Influence of the prodrugs 5‐fluorocytosine and CPT‐11 on ovarian cancer cells using genetically engineered stem cells: tumor‐tropic potential and inhibition of ovarian cancer cell growth

Abstract

Recent studies have shown that genetically engineered stem cells (GESTECs) to produce suicide enzymes that convert non-toxic prodrugs to toxic metabolites selectively migrate toward tumor sites and reduce tumor growth. In the present study, we evaluated whether these GESTECs were capable of migrating to human ovarian cancer cells and examined the potential therapeutic efficacy of the gene-directed enzyme prodrug therapy against ovarian cancer cells in vitro. The expression of cytosine deaminase (CD) or carboxyl esterase (CE) mRNA of GESTECs was confirmed by RT-PCR. A modified transwell migration assay was performed to determine the migratory capacity of GESTECs to ovarian cancer cells. GESTECs O varian malignancies have a significant impact upon women's health, but the mechanism(s) of the transformation of health cells into cancerous cells and the development of these lethal cancers remain unclear. In order to enhance the effectiveness of therapeutics for treating ovarian cancers, novel strategies are required.(1,2)

Tumor-specific gene therapy for pancreatic cancer using human neural stem cells encoding carboxylesterase

“…In turn, SN-38 preferentially kills dividing cancer cells specifically at the tumor sites [30]. We have previously reported that F3.CE cells migrate selectively to tumor sites and they have a therapeutic effect on disseminated neuroblastoma [26, 30], melanoma [28], ovarian cancer [19], breast cancer brain metastasis [17] and medulloblastoma [29] upon administration of prodrug CPT-11. Recently we also have reported that the NSCs expressing the cytosine deaminase (CD).…”

“…Previously we have adopted CE/CPT-11 enzyme/prodrug gene therapy approach for treatment of gliomas and disseminated neurobastoma animal models [19, 26–30] involving the conversion of a prodrug CPT-11 into SN-38 [30, 34]. CPT-11 (Irinotecan) is known to induce severe toxicities (diarrhea, neutropenia) that limit its clinical use [34].…”

“…There was significant inhibition of cancer growth in cancer bearing animals. We established the proof of concept that various cancers including brain tumors and other solid cancers can be effectively targeted using this approach [19, 26–30]. In the present study, we evaluated the therapeutic efficacy of F3 human NSCs encoding carboxylesterase administered in combination with prodrug CPT-11 to nude mice bearing pancreatic cancer.…”

Stem cell-based therapies for cancer treatment: separating hope from hype

“…The HSV-tk system, which relies on the formation of gap junctions between the SC and surrounding target cells for an efficient bystander effect, has shown efficacy in several animal models of cancer, including glioblastoma 55,56 , breast 14 and prostate 57 . Human NSCs harnessing the CE–irinotecan system have proved to be effective in preclinical models of ovarian and lung cancer, as well as medulloblastoma 58–60 .…”

Engineering Stem Cells for Biomedical Applications

“…[286] For instance, Kim et al engineered immortalized HB1.F3 NSCs to express CE using a retroviral vector to enhance the treatment of ovarian cancer. [283,287] In this study, the authors reported that the engineered NSCs retained their ability to migrate to ovarian tumors and greatly inhibited cancer cell proliferation. Interestingly, the authors compared engineered stem cells using the CD-5-FC system to engineered NSCs expressing CE for the CE-CPT-11 system and found that the CE approach seems to be more promising than the CD approach because the CE approach decreased proliferation with a lower engineered NSC cell number and at a lower concentration of CPT-11 when compared to the concentration of cells and prodrug needed for the CD approach.…”