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Updated: Jun 24, 2026
A Human Peripheral Blood Mononuclear Cell (PBMC) Engrafted Humanized Xenograft Model for Translational Immuno-oncology (I-O) Research
Published on: August 15, 2019
Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs
Rebecca G Bagley1, Stephanie Roth, Leslie S Kurtzberg
1Genzyme Corporation, Framingham, MA 01701, USA. rebecca.bagley@genzyme.com
Abstract:
Nucleoside analogs are rationally designed anticancer agents that disrupt DNA and RNA synthesis. Fludarabine and cladribine have important roles in the treatment of hematologic malignancies. Clofarabine is a next generation nucleoside analog which is under clinical investigation. The bone marrow toxicity, tumor cell cytotoxicity and human tumor xenograft activity of fludarabine, cladribine and clofarabine were compared. Mouse and human bone marrow were subjected to colony forming (CFU-GM) assays over a 5-log concentration range in culture. NCI-60 cell line screening data were compared. In vivo, a range of clofarabine doses was compared with fludarabine for efficacy in several human tumor xenografts. The IC90 concentrations for fludarabine and cladribine for mouse CFU-GM were >30 and 0.93 microM, and for human CFU-GM were 8 and 0.11 microM, giving mouse to human differentials of >3.8- and 8.5-fold. Clofarabine produced IC90s of 1.7 microM in mouse and 0.51 microM in human CFU-GM, thus a 3.3-fold differential between species. In the NCI-60 cell line screen, fludarabine and cladribine showed selective cytotoxicity toward leukemia cell lines while for clofarabine there was no apparent selectivity based upon origin of the tumor cells. In vivo, clofarabine produced a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI-8226 multiple myeloma, and HT-29 colon carcinoma models. The PC3 prostate carcinoma was equally responsive to clofarabine and fludarabine. Bringing together bone marrow toxicity data, tumor cell line cytotoxicity data, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.
Insights
Clofarabine, a novel nucleoside analog, shows promising anticancer activity with manageable bone marrow toxicity compared to fludarabine and cladribine. This research aids in translating preclinical findings for hematologic malignancies and solid tumors to clinical applications.
Area of Science:
- Pharmacology and Toxicology
- Oncology
- Drug Development
Background:
- Nucleoside analogs are key anticancer agents disrupting DNA/RNA synthesis.
- Fludarabine and cladribine are established treatments for hematologic malignancies.
- Clofarabine represents a next-generation nucleoside analog under clinical investigation.
Purpose of the Study:
- To compare the bone marrow toxicity, tumor cell cytotoxicity, and in vivo efficacy of clofarabine against fludarabine and cladribine.
- To evaluate the translational potential of preclinical data for clofarabine in cancer treatment.
Main Methods:
- Colony-forming unit-granulocyte-macrophage (CFU-GM) assays were used to assess bone marrow toxicity in mouse and human samples.
- NCI-60 cell line screening data were analyzed for tumor cell cytotoxicity.
- In vivo efficacy was evaluated using human tumor xenografts treated with clofarabine and fludarabine.
Main Results:
- Clofarabine demonstrated a lower mouse-to-human bone marrow toxicity differential (3.3-fold) compared to fludarabine (>3.8-fold) and cladribine (8.5-fold).
- Fludarabine and cladribine showed selective cytotoxicity for leukemia cell lines, while clofarabine exhibited broader cytotoxicity across tumor types.
- Clofarabine demonstrated dose-dependent tumor growth delay in lymphoma, multiple myeloma, and colon carcinoma xenografts, with efficacy comparable to fludarabine in prostate cancer models.
Conclusions:
- Clofarabine presents a favorable preclinical profile with broad-spectrum anti-tumor activity and reduced species-specific bone marrow toxicity.
- The integrated analysis of toxicity, cytotoxicity, and xenograft data supports clofarabine's clinical translation for various cancers.
- Clofarabine's distinct activity profile warrants further clinical investigation in hematologic malignancies and solid tumors.
