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-αCaSm) can decrease pancreatic tumor growth in vivo but is not curative. In the current study we investigated the mechanism of Ad-αCaSm'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-αCaSm 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-αCaSm 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-αCaSm, gemcitabine, or the combination and monitored for tumor growth and survival. Results. Treatment with Ad-αCaSm 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 G1 phase and increased DNA content in treated cells. The combination of Ad-αCaSm 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-αCaSm with gemcitabine is more effective than either agent used separately. (Surgery 2001;130:280-8.)