The dominant negative H-ras mutant, N116Y, suppresses growth of metastatic human pancreatic cancer cells in the liver of nude mice.
In pancreatic cancer, the mutation of c-K-ras is a critical event of tumor growth and metastasis. We have previously demonstrated a dominant negative effect of N116Y on the growth of pancreatic cancer cells. To evaluate the potential of N116Y for suppressing the metastatic growth of pancreatic tumor cells, we made a replication-deficient recombinant N116Y adenovirus driven by the carcinoembryonic antigen (CEA) promoter (Ad CEA-N116Y). We demonstrated that the expression of N116Y, growth inhibition, and apoptotic death induction were all specific to pancreatic cancer cell lines (PCI-35 and PCI-43) that were promoter positive, whereas no growth retardation was observed in human embryonic pancreas-derived cell line 1C3D3 after Ad CEA-N116Y infection. We examined the effect of Ad CEA-N116Y on the metastatic growth of PCI-43 colonies in liver, which was generated by tumor injection into the spleen of nude mice. The results showed that Ad CEA-N116Y effectively reduced the number of metastatic colonies without any complication by injecting intrasplenically 5 days after tumor cell inoculation. Thus, N116Y can selectively suppress the metastatic growth of pancreatic tumor cell by using the CEA promoter-driven adenovirus vector indicating that N116Y gene therapy may be potentially useful for the treatment of pancreatic cancer patients with liver micrometastasis.
Takeuchi
M
M
Division of Gene Regulation, Hokkaido University School of Medicine, Sapporo, Japan.
Shichinohe
T
T
Senmaru
N
N
Miyamoto
M
M
Fujita
H
H
Takimoto
M
M
Kondo
S
S
Katoh
H
H
Kuzumaki
N
N
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002272:Carcinoembryonic Antigen / Q000235:genetics; D002460:Cell Line; D015870:Gene Expression; D005799:Genes, Dominant; D011905:Genes, ras; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007267:Injections; D008113:Liver Neoplasms / Q000503:physiopathology / Q000556:secondary* / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000503:physiopathology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen
D002272:Carcinoembryonic Antigen