A novel strategy for cancer therapy by mutated mammalian degenerin gene transfer

Abstract

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.