title: E1A, E1B double-restricted adenovirus enhances the cytotoxicity and antitumor activity of gemcitabine to renal cell carcinoma.
abstract: BACKGROUND
  Our previous studies have demonstrated potent oncolysis efficacy of the E1A, E1B double-restricted replication-competent oncolytic adenovirus AxdAdB-3 for treatment of bladder cancer. Here, we reported the feasibility and efficacy of AxdAdB-3 alone, or in combination with gemcitabine for treating renal cell carcinoma.
  
  
  METHODS
  Cytopathic effects of AxdAdB-3 were evaluated in human renal cell carcinoma cell lines TOS-1, TOS-2, TOS-3, TOS-3LN, SMKT-R3, SMKT-R4 and ACHN, and in normal human renal proximal tubule epithelial cells (RPTEC). AxdAdB-3 induced down-regulation of the cell cycle was determined by flow cytometry. Combination therapies of AxdAdB-3 with gemcitabine were evaluated in vitro and in vivo on subcutaneous TOS-3LN tumors in a severe combined immunodeficiency disease (SCID) mouse model.
  
  
  RESULTS
  AxdAdB-3 was potently cytopathic against the tested most renal cell carcinoma cell lines including TOS-2, TOS-3, TOS-3LN, SMKT-R3 and SMKT-R4, while normal human RPTEC were not destroyed. AxdAdB-3 effectively induced cell cycle S-phase entry. Combined therapy of AxdAdB-3 with gemcitabine demonstrated stronger antitumor effects in vitro and in vivo compared with either AxdAdB-3 or gemcitabine alone.
  
  
  CONCLUSIONS
  AxdAdB-3 alone, or in combination with gemcitabine may be a promising strategy against renal cell carcinoma.
authors.affiliation: Department of Urology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China. hwangua@yahoo.com.cn
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Makoto
authors.initials: M
authors.lastname: Satoh
authors.forename: Gui-Ping
authors.initials: GP
authors.lastname: Chen
authors.forename: De-Chuan
authors.initials: DC
authors.lastname: Li
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hamada
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Arai
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000628:therapy*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D050130:Oncolytic Virotherapy; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D000964:Antimetabolites, Antineoplastic; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; D003841:Deoxycytidine; D000093542:Gemcitabine