title: Antitumor Effect of IP-10 by Using Two Different Approaches: Live Delivery System and Gene Therapy.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biology, College of Basic Sciences, Damghan Branch, Islamic Azad University, Damghan, Iran.; Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Taslimi
authors.affiliation: Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Farnaz
authors.initials: F
authors.lastname: Zahedifard
authors.affiliation: Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Sima
authors.initials: S
authors.lastname: Habibzadeh
authors.affiliation: Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Tahereh
authors.initials: T
authors.lastname: Taheri
authors.affiliation: Department of Biology, College of Basic Sciences, Damghan Branch, Islamic Azad University, Damghan, Iran.
authors.forename: Hossain
authors.initials: H
authors.lastname: Abbaspour
authors.affiliation: Department of Pathology, Hazrat-e-Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Sadeghipour
authors.affiliation: Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Elham
authors.initials: E
authors.lastname: Mohit
authors.affiliation: Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Sima
authors.initials: S
authors.lastname: Rafati
keywords: Breast neoplasms; Chemokine CXCL10; Gene therapy; Immunotherapy