Inhibition of DNA Repair as a Therapeutic Target

This chapter discusses the inhibition of DNA repair as a therapeutic target. Inhibition of DNA repair represents an excellent target for cancer therapy. DNA repair inhibitors can increase the specificity and toxicity of radio- and chemotherapy, or be stand-alone treatments for cancers that are defective in other DNA repair pathways by amplifying endogenous lesions present in the cancer cells. DNA repair can affect the response to cancer therapy in two ways. First, as radiotherapy and most chemotherapy drugs cause DNA damage, DNA repair is an important determinant for treatment efficiency. High levels of DNA repair contribute to removal of the DNA lesions, resulting in resistance and failed cancer treatments. Secondly, the defects in DNA repair in cancers influence the chemotherapy outcome. For instance, mismatch repair defective tumors are resistant to a variety of drugs, while homologous recombination defective tumors are highly sensitive to cross-linkers. There is a major therapeutic potential to enhance the persistence of toxic lesions in cancer cells through inhibition of DNA repair enzymes. The success following preclinical and clinical trials using inhibition of O6-alkylguanine DNA alkyltransferase, poly (ADP-ribose) polymerase, and DNA dependent protein kinase provides a strong rationale for further development of inhibitors for DNA repair as future sensitizers to current anticancer treatments.