title: Intravenous siRNA Silencing of Survivin Enhances Activity of Mitomycin C in Human Bladder RT4 Xenografts.
abstract: OBJECTIVE
  Survivin inhibits apoptosis and enables tumor cells to escape from therapy induced senescence. High survivin expression is associated with bladder cancer aggressiveness and recurrence. We evaluated whether survivin expression is reduced by siRNA and whether survivin silencing would enhance mitomycin C activity in human RT4 bladder transitional cell tumors in vitro and in vivo.
  
  
  METHODS
  We assessed the effectiveness of siRNA therapy using 2 newly developed pegylated cationic liposome carriers, PCat and PPCat. Each has a fusogenic lipid to destabilize the endosomal membrane. PPCat further contains paclitaxel to enhance in vivo delivery and transfection of survivin siRNA. In vitro antitumor activity was evaluated by short-term MTT and long-term clonogenicity cytotoxicity assays. In vivo intravenous therapy was assessed in mice bearing subcutaneous tumors.
  
  
  RESULTS
  Nontarget siRNA showed no antitumor activity in vitro or in vivo. Treatment of cultured cells with mitomycin C at a 50% cytotoxic concentration enhanced survivin mRNA and protein levels. Adding PPCat or PCat containing survivin siRNA reversed survivin induction and enhanced mitomycin C activity (p <0.05). In tumor bearing mice single agent mitomycin C delayed tumor growth and almost tripled the survivin protein level in residual tumors. Adding PPCat-survivin siRNA, which alone resulted in a minor survivin decrease of less than 10%, completely reversed mitomycin C induced survivin and enhanced mitomycin C activity (p <0.05).
  
  
  CONCLUSIONS
  Results indicate that there is effective in vivo survivin silencing and synergism between mitomycin C and PPCat-survivin siRNA. This combination represents a potentially useful chemo-gene therapy for bladder cancer.
authors: Optimum Therapeutics LLC, San Diego, California.
authors: Minjian
authors: M
authors: Cui
authors: Optimum Therapeutics LLC, San Diego, California; Department of Pharmaceutical Sciences, University of Oklahoma, Oklahoma City, Oklahoma; Medical University of South Carolina, Charleston, South Carolina; Taipei Medical University, Taipei, Taiwan, Republic of China.
authors: Jessie L-S
authors: JL
authors: Au
authors: Optimum Therapeutics LLC, San Diego, California.
authors: M Guillaume
authors: MG
authors: Wientjes
authors: University of Iowa, Iowa City, Iowa.
authors: Michael A
authors: MA
authors: O'Donnell
authors: Brigham and Women's Hospital, Boston, Massachusetts.
authors: Kevin R
authors: KR
authors: Loughlin
authors: Optimum Therapeutics LLC, San Diego, California. Electronic address: zlu@optimumtx.com.
authors: Ze
authors: Z
authors: Lu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D064593:Heterografts; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000627:therapeutic use*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology* / Q000627:therapeutic use*; D000077022:Survivin; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D016685:Mitomycin
keywords: BIRC5 protein; RNA; genetic therapy; human; mitomycin; small interfering; urinary bladder neoplasms