J Breast Cancer.  2016 Mar;19(1):34-44. 10.4048/jbc.2016.19.1.34.

Antitumor Effect of IP-10 by Using Two Different Approaches: Live Delivery System and Gene Therapy

Affiliations
  • 1Department of Biology, College of Basic Sciences, Damghan Branch, Islamic Azad University, Damghan, Iran.
  • 2Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran. s_rafati@yahoo.com
  • 3Department of Pathology, Hazrat-e-Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran.
  • 4Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. el_mohit@yahoo.com, e.mohit@sbmu.ac.ir

Abstract

PURPOSE
Immunotherapy is one of the treatment strategies for breast cancer, the most common cancer in women worldwide. In this approach, the patient's immune system is stimulated to attack microscopic tumors and control metastasis. Here, we used interferon γ-induced protein 10 (IP-10), which induces and strengthens antitumor immunity, as an immunotherapeutic agent. We employed Leishmania tarentolae, a nonpathogenic lizard parasite that lacks the ability to persist in mammalian macrophages, was used as a live delivery system for carrying the immunotherapeutic agent. It has been already shown that arginase activity, and consequently, polyamine production, are associated with tumor progression.
METHODS
A live delivery system was constructed by stable transfection of pLEXSY plasmid containing the IP-10-enhanced green fluorescent protein (IP-10-egfp) fusion gene into L. tarentolae. Then, the presence of the IP-10-egfp gene and the accurate integration location into the parasite genome were confirmed. The therapeutic efficacy of IP-10 delivered via L. tarentolae and recombinant pcDNA-(IP-10-egfp) plasmid was compared by determining the arginase activity in a mouse 4T1 breast cancer model.
RESULTS
The pcDNA-(IP-10-egfp) group showed a significant reduction in tumor weight and growth. Histological evaluation also revealed that only this group demonstrated inhibition of metastasis to the lung tissue. The arginase activity in the tissue of the pcDNA-(IP-10-egfp) mice significantly decreased in comparison with that in normal mice. No significant difference was observed in arginase activity in the sera of mice receiving other therapeutic strategies.
CONCLUSION
Our data indicates that IP-10 immunotherapy is a promising strategy for breast cancer treatment, as shown in the 4T1-implanted BALB/c mouse model. However, the L. tarentolae-(IP-10-EGFP) live delivery system requires dose modifications to achieve efficacy in the applied regimen (six injections in 3 weeks). Our results indicate that the arginase assay could be a good biomarker to differentiate tumoral tissues from the normal ones.

Keyword

Breast neoplasms; Chemokine CXCL10; Gene therapy; Immunotherapy

MeSH Terms

Animals
Arginase
Breast Neoplasms
Chemokine CXCL10
Female
Genetic Therapy*
Genome
Humans
Immune System
Immunotherapy
Interferons
Leishmania
Lizards
Lung
Macrophages
Mice
Neoplasm Metastasis
Parasites
Plasmids
Transfection
Tumor Burden
Arginase
Chemokine CXCL10
Interferons
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