title: CaSm/gemcitabine chemo-gene therapy leads to prolonged survival in a murine model of pancreatic cancer.
abstract: BACKGROUND
  CaSm, the cancer-associated Sm-like oncogene, is overexpressed in greater than 80% of pancreatic tumors. We previously reported that an adenovirus expressing antisense RNA to CaSm (Ad-alpha CaSm) can decrease pancreatic tumor growth in vivo but is not curative. In the current study we investigated the mechanism of Ad-alpha CaSm's antitumor effect to rationally approach combinatorial therapy for improved efficacy.
  
  
  METHODS
  AsPC-1 and Panc-1 human pancreatic cancer cells were treated with Ad-alpha CaSm and examined by MTT assay for in vitro proliferation changes. Flow cytometry determined the effect of CaSm down-regulation on the cell cycle, and then cells treated with Ad-alpha CaSm in combination with cisplatin, etoposide, or gemcitabine chemotherapies were reexamined by MTT assay. SCID-Bg mice bearing subcutaneous AsPC-1 tumors were treated with Ad-alpha CaSm, gemcitabine, or the combination and monitored for tumor growth and survival.
  
  
  RESULTS
  Treatment with Ad-alpha CaSm reduced the proliferation of AsPC-1 and Panc-1 cells (59% and 44%, respectively; P <.05). The cell cycle revealed a cytostatic block with decreased G(1) phase and increased DNA content in treated cells. The combination of Ad-alpha CaSm with gemcitabine significantly reduced in vitro proliferation (66% vs 39% and 48% for controls), decreased in vivo AsPC-1 tumor growth by 71% (n = 10), and extended survival time from 57 to 100 days.
  
  
  CONCLUSIONS
  Down-regulation of CaSm reduces the growth of pancreatic cancer cells by altering the cell cycle in a cytostatic manner. The combination of Ad-alpha CaSm with gemcitabine is more effective than either agent used separately.
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Kelley
authors.forename: M M
authors.initials: MM
authors.lastname: Fraser
authors.forename: C W
authors.initials: CW
authors.lastname: Schweinfest
authors.forename: J N
authors.initials: JN
authors.lastname: Vournakis
authors.forename: D K
authors.initials: DK
authors.lastname: Watson
authors.forename: D J
authors.initials: DJ
authors.lastname: Cole
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D015536:Down-Regulation; D015316:Genetic Therapy; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D003841:Deoxycytidine; D000093542:Gemcitabine