Checkpoint pathways provide cells with multiple molecular mechanisms to overcome DNA lesions.1 However, in tumor cells, DNA damage detection or repair pathways may be missing or defective, resulting in increased susceptibility to DNA damaging agents; therefore agents inducing DNA damage may have clinical efficacy.1 For example, the G1 checkpoint of the cell cycle is compromised in many tumor cells by the loss of p53 but it remains intact in noncancerous tissues.
Nevertheless, remaining checkpoints produce a resistance response to DNA damaging therapies. Chk1 is one of the remaining cell cycle checkpoints and has recently been demonstrated to be a resistance response to DNA damaging therapies such as radiotherapy.2 Such resistance may be overcome through pharmacologic inhibition of Chk1 kinase, leading ultimately to cell death. Potential exists for selectively increasing cytotoxicity in tumors that are currently treated with a wide range of DNA damaging agents, including: radiation, alkylating agents, platinating agents, antimetabolites, and topoisomerase 1 inhibitors.3-5
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