INVESTIGADORES
PODHAJCER Osvaldo Luis
artículos
Título:
Suppression of cancer growth by nonviral gene therapy based on a novel reactive oxygen species-responsive promoter.
Autor/es:
POLICASTRO LL; IBAÑEZ IL; DURÁN HA; SORIA G; GOTTIFREDI V; PODHAJCER OL
Revista:
MOLECULAR THERAPY (PRINT)
Editorial:
NATURE PUBLISHING GROUP
Referencias:
Año: 2009 vol. 17 p. 1355 - 1364
ISSN:
1525-0016
Resumen:
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