Abstract B14: Injection of therapeutic stem cells expressing cytosine deaminase and interferon-beta resulted in the inhibition of K562 human chronic myeloid leukemia cells in a xenograft model

Abstract

Abstract Gene-directed enzyme/prodrug therapies have been found to be more advantageous compared to conventional cancer treatment method. One of these, a cytosine deaminase (CD)/5-fluorocytosine (5-FC) system, is known to induce apoptosis of cancer cells by converting 5-FC, a prodrug, to its metabolically active form, 5-fluorouracil. In this study, human neural stem cells (hNSCs) derived enzyme/prodrug therapy was used to treat leukemia. The parental hNSCs, HB1.F3, were engineered to express E. coli CD and/or human interferon-β. To manufacture animal models xenografted with leukemia, K-562 cells (1×106) were mixed with Matrigel (BD Biosciences, Bedford, MA, USA) at 1:1 volume ratio of Matrigel to PBS in 100 μl and injected subcutaneously (s.c.) into the back of athymic nude mice. This animal study was performed for 24 days after hNSCs injections. When tumor volume reached 500 mm3, CM-Dil pre-labeled hNSCs (4 x 106 cells per mouse) were injected subcutaneously adjacent to the tumor mass. Another group, CM-dil pre-labeled hNSCs (4 x 106 cells per mouse) was injected intravenously. hNSCs were injected on the first day of each week. Two days after the injection of hNSCs, all mice received i.p. injections of 5-FC (500 mg/kg/day in 100 μl PBS) every day for 24 days. At 24 h after the last 5-FC treatment, the mice were euthanized and tumor masses were harvested for molecular analysis. In a xenografted mouse model administered with hNSCs intravenously or subcutaneously, hNSC significantly inhibits the growth of tumor mass and extends survival date in the presence of a prodrug. In addition, HB1.F3.CD.IFN-β treatment group showed more antitumor effect compared with HB1.F3.CD treatment group, indicating that IFN- β may have a synergistic effect for directly killing leukemia tumors. The present results represent that engineered hNSCs and prodrug treatment inhibited the proliferation of leukemia. These results suggest that gene therapy employing genetically engineered stem cells expressing CD and IFN-β may be effective for treating leukemia. Note: This abstract was not presented at the conference. Citation Format: Geon-Tae Park, Kyung-Chul Choi. Injection of therapeutic stem cells expressing cytosine deaminase and interferon-beta resulted in the inhibition of K562 human chronic myeloid leukemia cells in a xenograft model [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B14.