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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 tubulin binding agents
Leslie S Kurtzberg1, Stephanie D Roth, Rebecca G Bagley
1Genzyme Corporation, Framingham, MA 01701, USA. Leslie.Kurtzberg@Genzyme.com
Purpose:
The dynamic instability of microtubules in cells is one of the key targets of anticancer therapeutics. Microtubule-disrupting agents such as vinca alkaloids and microtubule-stabilizing agents such as taxanes are important antitumor agents. The bone marrow toxicity and human tumor xenograft activity of three tubulin-binding compounds, vincristine, paclitaxel, and tasidotin were compared.
Methods:
Mouse and human bone marrow were subjected to colony-forming (CFU-GM) assays over a 5-log concentration range in culture. In vivo, a range of tasidotin doses was compared with vincristine, paclitaxel, and docetaxel for efficacy in several human tumor xenografts.
Results:
The IC(90) concentrations for vincristine and paclitaxel for mouse CFU-GM were 30 and 27 nM, and for human CFU-GM were 3 and 9 nM, giving mouse to human differentials of ten- and threefold. Tasidotin produced IC(90)s of >300 nM in mouse and 65 nM in human CFU-GM, thus a >4.6-fold differential between species. In vivo, tasidotin resulted in a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI 8226 multiple myeloma, and MX-1 breast carcinoma models. Vincristine and tasidotin were also very effective against these tumors. The PC-3 prostate carcinoma was very responsive to full-dose paclitaxel and docetaxel while tasidotin generated a dose dependent effect.
Conclusions:
Bringing together bone marrow toxicity data, pharmacokinetic parameters, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.
Insights
This study compared the anti-cancer effects of vincristine, paclitaxel, and tasidotin. Tasidotin showed promising results in human tumor models with manageable bone marrow toxicity, aiding clinical translation.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Microtubules are crucial targets for anticancer drugs.
- Vinca alkaloids and taxanes are established microtubule-targeting agents.
- Understanding drug toxicity and efficacy is vital for clinical application.
Purpose of the Study:
- To compare the bone marrow toxicity and in vivo efficacy of three tubulin-binding compounds: vincristine, paclitaxel, and tasidotin.
- To evaluate the translational potential of tasidotin based on preclinical data.
Main Methods:
- Colony-forming unit-granulocyte-macrophage (CFU-GM) assays were used to assess bone marrow toxicity in mouse and human samples.
- In vivo efficacy was evaluated using human tumor xenograft models, comparing tasidotin doses with vincristine, paclitaxel, and docetaxel.
Main Results:
- Tasidotin demonstrated a favorable >4.6-fold differential in toxicity between mouse and human bone marrow cells.
- Tasidotin showed dose-dependent tumor growth delay in lymphoma, multiple myeloma, and breast cancer xenografts.
- Vincristine and tasidotin were highly effective against tested tumors, while paclitaxel and docetaxel were effective against prostate cancer.
Conclusions:
- Integrating bone marrow toxicity, pharmacokinetics, and xenograft efficacy data is essential for translating preclinical findings to clinical settings.
- Tasidotin exhibits potential as an anticancer therapeutic with a manageable toxicity profile.
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