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Updated: Aug 14, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Stem Cell-Delivered Cytosine Deaminase/5-Fluorocytosine and TRAIL Gene Therapy for Castration-Resistant Prostate
Jae Heon Kim1, Miho Song1, Kisoo Lee2
1Department of Urology, Soonchunhyang University School of Medicine, Seoul 04401, Republic of Korea.
Abstract:
Castration-resistant prostate cancer (CRPC) is characterised by persistent androgen receptor (AR)-axis activity, therapy-driven resistance, and limited durability of available systemic treatments. Tumour-tropic mesenchymal stem/stromal cells (MSCs), including adipose-derived MSCs (ADSCs), have emerged as promising vehicles for targeted gene therapeutics. This review synthesises our three experimental studies examining stem cell-delivered gene-directed enzyme prodrug therapy (GDEPT) using cytosine deaminase (CD)/5-fluorocytosine (5-FC) and secreted TRAIL in CRPC xenograft models. We performed a comparative analysis of three studies in which hTERT-immortalised human ADSCs were engineered via lentiviral vectors to deliver CD alone, secreted TRAIL alone, or CD+TRAIL in combination, and were administered by intracardiac injection into male nude mice bearing PC3 xenografts. In vitro conversion efficiency, cell viability, apoptosis markers, and in vivo tumour volume endpoints were compared across studies. All three therapeutic platforms demonstrated measurable tumour growth inhibition relative to controls. The CD+TRAIL combination achieved the greatest in vivo efficacy (tumours approximately 26% of control at day 14), compared with CD alone (approximately 71%) or TRAIL paired with irinotecan. Enzymatic conversion of 5-FC to 5-FU exceeded 93% in conditioned medium. Primary translational risks include thrombotic events associated with systemic MSC dosing, tumourigenicity and genotoxicity of hTERT-immortalised, integrating-vector-engineered cells, immunogenicity of xenogeneic CD enzyme, and systemic 5-fluorouracil leakage from flucytosine metabolism. Stem cell-delivered CD/5-FC and TRAIL constitutes a biologically rational, modular strategy for local cytotoxicity and resistance circumvention in CRPC. Successful clinical translation will require resolution of delivery-route feasibility, thrombosis risk mitigation, and a rigorous investigational new drug (IND)-enabling safety package.
Insights
Mesenchymal stem cells engineered to deliver gene-directed enzyme prodrug therapy (GDEPT) show promise for castration-resistant prostate cancer (CRPC). The combination of cytosine deaminase (CD) and TRAIL demonstrated significant tumor growth inhibition in preclinical models.
Area of Science:
- Oncology
- Gene Therapy
- Stem Cell Biology
Background:
- Castration-resistant prostate cancer (CRPC) presents challenges due to persistent androgen receptor (AR)-axis activity and treatment resistance.
- Mesenchymal stem/stromal cells (MSCs), including adipose-derived MSCs (ADSCs), are being explored as delivery vehicles for targeted gene therapeutics.
- Gene-directed enzyme prodrug therapy (GDEPT) offers a strategy to enhance localized drug delivery and overcome resistance.
Purpose of the Study:
- To evaluate the efficacy of stem cell-delivered gene-directed enzyme prodrug therapy (GDEPT) using cytosine deaminase (CD)/5-fluorocytosine (5-FC) and secreted TRAIL in preclinical models of CRPC.
- To compare the therapeutic effects of CD alone, secreted TRAIL alone, and a combination of CD and TRAIL delivered by engineered ADSCs.
- To assess in vitro and in vivo parameters, including enzymatic conversion efficiency, cell viability, apoptosis, and tumor volume reduction.
Main Methods:
- Human ADSCs were engineered using lentiviral vectors to express CD, secreted TRAIL, or both.
- Engineered ADSCs were administered via intracardiac injection into male nude mice bearing CRPC (PC3) xenografts.
- Comparative analysis of in vitro conversion efficiency, cell viability, apoptosis markers, and in vivo tumor growth inhibition was performed across the three therapeutic strategies.
Main Results:
- All three therapeutic platforms (CD alone, TRAIL alone, CD+TRAIL) demonstrated significant tumor growth inhibition compared to controls.
- The combination of CD and TRAIL delivered by ADSCs achieved the greatest in vivo efficacy, reducing tumor volume to approximately 26% of control at day 14.
- Enzymatic conversion of 5-FC to 5-FU exceeded 93% in conditioned medium, indicating efficient prodrug activation.
Conclusions:
- Stem cell-delivered CD/5-FC and TRAIL represents a biologically rational and modular strategy for inducing local cytotoxicity and overcoming resistance in CRPC.
- The combination therapy shows superior efficacy in preclinical models, highlighting its potential for CRPC treatment.
- Further research is needed to address translational challenges, including delivery route optimization, mitigation of thrombotic risks, and comprehensive safety assessments for clinical application.
