306 ANTITUMOR EFFECT OF ENDOMETRIAL CANCER MASS WAS INDUCED BY THERAPEUTIC STEM CELLS FUSED CYTOSINE DEAMINASE AND INTERFERON-BETA IN A NUDE MOUSE MODEL

Abstract

Endometrial cancer has been reported as the most common malignancy, accounting for ~50% of the uterine tumour cases in the Western world. An exact mechanism underlying the development of this type of cancer is unclear. In our previous study, we confirmed the therapeutic efficacy of stem cells expressing bacterial cytosine deaminase (CD) and/or human interferon-β (IFN-b) gene against endometrial Ishikawa cells in an in vitro model. The CD gene can convert a nontoxic prodrug, 5-fluorocytosine (5-FC), to the toxic agent, 5-fluorouracil (5-FU), and IFN-b is a powerful cytokine that has antiviral effects. In this study, we generated xenografted mice baring Ishikawa endometrial cancer cells and confirmed the therapeutic efficacy of these stem cells. For generation of an animal model of endometrial cancer, Ishikawa cells (2 × 10⁶ cells/mouse) were implanted subcutaneously in severe combined immunodeficiency (SCID) mice. Next, the stem cells stained CM-DiI as red fluorescence were injected into nearby tumour mass and, 1 day after stem cell injection, 5-FC (500 mg kg^–1 per day) was adminstered through an intraperitoneal injection per day for 14 days. Two days after final injection of the prodrug, we killed these mice and extracted the endometrial tumour mass. Tumour volumes reached 1400 and 450 mm³ in control mice and mice injected with stem cells, respectively, and fused gene expression of CD and/or IFN-b significantly inhibited the growth of endometrial cancer mass in the presence of 5-FC (~50 to 60%). In addition, we confirmed the migratory effect of the stem cells using a fluorescent analysis; red-stained HB1.F3.CD and HB1.F3.CD.IFN-b cells were found in the extracted endometrial cancer mass. A histological analysis of tumour mass showed that the aggressive property of endometrial cancer was inhibited in the presence of a prodrug in mice treated with therapeutic stem cells. Taken together, these results provide evidence for the usefulness of therapeutic stem cell-based gene therapy through a targeted delivery of therapeutic gene products to endometrial cancer sites.

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST) of Korea government (no. 2010-0003093).