DNA adducts and DNA damage by antineoplastic and carcinogenic N-nitrosocompounds

Abstract

Mechanisms of DNA adduct formation by antineoplastic 2-chloroethyl-N-nitrosoureas (CNUs) and of DNA damage induced by these compounds as well as by carcinogenic 2-hydroxyalkylnitrosamines are discussed. CNUs are monofunctional and bifunctional alkylating agents that form, in a quantitatively minor reaction, DNA-DNA crosslinks (XL). In vitro, by far the most abundant alkylation products of DNA are those resulting from 2-hydroxyethylation. The reaction sequence responsible for 2-hydroxyethylation comprises intermediate oxazolidine ring closure followed by generation of 2-hydroxyethylnitrosourea and ethylene oxide. Oxadiazolium intermediates have not been found to play a role. In contrast to the in vitro experiments, in vivo 2-hydroxyethyl adducts are formed to a much lesser extent und 2-chloroethyl adducts are predominant in rat kidney DNA. 2-Hydroxyethylation of phosphate groups introduces extreme instability into the sugar-phosphate backbone since the resulting phosphotriester rapidly breaks down through a dioxaphospholane ring intermediate. Measurements of DNA XL in target tumor tissue and in bone marrow provides a sensitive tool for evaluation in bone marrow provides a sensitive tool for evaluation of hormone-linked cytotoxic agents. The potent environmental carcinogen N-nitrosodiethanolamine (NDELA) has been found to be activated in the rat liver by a two-step metabolic transformation sequence involving alcohol dehydrogenase and, subsequently, sulfotransferase. Evidence for this mechanism is provided by measuring DNA single strand breaks in rat liver DNA and by studying the effect of various enzyme inhibitors on the extent of DNA damage induced in vivo by NDELA and its metabolites.

Alleviation of 1, N 6 -ethanoadenine genotoxicity by the Escherichia coli adaptive response protein AlkB

“…The anticancer chemotherapeutic agent BCNU is a bifunctional electrophile that reacts with DNA to form a range of adducts, including chloroethyl-and hydroxyethyl-monosubstituted bases, saturated ethano adducts, and inter-and intrastrand cross-links (30)(31)(32)(33). The compound has been shown to exhibit both genotoxic and mutagenic properties and, although the potent toxicity of the drug is attributed to quantitatively minor 1-(3-cytosinyl)-2-(1-guanyl)ethane interstrand cross-links (32), the mutagenic characteristics are thought to be due to other damaged bases (33).…”

Inhibition of human glutathione reductase by the nitrosourea drugs 1,3‐bis(2‐chloroethyl)‐1‐nitrosourea and 1‐(2‐chloroethyl)‐3‐(2‐hydroxyethyl)‐1‐nitrosourea

“…1) [14]. BCNU and HeCNU possess very similar alkylating capacities towards DNA [14]. With glutathione reductase in vitro, however, BCNU and HeCNU show very different reaction patterns and rates.…”

“…Two mechanisms are known by which the inhibition of GR could impair tumor growth: (a) the resulting build-up of the substrate GSSG could inhibit protein synthesis [2]; (b) the tumor cells may become unable to cope with the cytotoxic reactive-oxygen species launched against them by activated macrophages [ll]. Here we report on the X-ray diffraction analyses of GR inactivated in vitro by BCNU as well as by 1-(2-chloroethyl)-3-(2-hydroxyethyl)-l-nitrosourea (HeCNU), a less toxic analogue of BCNU [14]. Both nitrosoureas are used clinically in tumor therapy.…”

Mechanisms of Action of Cancer Chemotherapeutic Agents:DNA‐Interactive Alkylating Agents and Antitumour Platinum‐Based Drugs

“…Irrespective of their nature, both GG and CG cross-links correlate strongly with cytotoxicity. Eisenbrand et al ., 1986, Pratt et al ., 1994.) Figure 12 Mechanisms responsible for the conversion of monofunctional adducts of CENU to GG intrastrand (pathway A) and CG interstrand (pathway B) cross-links.…”