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

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Ogawa K, Hiraku Y, Oikawa S, Murata M, Sugimura Y, Kawamura J, Kawanishi S

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

Mutat Res. 2003 Aug 5;539(1-2):145-55.

PubMed ID

12948823 [ View in PubMed

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Abstract

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

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Procarbazine	DNA	Nucleotide	Humans	Yes	Cross-linking/alkylation	Details