INVESTIGADORES
ATORRASAGASTI FERNANDEZ Maria Catalina
artículos
Título:
A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice
Autor/es:
MARIANA MALVICINI; MIGUEL RIZZO; LAURA ALANIZ; FEDERICO PIÑERO; MARIANA GARCIA; CATALINA ATORRASAGASTI; JORGE B. AQUINO; VIVIANA ROZADOS; GRACIELA SCHAROVSKY; PABLO MATAR; GUILLERMO MAZZOLINI
Revista:
CLINICAL CANCER RESEARCH
Editorial:
AMER ASSOC CANCER RESEARCH
Referencias:
Año: 2009 p. 7256 - 7265
ISSN:
1078-0432
Resumen:
Purpose: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor
effects in several animal models. However, serious toxicity has been associated with its
systemic application in humans. Gene transfer has emerged as a tool to specifically
express therapeutic genes into the tumor/peritumoral milieu, thus avoiding systemic
toxicity. The aim of this study was to analyze whether subtherapeutic doses of an adenovirus
encoding IL-12 (AdIL-12) might synergize with low immunopotentiating doses
of cyclophosphamide in the treatment of colorectal carcinoma.
Experimental Design: The antitumor effect of combining a single low dose of cyclophosphamide
with an intratumoral injection of AdIL-12 was evaluated in an in vivo
murine colorectal carcinoma model. The immune responses achieved with different
treatments were monitored, comparing the effect of combining both therapies with
individual treatments.
Results: Thecombined therapy induced a complete tumor regression in >50%ofmice in a
synergistic fashion, and it significantly prolonged their survival. This strategy was superior
to each single treatment in reducing both peripheral and splenic CD4+CD25+Foxp3+
regulatory T cells, increasing the number of activated dendritic cells, and inducing IFN-
γ-secreting CD4-positive T lymphocytes. Importantly, the combined treatment generated
a powerful tumor-specific CTL response. Consistently, a significant reduction in IL-10
levels was found. Our data suggest that the combination of nontoxic doses of cyclophosphamide
with AdIL-12 allows the generation of good antitumoral responses, thus avoiding
undesired side effects of both agents.
Conclusions: Our data strongly support the use of a combination of cyclophosphamide
and AdIL-12 as a novel therapeutic strategy against colorectal carcinoma.