Chemotherapeutic intervention by inhibiting DNA polymerases

DNA replication is arguably the most important biological process associated with cancer progression. This is evident as the inhibition of DNA synthesis remains one of the key therapeutic strategies used to treat this disease. This chapter describes the biological process of DNA replication focusing primarily on the roles of DNA polymerases in cancer progression and chemotherapy. The function of human DNA polymerases in replication, repair, recombination, and translesion DNA synthesis (TLS) are discussed with a special emphasis on their biochemical, structural, and mechanistic features. The current arsenal of therapeutic agents used to inhibit DNA polymerase activity is described, paying particular attention to purine and pyrimidine nucleoside analogs. Preclinical and clinical applications of these nucleoside analogs are described with respect to mono- and combination therapy using DNA-damaging agents such as chlorambucil and cisplatin.