INVESTIGADORES
MAZZOLINI RIZZO Guillermo Daniel
artículos
Título:
A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice
Autor/es:
MALVICINI M, RIZZO M, ALANIZ L, PINERO F, GARCIA M, ATORRASAGASTI C, AQUINO JB, ROZADOS V, SCHAROVSKY OG, MATAR P, MAZZOLINI G
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.
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.
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
with an intratumoral injection of AdIL-12 was evaluated in an in vivo
The antitumor effect of combining a single low dose of cyclophosphamide
with an intratumoral injection of AdIL-12 was evaluated in an in vivoin 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-
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-
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-
ã-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.
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.
-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.
and AdIL-12 as a novel therapeutic strategy against colorectal carcinoma.
Our data strongly support the use of a combination of cyclophosphamide
and AdIL-12 as a novel therapeutic strategy against colorectal carcinoma.