title: Suppression of Reserve MCM Complexes Chemosensitizes to Gemcitabine and 5-Fluorouracil.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and is very difficult to treat with conventional chemotherapeutic regimens. Gemcitabine and 5-fluorouracil are used in the management of PDAC and act by indirectly blocking replicative forks. However, these drugs are not highly effective at suppressing disease progression, indicating a need for the development of innovative therapeutic approaches. Recent studies indicate that suppression of the MCM helicase may provide a novel means to sensitize cancer cells to chemotherapeutic agents that inhibit replicative fork progression. Mammalian cells assemble more MCM complexes on DNA than are required to start S-phase. The excess MCM complexes function as backup initiation sites under conditions of replicative stress. The current study provides definitive evidence that cosuppression of the excess/backup MCM complexes sensitizes PDAC tumor lines to both gemcitabine and 5-FU, leading to increased loss of proliferative capacity compared with drugs alone. This occurs because reduced MCM levels prevent efficient recovery of DNA replication in tumor cells exposed to drug. PDAC tumor cells are more sensitive to MCM loss in the presence of gemcitabine than are nontumor, immortalized epithelial cells. Similarly, colon tumor cells are rendered less viable when cosuppression of MCM complexes occurs during exposure to the crosslinking agent oxaliplatin or topoisomerase inhibitor etoposide.
  
  
  CONCLUSIONS
  These studies demonstrate that suppressing the backup complement of MCM complexes provides an effective sensitizing approach with the potential to increase the therapeutic index of drugs used in the clinical management of PDAC and other cancers.
authors.affiliation: University of South Florida Cancer Biology Graduate Program, Moffitt Cancer Center, Tampa, Florida. Molecular Oncology Department, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bryant
authors.affiliation: Molecular Oncology Department, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Elias
authors.affiliation: Department of Pathology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Susan M
authors.initials: SM
authors.lastname: McCarthy
authors.affiliation: Gibbs Cancer Center and Research Institute, Spartanburg, South Carolina.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Yeatman
authors.affiliation: University of South Florida Cancer Biology Graduate Program, Moffitt Cancer Center, Tampa, Florida. Molecular Oncology Department, Moffitt Cancer Center, Tampa, Florida. Mark.Alexandrow@Mofffitt.org.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Alexandrow
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D064110:Minichromosome Maintenance Proteins / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D005047:Etoposide; D064110:Minichromosome Maintenance Proteins; D005472:Fluorouracil; D000093542:Gemcitabine