https://cancerres.aacrjournals.org/content/canres/38/6/1479.full.pdf

Some Current Perspectives on Chemical Carcinogenesis in Humans and Experimental Animals: Presidential Address

On the basis of chemical considerations and model building, the Watson–Crick concept of complementary base pairing is extended to a wider range of DNA pairs than A–T and G–C (including A–C, G–T, A–A, G–G and G–A) by invoking imino or enol tautomers (or protonated species) and syn isomers. The virtual absence of these additional base pairs from DNA is explained in terms of the low frequency with which these unfavoured forms occur and the two-step mechanism of DNA synthesis, whereby residues are first incorporated by the DNA polymerase and then checked. This base-pairing hypothesis is used to explain the origin, nature and level of spontaneous substitution mutations, their enhancement by base analogues, and the unique effects of certain mutator alleles.

Complementary base pairing and the origin of substitution mutations

The covalent binding of chemical carcinogens to DNA of mammalian organs is expressed per unit dose, and a 'Covalent-Binding Index', CBI, is defined. CBI for various carcinogens span over 6 orders of magnitude. A similar range is observed for the carcinogenic potency in long-term bioassays on carcinogenicity. For the assessment of a risk from exposure to a carcinogen, the total DNA dmaage can be estimated if the actual dose is also accounted for. A detailed description is given for planning and performing a DNA-binding assay. A complete literature survey on DNA binding in vivo (83 compounds) is given with a calculation of CBI, where possible, 153 compounds are listed where a covalent binding to any biological macromolecule has been shown in vivo or in vitro. Recent, so far unpublished findings with aflatoxin M1, macromolecule-bound aflatoxin B1, diethylstilbestrol, and 1,2-epithiobutyronitrile are included. A comparison of CBI for rat-liver DNA with hepatocarcinogenic potency reveals a surprisingly good quantitative correlation. Refinements for a DNA-binding assay are proposed. Possibilites and limitations in the use of DNA binding in chemical carcinogenesis are discussed extensively.

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In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis.

It is generally acknowledged that geometrical and conformational properties of biopolymers have an important effect on their biochemical behaviour. It is less easily recognized that these properties depend also on their macromolecular electronic characteristics.The aim of this review is to demonstrate the significance of such macromolecular electronic effects. Particularly useful for this sake is the recently much developed concept of ‘molecular electrostatic potential’ (MEP) (Scrocco & Tomasi, 1973, 1978) by which is defined the electrostatic (Coulomb) potential created in the neighbouring space by the nuclear charges and the eletronic distribution of a molecule.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0033583500002341

Molecular electrostatic potential of the nucleic acids.

Bifunctional alkylating agents are known to cross-link DNA by simultaneously alkylating two guanine residues located on opposite strands. Despite this apparent requirement for bifunctionality, 1-(2-chloroethyl)-1-nitrosoureas bearing a single alkylating function were found to cross-link DNA in vitro. Cross-linking was demonstrated by showing inhibition of alkali-induced strand separation. Extensive cross-linking was observed in DNA treated with 1-(2-chloroethyl)-1-nitrosourea, 1,3-bis-(2-chloroethyl)-1-nitrosourea, and 1-(2-chloroethyl(-3-cyclohexyl-1-nitrosourea. The reaction occurs in two steps, an intital binding followed by a second step which can proceed after removal of unbound drug. It is suggested that the first step is chloroethylation of a nucleophilic site on one strand and that the second step involves displacement of Cl- by a nucleophilic site on the opposite strand, resulting in an ethyl bridge between the strands. Consistent with this possibility, 1-(2-fluoroethyl)-3-cyclohexyl-1-nitrosourea produced much less cross-linking, as expected from the known low activity of F-, compared with Cl-, as leaving group. 1-Methyl-1-nitrosourea, which is known to depurinate DNA, produced no detectable cross-linking.

https://cancerres.aacrjournals.org/content/canres/37/5/1450.full.pdf

Interstrand Cross-linking of DNA by 1,3-Bis(2-chloroethyl)-1-nitrosourea and Other 1-(2-haloethyl)-1-nitrosoureas

Publisher Summary This chapter discusses the studies relating to the chemical nature of alkylation, from the products of nucleoside alkylation to in vivo effects of alkylating agents that are oncogenic. The reactions of simple methylating agents with nucleosides, nucleotides, and polynucleotides have also been discussed in the chapter. More recent studies of the mechanism of alkylation by nitroso compounds and ethylating agents have shown that both qualitatively and quantitatively the site of alkylation is a function of both the type of reagent used and the conformation and milieu of the nucleic acid. However, translation of this body of knowledge to an understanding of the biological mechanism of alkylation-induced mutagenesis and carcinogenesis is difficult. Further studies of mutation in picornaviruses or their RNAs would be fruitful since these viral RNAs are also messenger RNAs and are directly translated, whereas in vivo studies, definitive information is still lacking as to whether alkylation of DNA, RNA, or perhaps protein, is the biologically important event.

B Singer

Papers

The chemical effects of nucleic acid alkylation and their relation to mutagenesis and carcinogenesis.