CaSm/gemcitabine chemo-gene therapy leads to prolonged survival in a murine model of pancreatic cancer

Background. CaSm, the cancer-associated Sm-like oncogene, is overexpressed in greater than 80% of pancreatic tumors. We previously reported that an ad enovirus expressing antisense RNA to CaSm (Ad-alpha CaSm) can decrease panc reatic tumor growth in vivo but is not curative. In the current study we in vestigated 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 c ycle, and then cells treated with Ad-alpha CaSm in combination with cisplat in, etoposide, or gemcitabine chemotherapies were reexamined by MTT assay. SCID-Bg mice hearing subcutaneous AsPC-1 tumors were treated with Ad-alpha CaSm, gemcitabine, or the combination and monitored for tumor growth and su rvival. Results. Treatment with Ad-alpha CaSm reduced the proliferation of AsPC-1 a nd Panc-1 cells (59% and 44%, respectively; P < .05). The cell cycle reveal ed a cytostatic block with decreased G(1) phase and increased DNA content i n treated cells. The combination of Ad-<alpha>CaSm with gemcitabine signifi cantly reduced in vitro proliferation (66% vs 39% and 48% for controls), de creased 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 cance r 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.