Humanized bone marrow mouse model as a preclinical tool to assess therapy-mediated hematotoxicity
Open accessAbstract
PURPOSE: Preclinical in vivo studies can help guide the selection of agents and regimens for clinical testing. However, one of the challenges in screening anticancer therapies is the assessment of off-target human toxicity. There is a need for in vivo models that can simulate efficacy and toxicities of promising therapeutic regimens. For example, hematopoietic cells of human origin are particularly sensitive to a variety of chemotherapeutic regimens, but in vivo models to assess potential toxicities have not been developed. In this study, a xenograft model containing humanized bone marrow is utilized as an in vivo assay to monitor hematotoxicity. EXPERIMENTAL DESIGN: A proof-of-concept, temozolomide-based regimen was developed that inhibits tumor xenograft growth. This regimen was selected for testing because it has been previously shown to cause myelosuppression in mice and humans. The dose-intensive regimen was administered to NOD.Cg-Prkdc(scid)IL2rg(tm1Wjl)/Sz (NOD/SCID/γchain(null)), reconstituted with human hematopoietic cells, and the impact of treatment on human hematopoiesis was evaluated. RESULTS: The dose-intensive regimen resulted in significant decreases in growth of human glioblastoma xenografts. When this regimen was administered to mice containing humanized bone marrow, flow cytometric analyses indicated that the human bone marrow cells were significantly more sensitive to treatment than the murine bone marrow cells and that the regimen was highly toxic to human-derived hematopoietic cells of all lineages (progenitor, lymphoid, and myeloid). CONCLUSIONS: The humanized bone marrow xenograft model described has the potential to be used as a platform for monitoring the impact of anticancer therapies on human hematopoiesis and could lead to subsequent refinement of therapies prior to clinical evaluation.
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Toxicity data in mice should be interpreted with caution because murine and human bone marrow differ in sensitivity to oncolytics.
“Toxicity data in mice should be interpreted with caution because differential sensitivity to oncolytics between murine and human bone marrow has been reported.7,15”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [7]
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- Authors
- Cai, S., Wang, H., Bailey, B., Ernstberger, A., Juliar, B. E., Sinn, A. L., Chan, R. J., Jones, D. R., Mayo, L. D., Baluyut, A. R., Goebel, W. S., & Pollok, K. E.
- Affiliations
- St Vincent Hospital (US)
- Corresponding author
- Pollok, Karen E
- Venue
- Clinical Cancer Research
- Published
- 2011-04-14
- Volume
- 17
- Issue
- 8
- Pages
- 2195-2206
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3078977
- OpenAlex
- W2037911087
- Cited by
- 32
- References
- 50
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 1 · 2020: 2 · 2019: 1 · 2017: 3 · 2016: 1 · 2015: 5 · 2014: 3 · 2013: 5 · 2012: 4
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (KO8 HL75253, K08HL075253)
- National Cancer Institute (R01CA138798)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- hematologic toxicity, temozolomide, myelosuppression, glioblastoma xenografts, human hematopoiesis, off-target toxicity
- MeSH terms
- Temozolomide, Animals, Antineoplastic Combined Chemotherapy Protocols, Bone Marrow, Bone Marrow Cells, Dacarbazine, Dose-Response Relationship, Drug, Female, Glioblastoma, Guanine, Humans, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Survival Analysis, Mice, SCID, Mice, Inbred NOD, Treatment Outcome, Transplantation Chimera, Mice, Knockout, Xenograft Model Antitumor Assays, Cord Blood Stem Cell Transplantation, Cell Line, Tumor, Tumor Burden, Mice
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