Abstract
BackgroundThere is an urgent need for targeted biological therapies for prostate cancer with greater efficacy and less toxicity, particularly for metastatic disease, where current therapies are not curative. Therapeutic adenoviral vectors or oncolytic adenoviruses offer the possibility of a competent, nontoxic therapeutic alternative for prostate cancer. However, free viral particles must be delivered locally, an approach that does not address metastatic disease, and they display poor tumor penetration. To fully exploit the potential of these vectors, we must develop methods that improve intratumoral dissemination and allow for systemic delivery. This study establishes a proof-of-principle rationale for a novel human mesenchymal stem (stromal) cell-based approach to improving vector delivery to tumors.Methods/resultsWe have generated mesenchymal stem cell-derived packaging cells for adenoviruses (E1-modified mesenchymal stem cells) by modifying human mesenchymal stem cells with the adenovirus (type C) E1A/B genes needed for viral replication. Using cell-based assays, we have demonstrated that two adenoviral vectors, replication-defective adenovirus expressing p14 and p53 or conditionally replicating oncolytic adenovirus, packaged by E1A/B-modified mesenchymal stem cells, suppress the growth of prostate cancer cells in culture. Using subcutaneous xenograft models for human prostate cancer in mice, we have shown that E1A/B-modified mesenchymal stem cells display tumor tropism in tumor-bearing nude mice, that E1A/B-modified mesenchymal stem cells disseminate well within tumors, and that replication-defective adenovirus expressing p14 and p53 or conditionally replicating oncolytic adenovirus-loaded E1-modified mesenchymal stem cells suppresses tumor growth in mice.ConclusionThe results show that this approach, if optimized, could circumvent the obstacles to efficient gene delivery encountered with current gene delivery approaches and provide an effective, nontoxic therapeutic alternative for metastatic disease.
Highlights
Prostate tumors are the second leading tumors in men globally [1, 2], with about 1.6 million new cases registered in 2015 [3]
The results show that this approach, if optimized, could circumvent the obstacles to efficient gene delivery encountered with current gene delivery approaches and provide an effective, nontoxic therapeutic alternative for metastatic disease
Antitumor activity of Conditionally replicating adenovirus (CRAd) and Replication-defective adenovirus expressing p14 and p53 (Adbic) adenoviral vectors in vitro We evaluated the in vitro antitumor activity of adenoviral vectors, 48 h after the treatment of C4–2 and LNCaP cells with CRAd and Adbic adenoviral vectors at 50 and 100 multiplicity of infection (MOI)
Summary
Prostate tumors are the second leading tumors in men globally [1, 2], with about 1.6 million new cases registered in 2015 [3]. Muhammad et al Stem Cell Research & Therapy (2019) 10:190 to tumor site as well as selective expression of therapeutic genes on tumor sites. Both considered as important mechanisms for successful gene therapy [8]. For systemic delivery of therapeutic genes to tumor sites, a variety of viral, synthetic, and cell-based vectors have engineered, but most have shown low practical efficiency [12]. The development of new approaches is urgently required to transfer therapeutic genes selectively to tumor sites, to disseminate the therapeutic vectors into the tumors and to address the metastatic condition of disease while avoiding the adverse effects to healthy cells. This study establishes a proof-ofprinciple rationale for a novel human mesenchymal stem (stromal) cell-based approach to improving vector delivery to tumors
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