A novel strategy for cancer therapy by mutated mammalian degenerin gene transfer.
Mammalian degenerin (MDEG) is a member of the amiloride-sensitive sodium ion channel family, and its site-directed active mutant (MDEG-G430F) induces massive Na+ influx into cells, leading to cell ballooning and cell bursting. We attempted a novel therapeutic approach for gastric cancers by transferring MDEG-G430F into cancer cells using tumor-specific promoters. In carcinoembryonic antigen (CEA)-producing gastric cancer cells, the level of cell death observed when MDEG-G430F was used with a CEA promoter was similar to that observed when using a potent nonspecific promoter such as the cytomegalovirus promoter. In an in vivo study, fusogenic liposome complexes containing MDEG-G430F driven by the CEA promoter were injected intraperitoneally into CEA-producing gastric cancer cells in a mouse peritoneal dissemination model. Although all 15 of the control mice were dead by 50 days postinoculation, 13 of the 15 mice treated with MDEG-G430F survived. These results indicate that transferring MDEG-G430F into cancer tissues using tumor-specific promoters can achieve striking and selective cancer cell death irrespective of the transcriptional efficiency of the promoters used in vivo, and suggest that this approach is a promising new strategy for cancer gene therapy.
Horimoto
M
M
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Japan.
Sasaki
Y
Y
Ugawa
S
S
Wada
S
S
Toyama
T
T
Iyoda
K
K
Yakushijin
T
T
Minami
Y
Y
Ito
T
T
Hijioka
T
T
Eguchi
A
A
Nakanishi
M
M
Shimada
S
S
Tohyama
M
M
Hayashi
N
N
Hori
M
M
D062565:Acid Sensing Ion Channels; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D062626:Degenerin Sodium Channels; D053503:Epithelial Sodium Channels; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D008081:Liposomes; D008113:Liver Neoplasms / Q000378:metabolism / Q000628:therapy*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D010532:Peritoneal Diseases / Q000473:pathology; D013274:Stomach Neoplasms / Q000628:therapy*; D015996:Survival Rate; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods*; D014407:Tumor Cells, Cultured
C568424:ASIC2 protein, human; D062565:Acid Sensing Ion Channels; D002272:Carcinoembryonic Antigen; D062626:Degenerin Sodium Channels; D053503:Epithelial Sodium Channels; D007473:Ion Channels; D008081:Liposomes; D009419:Nerve Tissue Proteins; D008156:Luciferases