Effects of Genetically Engineered Stem Cells Expressing Cytosine Deaminase and Interferon-Beta or Carboxyl Esterase on the Growth of LNCaP Prostate Cancer Cells

International Journal of Oncology

Choi

2015

Self Cite

Abstract. Endometrial cancer is the most common gynecologic malignancy in women worldwide. In the present study, we evaluated the effects of neural stem cell-directed enzyme/prodrug therapy (NDEPT) designed to more selectively target endometrial cancer. For this, we employed two different types of neural stem cells (NSCs), HB1.F3.CD and HB1.F3.CD.IFN-β cells. Cytosine deaminase (CD) can convert the non-toxic prodrug, 5-fluorocytosine (5-FC), into a toxic agent, 5-fluorouracil (5-FU), which inhibits DNA synthesis. IFN-β is a powerful cytotoxic cytokine that is released by activated immune cells or lymphocytes. In an animal model xenografted with endometrial Ishikawa cancer cells, the stem cells stained with CM-DiI were injected into nearby tumor masses and 5-FC was delivered by intraperitoneal injection. Co-expression of CD and IFN-β significantly inhibited the growth of cancer (~50-60%) in the presence of 5-FC. Among migration-induced factors, VEGF gene was highly expressed in endometrial cancer cells. Histological analysis showed that the aggressive nature of cancer was inhibited by 5-FC in the mice treated with the therapeutic stem cells. Furthermore, PCNA expression was more decreased in HB1.F3.CD.IFN-β treated mice rather than HB1.F3.CD treated mice. To confirm the in vitro combined effects of 5-FU and IFN-β, 5-FU was treated in Ishikawa cells. 5-FU increased the IFN-β/receptor 2 (IFNAR2) and BXA levels, indicating that 5-FU increased sensitivity of endometrial cancer cells to IFN-β, leading to apoptosis of cancer cells. Taken together, these results provide evidence for the efficacy of therapeutic stem cell-based immune therapy involving the targeted expression of CD and IFN-β genes at endometrial cancer sites.

Section: Discussionmentioning

confidence: 53%

Additional effects of engineered stem cells expressing a therapeutic gene and interferon-β in a xenograft mouse model of endometrial cancer

International Journal of Oncology

Choi

2015

Self Cite

“…Two types of NSCs, HB1.F3.CD and HB1.F3.CD.IFN-β cells, may represent a novel approach for treating invasive tumors due to their inherent migratory and tumor-tropic properties as well as transgene expression (69)(70)(71). Since no effective treatments are available for most metastatic tumors, stem/progenitor cells expressing a suicide gene (CD) and cytokine (IFN-β) have the potential to improve the prognosis of patients with metastatic cancer (70).…”

Section: Other Origins Of Stem Cellsmentioning

confidence: 99%

Gene therapy strategies using engineered stem cells for treating gynecologic and breast cancer patients (Review)

Hwang

et al. 2015

Oncology Reports

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There are three types of stem cells: embryonic stem (ES) cells, adult stem (AS) cells and induced pluripotent stem (iPS) cells. These stem cells have many benefits including the potential ability to differentiate into various organs. In addition, engineered stem cells (GESTECs) designed for delivering therapeutic genes may be capable of treating human diseases including malignant cancers. Stem cells have been found to possess the potential for serving as novel delivery vehicles for therapeutic or suicide genes to primary or metastatic cancer formation sites as a part of gene-directed enzyme/prodrug combination therapy (GEPT). Given the advantageous properties of stem cells, tissue-derived stem cells are emerging as a new tool for anticancer therapy combined with prodrugs. In this review, the effects of GESTECs with different origins, i.e., neural, amniotic membrane and amniotic fluid, introduced to treat patients with diverse types of gynecologic and breast cancers are discussed. Data from the literature indicate the therapeutic potential of these cells as a part of gene therapy strategies to selectively target malignancies in women at clinically terminal stages.

“…Among these agents, genetic modification to overexpress interferon β was used in two preclinical trials (Table 1) [46, 52]. A significant increase in the natural kill cell activity was observed following IFN- β therapy correlating with the antitumor effect in prostate cancer model.…”

Section: Stem Cell Therapy Of Other Therapeutic Agentsmentioning

confidence: 99%

Stem Cell Based Gene Therapy in Prostate Cancer

BioMed Research International

Lee

Song

2014

Current prostate cancer treatment, especially hormone refractory cancer, may create profound iatrogenic outcomes because of the adverse effects of cytotoxic agents. Suicide gene therapy has been investigated for the substitute modality for current chemotherapy because it enables the treatment targeting the cancer cells. However the classic suicide gene therapy has several profound side effects, including immune-compromised due to viral vector. Recently, stem cells have been regarded as a new upgraded cellular vehicle or vector because of its homing effects. Suicide gene therapy using genetically engineered mesenchymal stem cells or neural stem cells has the advantage of being safe, because prodrug administration not only eliminates tumor cells but consequently kills the more resistant therapeutic stem cells as well. The attractiveness of prodrug cancer gene therapy by stem cells targeted to tumors lies in activating the prodrug directly within the tumor mass, thus avoiding systemic toxicity. Therapeutic achievements using stem cells in prostate cancer include the cytosine deaminase/5-fluorocytosine prodrug system, herpes simplex virus thymidine kinase/ganciclovir, carboxyl esterase/CPT11, and interferon-beta. The aim of this study is to review the stem cell therapy in prostate cancer including its proven mechanisms and also limitations.