Jr. Kelley et al., CaSm/gemcitabine chemo-gene therapy leads to prolonged survival in a murine model of pancreatic cancer, SURGERY, 130(2), 2001, pp. 280-288
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.