title: The cancer therapeutic potential of Chk1 inhibitors: how mechanistic studies impact on clinical trial design.
abstract: Many anticancer agents damage DNA and activate cell cycle checkpoints that permit time for the cells to repair their DNA and recover. These checkpoints have undergone intense investigation as potential therapeutic targets and Chk1 inhibitors have emerged as promising novel therapeutic agents. Chk1 was initially recognized as a regulator of the G2/M checkpoint, but has since been demonstrated to have additional roles in replication fork stability, replication origin firing and homologous recombination. Inhibition of these pathways can dramatically sensitize cells to some antimetabolites. Current clinical trials with Chk1 inhibitors are primarily focusing on their combination with gemcitabine. Here, we discuss the mechanisms of, and emerging uses for Chk1 inhibitors as single agents and in combination with antimetabolites. We also discuss the pharmacodynamic issues that need to be addressed in attaining maximum efficacy in vivo. Following administration of gemcitabine to mice and humans, tumour cells accumulate in S phase for at least 24 h before recovering. In addition, stalled replication forks evolve over time to become more Chk1 dependent. We emphasize the need to assess cell cycle perturbation and Chk1 dependence of tumours in patients administered gemcitabine. These assessments will define the optimum dose and schedule for administration of these drug combinations.
authors.affiliation: Department of Pharmacology and Toxicology, The Geisel School of Medicine at Dartmouth, Lebanon, NH, USA; Norris Cotton Cancer Center, Lebanon, NH, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Thompson
authors.forename: Alan
authors.initials: A
authors.lastname: Eastman
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D002986:Clinical Trials as Topic; D004249:DNA Damage; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D012107:Research Design
chemical_list: D000964:Antimetabolites, Antineoplastic; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse
keywords: Chk1; cell cycle checkpoints; gemcitabine; homologous recombination; hydroxyurea; pharmacodynamics