Molecular mechanisms of DNA damage induced by procarbazine in the presence of Cu(II).

摘要: Procarbazine [N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide], a hydrazine derivative, which has been shown to have effective antineoplastic activity, induces cancer in some experimental animals and humans. To clarify new mechanism for its carcinogenic effect, we examined DNA damage induced by procarbazine the presence of metal ion, using 32P-5'-end-labeled fragments obtained from human p53 tumor suppressor gene c-Ha-ras-1 protooncogene. plus Cu(II) piperidine-labile formamidopyrimidine-DNA glycosylase-sensitive lesions at 5'-ACG-3' sequence, complementary hotspot gene, 5'-TG-3' sequence. Catalase partially inhibited damage, suggesting that not only H(2)O(2) but also other reactive species are involved. significantly increased formation 8-oxo-7,8-dihydro-2'-deoxyguanosine, was completely calatase. Electron spin resonance spin-trapping experiments revealed methyl radicals were generated Cu(II). On basis these findings, it is considered causes through non-enzymatic Cu(I)-hydroperoxo complex radicals. In conclusion, addition alkylation, oxidative may play important roles antitumor effects mutagenesis carcinogenesis procarbazine.