Suppression of Cancer Growth by Nonviral Gene Therapy Based on a Novel Reactive Oxygen Species-responsive Promotor

POLICASTRO L; IBAÑEZ IL; DURAN HA; SORIA G; GOTTIFREDI V; PODHAJCER OL

MOLECULAR THERAPY (PRINT)

NATURE PUBLISHING GROUP

Año: 2009 vol. 17 p. 1355 - 1364

1525-0016

Increased reactive oxygen species (ROS) production hasbeen reported as a distinctive feature of different pathologiesincluding cancer. Therefore, we assessed whetherincreased ROS production in the cancer microenvironmentcould be selectively exploited to develop a selectiveanticancer therapy. For this purpose, we constructeda novel chimeric promoter, based on a ROS-responsemotif located in the VEGF gene promoter placed, in turn,downstream of a second ROS-response motif obtainedfrom the early growth response 1 (Egr-1) gene promoter.The activity of the chimeric promoter was largely dependenton variations in intracellular ROS levels and showeda high inducible response to exogenous H2O2. Transientexpression of the thymidine kinase (TK) gene driven bythe chimeric promoter, followed by gancyclovir (GCV)administration, inhibited human colorectal cancer andmelanoma cell growth in vitro and in vivo. Moreover,electrotransfer of the TK gene followed by GCV administrationexerted a potent therapeutic effect on establishedtumors. This response was improved when combinedwith chemotherapeutic drugs. Thus, we show for thefirst time that a distinctive pro-oxidant state can be usedto develop new selective gene therapeutics for cancer.