Drugs and nucleic acids
The deoxyribonucleic acid or DNA contains the genetic information necessary for the replication of the cell and its functioning after transcription of DNA into RNA and translation of RNA into proteins.
DNA is a linear polymer, constituted of deoxyribonucleotides (deoxyadenosine, deoxyguanosine, deoxycytidine and deoxythymidine) bound by phosphodiester bonds. At pH = 7, the phosphodiester groups are ionized as anions and bind to elements such as magnesium.
DNA exists as a double helix, or double strand, maintained between them by hydrogen bonds drawn up between two complementary bases, adenine and thymine by two hydrogen bonds, and guanine and cytosine by three hydrogen bonds.
The double helix of DNA undergoes supercoiling known as positive or negative according to the direction of rotation. Under supercoiled form, replication and transcription of DNA are not possible. A specific and transitional separation of the strands, after their cut, is necessary. The enzymes which cut and then restore the bond on only one strand of the double helix are called topoisomerases I and those which act on the two strands are called topoisomerases II or DNA-gyrases. These enzymes can add or remove crossings.
RNA is a polymer constituted of ribonucleotides in the form of one strand. The four bases of RNA are adenine, uracil, guanine and cytosine.
DNA is a biological molecule having the capacity for self repairing. The damage affects generally only one strand of DNA and the intact strand is used as reference for the repair of the damaged strand. Moreover, the bases having bound an alkyl group can be de-alkylated by suicide enzymes which remove and bind the alkyl group. Finally there exist mechanisms of excision of damaged nucleotides. These mechanisms of repair are useful for repairing not desired lesions but become adverse when they antagonize the action of antineoplastic agents in the cancerous cells.
One can schematically distinguish two groups of medications concerning DNA: those which protect DNA from alterations, due for example to radical reactions, causing cancers and those which damage DNA of cancerous cells and microorganisms, while respecting if possible DNA of normal cells. At present there is no drug really able to protect DNA; the only mean available is the decrease of the exposure to the risk factors such as sun, tobacco, irradiations, toxic compounds. This chapter is devoted to drugs which damage DNA.
Drugs which damage nucleic acids, DNA and RNA, already constituted, inhibit cellular replication and function. They are used as antineoplastic agents and also as antibiotics.
The majority of antineoplastic agents damaging DNA are old drugs, not very specific because they do not respect healthy cells and have many adverse effects, but their use, generally in combination, gives appreciable results.
The antibiotics which damage DNA have a sufficient specificity of action against the pathogenic microorganisms to be generally well tolerated.