A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice
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 tumo...
| Autores principales: | , , , , , , , , , , |
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| Formato: | article artículo publishedVersion |
| Lenguaje: | Inglés |
| Publicado: |
American Association for Cancer Research
2012
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| Acceso en línea: | http://hdl.handle.net/2133/2009 http://hdl.handle.net/2133/2009 |
| Aporte de: |
| id |
I15-R121-2133-2009 |
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| record_format |
dspace |
| institution |
Universidad Nacional de Rosario |
| institution_str |
I-15 |
| repository_str |
R-121 |
| collection |
Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR) |
| language |
Inglés |
| orig_language_str_mv |
en |
| topic |
Combined immunotherapy Cyclophosphamide gene therapy Interleukin-12 Colorectal carcinoma |
| spellingShingle |
Combined immunotherapy Cyclophosphamide gene therapy Interleukin-12 Colorectal carcinoma Malvicini, Mariana Rizzo, Miguel Alaniz, Laura Piñero, Federico García, Mariana Atorrasagasti, Catalina Aquino, Jorge B. Rozados, Viviana R. Scharovsky, O. Graciela Matar, Pablo Mazzolini, Guillermo A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice |
| topic_facet |
Combined immunotherapy Cyclophosphamide gene therapy Interleukin-12 Colorectal carcinoma |
| description |
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:
The combined therapy induced a complete tumor regression in >50% of mice 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-gamma-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. |
| format |
article artículo publishedVersion |
| author |
Malvicini, Mariana Rizzo, Miguel Alaniz, Laura Piñero, Federico García, Mariana Atorrasagasti, Catalina Aquino, Jorge B. Rozados, Viviana R. Scharovsky, O. Graciela Matar, Pablo Mazzolini, Guillermo |
| author_facet |
Malvicini, Mariana Rizzo, Miguel Alaniz, Laura Piñero, Federico García, Mariana Atorrasagasti, Catalina Aquino, Jorge B. Rozados, Viviana R. Scharovsky, O. Graciela Matar, Pablo Mazzolini, Guillermo |
| author_sort |
Malvicini, Mariana |
| title |
A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice |
| title_short |
A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice |
| title_full |
A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice |
| title_fullStr |
A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice |
| title_full_unstemmed |
A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice |
| title_sort |
novel synergistic combination of cyclophosphamide and gene transfer of interleukin-12 eradicates colorectal carcinoma in mice |
| publisher |
American Association for Cancer Research |
| publishDate |
2012 |
| url |
http://hdl.handle.net/2133/2009 http://hdl.handle.net/2133/2009 |
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