Improved chemotherapy modeling with RAG-based immune deficient mice


Autoři: Mark Wunderlich aff001;  Nicole Manning aff001;  Christina Sexton aff001;  Anthony Sabulski aff002;  Luke Byerly aff002;  Eric O’Brien aff002;  John P. Perentesis aff002;  Benjamin Mizukawa aff002;  James C. Mulloy aff001
Působiště autorů: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Disease Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America aff001;  Division of Hematology and Oncology, Cancer and Blood Disease Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225532

Souhrn

We have previously characterized an acute myeloid leukemia (AML) chemotherapy model for SCID-based immune deficient mice (NSG and NSGS), consisting of 5 days of cytarabine (AraC) and 3 days of anthracycline (doxorubicin), to simulate the standard 7+3 chemotherapy regimen many AML patients receive. While this model remains tractable, there are several limitations, presumably due to the constitutional Pkrdcscid (SCID, severe combined immune deficiency) mutation which affects DNA repair in all tissues of the mouse. These include the inability to combine preconditioning with subsequent chemotherapy, the inability to repeat chemotherapy cycles, and the increased sensitivity of the host hematopoietic cells to genotoxic stress. Here we attempt to address these drawbacks through the use of alternative strains with RAG-based immune deficiency (NRG and NRGS). We find that RAG-based mice tolerate a busulfan preconditioning regimen in combination with either AML or 4-drug acute lymphoid leukemia (ALL) chemotherapy, expanding the number of samples that can be studied. RAG-based mice also tolerate multiple cycles of therapy, thereby allowing for more aggressive, realistic modeling. Furthermore, standard AML therapy in RAG mice was 3.8-fold more specific for AML cells, relative to SCID mice, demonstrating an improved therapeutic window for genotoxic agents. We conclude that RAG-based mice should be the new standard for preclinical evaluation of therapeutic strategies involving genotoxic agents.

Klíčová slova:

Acute myeloid leukemia – Cancer chemotherapy – Cancer treatment – Chemotherapy – Leukemias – Mouse models – Toxicity – High-dose chemotherapy


Zdroje

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