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26 Pharmacological Agents That Target DNA Replication

Yves Pommier, Robert B. Diasio


DNA replication inhibitors are commonly used as anticancer and antiviral agents (see Appendix, Table VII). This review focuses on their molecular pharmacology. Drugs inhibit DNA synthesis by two mechanisms that are generally associated: (1) direct interference with molecules required for DNA polymerization or/and initiation of replication and (2) checkpoint response(s). The direct sites of drug action (“pharmacological targets”: nucleotide precursor pools, chain elongation, DNA polymerases, the DNA template, and cyclin-dependent kinases) are outlined in Figure 1. Structures of the corresponding drugs and detailed molecular mechanisms of actions are summarized in Figures 2–7. Checkpoint response (“intra S-phase checkpoint”) was first identified by its deficiency in cells from patients with ataxia telangiectasia (A-T). Checkpoints allow the repair of the drug-induced DNA lesions. Checkpoints can also activate programmed cell death (also referred to as apoptosis). Functionally, checkpoint response can be differentiated from direct replication block when replication inhibition can be alleviated by checkpoint inhibitors such as ATM/ATR or Chk1 or Chk2 inhibitors.

Historically, there have been several approaches in developing cancer therapeutics that bear chemical similarity to the various “building blocks” of nucleic acids and inhibit the formation of functional nucleotide triphosphates needed to synthesize either DNA or RNA. Many of these agents have been labeled “antimetabolites” because of their structural similarities to naturally occurring metabolites (Daher et al. 1994; Pizzorno et al. 2003). These include the antifolates (e.g., methotrexate), pyrimidines like 5-fluorouracil (5-FU), and purines like 6-mercaptopurine and 6-thioguanine (Fig. 2). Other drugs like hydroxyurea (HU) are not...

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