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A retroviral replicating vector (RRV) was developed to infect and replicate selectively in cancer cells, synchronizing killing after prodrug administration. 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Targeted Suicide Gene Therapy with Retroviral Replicating Vectors for Experimental Canine Cancers. Int. J. Mol. Sci. 2024, 25, 2657. [https://](https://)  \n[doi.org/10.3390/ijms25052657](doi.org/10.3390/ijms25052657)[ ](doi.org/10.3390/ijms25052657)Academic Editor: Aleksandra Klimczak  \nReceived: 2 February 2024  \nRevised: 17 February 2024  \nAccepted: 22 February 2024  \nPublished: 24 February 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Laboratory of Molecular and Genetic Therapeutics, Institute of Advanced Medical Science, Hyogo Medical University, Nishinomiya 663-8501, Japan  \n2 Departments of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, Sanda 669-1330, Japan  \n3 Laboratory of Veterinary Radiology, Graduate School of Veterinary Science, Osaka Metropolitan University, Izumisano 598-8531, Japan  \n4 Laboratory of Functional Molecular Chemistry, Kobe Pharmaceutical University, Kobe 658-8558, Japan  \n5 Departments of Neurological Surgery and Radiation Oncology, University of California, San Francisco, CA 94143, USA  \n* Correspondence: [s-kubo@hyo-med.ac.jp](s-kubo@hyo-med.ac.jp); Tel.: +81-798-45-6844  \nAbstract: Cancer in dogs has increased in recent years and is a leading cause of death. We have developed a retroviral replicating vector (RRV) that specifically targets cancer cells for infection and replication. RRV carrying a suicide gene induced synchronized killing of cancer cells when administered with a prodrug after infection. In this study, we evaluated two distinct RRVs derived from amphotropic murine leukemia virus (AMLV) and gibbon ape leukemia virus (GALV) in canine tumor models both in vitro and in vivo. Despite low infection rates in normal canine cells, both RRVs efficiently infected and replicated within all the canine tumor cells tested. The efficient intratumoral spread of the RRVs after their intratumoral injection was also demonstrated in nude mouse models of subcutaneous canine tumor xenografts. When both RRVs encoded a yeast cytosine deaminase suicide gene, which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil, they caused tumor-cell-specific 5-FC-induced killing of the canine tumor cells in vitro. Furthermore, in the AZACF-and AZACH-cell subcutaneous tumor xenograft models, both RRVs exerted significant antitumor effects. These results suggest that RRV-mediated suicide gene therapy is a novel therapeutic approach to canine cancers.  \nKeywords: canine cancer; retroviral replicating vectors; suicide gene therapy  \n1. Introduction  \nIn recent years, the life expectancy of dogs has increased and cancer is becoming more common. Canine cancer is now a major cause of death in dogs, accounting for approximately one-third to half of all deaths in older dogs [1–3] . The current first-line treatment for canine cancer is surgery, followed by chemotherapy, radiation therapy, and immunotherapy, including immune checkpoint inhibitors [1,3] . However, there are still several concerns in treating canine cancers, including the lack of experience in treating dogs compared with humans, the diversity of dog breeds, and the limited medical facilities available for dogs. Therefore, the development of effective treatment methods for canine cancers is required.  \nOncolytic virotherapy has been attra","cbCailZrxGmBFTQW","https://ap.wps.com/l/cbCailZrxGmBFTQW","pdf",2578528,11,"English","# Abstract\n# Introduction\n## Background on canine cancer and current treatments\n## Oncolytic virotherapy and related challenges\n## Rationale for retroviral replicating vectors","[{\"question\":\"What therapeutic strategy is evaluated in this study?\",\"answer\":\"The study evaluates retroviral replicating vectors (RRVs) carrying a suicide gene that enables tumor-cell-specific killing after prodrug administration.\"},{\"question\":\"How are the RVVs tested across experimental conditions?\",\"answer\":\"Two RRVs derived from AMLV and GALV are evaluated in canine tumor models in vitro and in vivo, including intratumoral injection and xenograft models.\"},{\"question\":\"Why do the RRVs show tumor-specific effects with the prodrug?\",\"answer\":\"When encoding yeast cytosine deaminase, the RRVs convert the prodrug 5-fluorocytosine into the active drug 5-fluorouracil, leading to tumor-cell-specific 5-FC-induced killing.\"}]","Targeted Suicide Gene Therapy with Retroviral Replicating Vectors for Experimental Canine Cancers - Research Overview | PDF",1790019647,28]