title: Hydroxyurea decreases gemcitabine resistance in pancreatic carcinoma cells with highly expressed ribonucleotide reductase.
abstract: OBJECTIVE
  This study aimed to determine whether the treatment of pancreatic carcinoma can be defined on the basis of the expression of genes involved in gemcitabine metabolism and whether combination treatment is more effective than conventional treatment.
  
  
  METHODS
  Four pancreatic carcinoma cell lines (Panc-1, MIAPaCa-2, BxPC-3, and Capan-2) were used to determine the patterns of gemcitabine-metabolizing genes and mesenchymal marker gene expressions using quantitative real-time polymerase chain reaction. Chemosensitivity and cell proliferation were measured using colorimetric assay. Gemcitabine was combined with hydroxyurea or small interfering RNA targeting ribonucleotide reductase to assess changes in chemoresistance.
  
  
  RESULTS
  Panc-1 and MIAPaCa-2 cell lines were profoundly chemoresistant and expressed genes corresponding to cells with distinct mesenchymal phenotypes. In addition, Panc-1 highly expressed ribonucleotide reductase and showed a 4-fold increase in gemcitabine sensitivity after treatment with hydroxyurea.
  
  
  CONCLUSIONS
  Combination treatment tailored to cells with highly expressed ribonucleotide reductase was more effective than treatment with gemcitabine alone. Moreover, phenotype and gemcitabine metabolism may independently confer chemoresistance.
authors.affiliation: Department of Molecular Cell Biology, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan. funamizujikei@yahoo.co.jp
authors.forename: Naotake
authors.initials: N
authors.lastname: Funamizu
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kamata
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Misawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Uwagawa
authors.forename: Curtis Ray
authors.initials: CR
authors.lastname: Lacy
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanaga
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Manome
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000093542:Gemcitabine
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D000970:Antineoplastic Agents; D015820:Cadherins; D003841:Deoxycytidine; D018398:Homeodomain Proteins; D006918:Hydroxyurea; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012264:Ribonucleotide Reductases; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000093542:Gemcitabine; C412573:ABCB9 protein, human; C116614:ABCG2 protein, human; C513384:CDH1 protein, human; C486307:ZEB1 protein, human; C421109:multidrug resistance-associated protein 1