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Clin Cancer Res. 2009 Dec 1;15(23):7256-65. doi: 10.1158/1078-0432.CCR-09-1861. Epub 2009 Nov 17.

A novel synergistic combination of cyclophosphamide and gene transfer of interleukin-12 eradicates colorectal carcinoma in mice.

Author information

1
Gene Therapy Laboratory, Liver Unit, School of Medicine, Austral University, Buenos Aires, Argentina.

Abstract

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.

PMID:
19920110
DOI:
10.1158/1078-0432.CCR-09-1861
[Indexed for MEDLINE]
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