Free radical damage to DNA
Free radical damage to DNA can occur as a result of exposure to ionizing radiation or to radiomimetic[1] compounds.
Malignant melanoma can be caused by indirect DNA damage because it is found in parts of the body not exposed to sunlight.
[2] Radiolysis of intracellular water by ionizing radiation creates peroxides, which are relatively stable precursors to hydroxyl radicals.
The Fenton reaction results in the creation of hydroxyl radicals from hydrogen peroxide and an Iron (II) catalyst.
[5] Hydroxyl radicals can attack the deoxyribose DNA backbone and bases, potentially causing a plethora of lesions that can be cytotoxic or mutagenic.
In general, radical hydroxyl attacks on base moieties do not cause altered sugars or strand breaks except when the modifications labilize the N-glycosyl bond, allowing the formation of baseless sites that are subject to beta-elimination.
The carbon radical reacts with molecular oxygen, which leads to a strand break in the DNA through a variety of mechanisms.
However, incorporating the enediyne into a 10-membered cyclic hydrocarbon makes the reaction more thermodynamically favorable by releasing the ring strain of the reactants.
These compounds are synthesized by bacteria as defense mechanisms due to their ability to cleave DNA through the formation of 1,4-didehydrobenzene from the enediyne component of the molecule.
The extended structures attached to the enediyne allow the compound to specifically bind DNA,[14] in most cases to the minor groove of the double helix.
The anthraquinone component allows for specific binding of DNA at the 3’ side of purine bases through intercalation, a site that is different from calicheamicin.
Most enediynes, including the ones listed above, have been used as potent antitumor antibiotics due to their ability to efficiently cleave DNA.
Calicheamicin and esperamicin are the two most commonly used types due to their high specificity when binding to DNA, which minimizes unfavorable side reactions.
[16] Additionally, calicheamicin is able to cleave DNA at low concentrations, proving to be up to 1000 times more effective than adriamycin at combating certain types of tumors.
The free radical then continues on to cleave DNA in a similar manner to 1,4-didehydrobenzene in order to treat cancerous cells.
