title: Acquired resistance to gemcitabine and cross-resistance in human pancreatic cancer clones.
abstract: The efficacy of gemcitabine (GEM), a standard treatment agent for pancreatic cancer, is insufficient because of primary or acquired resistance to this drug. Patients with tumors intrinsically sensitive to GEM gradually acquire resistance and require a shift to second agents, which are associated with the risk of cross-resistance. However, whether cross-resistance is actually present has long been disputed. Using six GEM-resistant and four highly GEM-resistant clones derived from the pancreatic cancer cell line BxPC-3, we determined the resistance of each clone and parent cell line to GEM and four anticancer agents (5-FU, CDDP, CPT-11, and DTX). The GEM-resistant clones had different resistances to GEM and other agents, and did not develop a specific pattern of cross-resistance. This result shows that tumor cells are heterogeneous. However, all highly GEM-resistant clones presented overexpression of ribonucleotide reductase subunit M1 (RRM1), a target enzyme for metabolized GEM, and showed cross-resistance with 5-FU. The expression level of RRM1 was high; therefore, resistance to GEM was high. We showed that a tumor cell acquired resistance to GEM, and cross-resistance developed in one clone. These results suggest that only cells with certain mechanisms for high-level resistance to GEM survive against selective pressure applied by highly concentrated GEM. RRM1 may be one of the few factors that can induce high resistance to GEM and a suitable therapeutic target for GEM-resistant pancreatic cancer.
authors.affiliation: aBiomedical Laboratory, Biomedical Research Center bDepartment of Pharmacy cDepartment of Surgery, Kitasato University Kitasato Institute Hospital dDepartment of Clinical Pharmacy, School of Pharmacy, Center for Clinical Pharmacy and Clinical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoneyama
authors.forename: Asako
authors.initials: A
authors.lastname: Takizawa-Hashimoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Koichiro
authors.initials: K
authors.lastname: Atsuda
authors.forename: Fumiki
authors.initials: F
authors.lastname: Asanuma
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamada
authors.forename: Yukio
authors.initials: Y
authors.lastname: Suzuki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002999:Clone Cells / Q000187:drug effects / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine