**6. Classic Anti-Cancer Therapy Relies on DNA Damage Induction to Which Cancer Cells Are More Sensitive**

Cancer cells deficient in DNA damage checkpoint and repair pathways are particularly sensitive to DNA damage upon which chemo and radiation cancer therapies rely.

In chemotherapy, the most common agents used are alkylating agents, which cause mainly intra-strand and few inter-strand crosslinks by adding alkyl groups to DNA [95]. Currently, platinum-based chemotherapeutic drugs, called "alkylating-like", are more frequently used because they form DNA crosslinks without having an alkyl group. Another group of DNA damaging agents used are inhibitors of topoisomerases, affecting the activity of two enzymes catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle, topoisomerase I and topoisomerase II. Topoisomerase I inhibitors stabilize the cleavable complex of topoisomerases I, preventing DNA relegation and thus inducing DNA strand breaks; some examples are topotecan and camptothecin. Drugs against topoisomerase II consist of chemicals which target the complex DNA-topoisomerases II and promote cleavage activity or prevent re-ligation of the DNA, and inhibitors that reduce the turn-over of the enzyme; some examples are etoposide and doxorubicin [96].

A third group are cytotoxic antibiotics that act by different mechanisms of action and share the ability to interrupt cell division. Among this group, important examples are bleomycin and mitomycin C that damage DNA by producing free radicals and DNA inter-strand crosslinks, respectively [97].

Anti-metabolites are a group of molecules with a structure similar to nucleotides, but with altered chemical groups. These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA and promoting DNA damage; some examples are capecitabine and gemcitabine [98].

Radiotherapy induces DNA damage using ionizing radiation (IR), either directly by ionizing the DNA strands or indirectly by producing free radicals as a result of ionized water molecules [99].

These treatments have proven to be effective against cancer, but resistance development is a common problem. Various factors drive drug resistance, such as increase of drug efflux, over-expression of DNA repair proteins or inhibition of proteins involved in apoptotic pathway [100]. To overcome this, it is now evident that combination with specific drugs targeting cancer deregulated pathways can greatly help, for this reason several compounds inhibiting different players in DDC and DNA repair are under study in pre-clinical and in clinical trials, alone or in combination with classic therapy.
