Suppression of cancer growth by nonviral gene therapy based on a novel reactive oxygen species-responsive promoter.
Increased reactive oxygen species (ROS) production has been reported as a distinctive feature of different pathologies including cancer. Therefore, we assessed whether increased ROS production in the cancer microenvironment could be selectively exploited to develop a selective anticancer therapy. For this purpose, we constructed a novel chimeric promoter, based on a ROS-response motif located in the VEGF gene promoter placed, in turn, downstream of a second ROS-response motif obtained from the early growth response 1 (Egr-1) gene promoter. The activity of the chimeric promoter was largely dependent on variations in intracellular ROS levels and showed a high inducible response to exogenous H(2)O(2). Transient expression of the thymidine kinase (TK) gene driven by the chimeric promoter, followed by gancyclovir (GCV) administration, inhibited human colorectal cancer and melanoma cell growth in vitro and in vivo. Moreover, electrotransfer of the TK gene followed by GCV administration exerted a potent therapeutic effect on established tumors. This response was improved when combined with chemotherapeutic drugs. Thus, we show for the first time that a distinctive pro-oxidant state can be used to develop new selective gene therapeutics for cancer.
Department of Radiobiology, National Atomic Energy Commission-CONICET, Buenos Aires, Argentina.
Lucía L
LL
Policastro
Irene L
IL
Ibañez
Hebe A
HA
Durán
Gastón
G
Soria
Vanesa
V
Gottifredi
Osvaldo L
OL
Podhajcer
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000628:therapy; D051766:Early Growth Response Protein 1 / Q000235:genetics; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D000998:Antiviral Agents; D051766:Early Growth Response Protein 1; D042461:Vascular Endothelial Growth Factor A; D006861:Hydrogen Peroxide; D013937:Thymidine Kinase; D015774:Ganciclovir