 2-haloethynitrosoureas which exhibit both Type I and Type II SSS (single strand scission) of DNA, the triazenes appear to react via Type II SSS of DNA by base alkylation followed by depurination or depyrimidination and subsequent hydrolysis of the apurinic site. The latter reaction was confirmed using apurinic site-specific endonuclease VI. A 3-(2-chloroethyl)aryltriazene readily degraded poly A by phosphate alkylation at a rate much faster than given by comparable nitrosoureas. Overall, the triazenes showed a preference for reaction at the more acidic phosphate sites in the DNA owing to their unique acid-promoted decomposition. This may, in part, account for the lack of detection of DNA interstrand cross-links and indicates a fundamentally different mechanism of action of the 3-(2-haloethyl)triazenes from the 2-haloethylnitrosoureas.
D000478:Alkylation; D000970:Antineoplastic Agents / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D043223:Deoxyribonuclease IV (Phage T4-Induced); D003851:Deoxyribonucleases / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D014226:Triazenes / Q000378:metabolism*
D000970:Antineoplastic Agents; D014226:Triazenes; D012313:RNA; D004247:DNA; D003851:Deoxyribonucleases; D004720:Endonucleases; D043223:Deoxyribonuclease IV (Phage T4-Induced); D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase