Introduction

The goal of cancer therapy is to exploit differences between cancer cells and normal cells, thereby gaining a “‘therapeutic advantage.” Current therapies achieve a narrow therapeutic advantage by exploiting the unregulated proliferation that is a hallmark of cancer cells, either by damaging DNA or disrupting other cellular processes that lead to cell death. Novel therapeutic approaches attempt to target receptors, such as tyrosine-kinase receptors, or deficiencies in the cancer cell that are not present in normal cells in order to expand the therapeutic advantage. These strategies rely on finding aspects of cancer cells that are either not present or not essential in normal cells. The DNA repair machinery offers an opportunity for such targets.

One major hallmark of cancer is genomic instability (1). Maintenance of the integrity of the genetic material is of such prime importance to cells that multiple complex pathways have evolved for the surveillance and repair of DNA. There are six major DNA-repair pathways: base-excision repair (BER), nucleotide-excision repair (NER), mismatch repair (MMR), homologous recombination (HR)/Fanconi anemia (FA), non-homologous end-joining (NHEJ), and translesion synthesis (TLS; 2,3). DNA damage may also be directly reversed. Adequate genome maintenance and fidelity of DNA transmission to daughter cells requires these DNA-repair pathways, as well as co-ordination with other cellular processes such as the cell-cycle checkpoint machinery. Cells become cancerous following multiple mutations; some of these mutations may be deleterious to the growth of the cancer (perhaps accounting for the high degree of apoptosis in some solid tumors), others may enhance tumor cell growth. While the probability of independently acquiring the multiple mutations required for tumorigenesis with normal repair and checkpoints is extremely low, cancer cells are said to have a “mutator phenotype” – they acquire mutations at much higher rates than normal cells. This phenotype is partially related to deficiencies that cancer cells develop in DNA repair (Figure 90.1).