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Published on: September 18, 2013
Combination testing of cediranib (AZD2171) against childhood cancer models by the pediatric preclinical testing
Christopher L Morton1, John M Maris, Stephen T Keir
1St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Background:
Cediranib (AZD2171) is a potent small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors. Cediranib has demonstrated single agent activity in several adult cancers and is being studied in combination with standard cytotoxic agents in multiple disease settings.
Procedures:
Cediranib was tested in vivo against six childhood tumor xenograft models (four sarcomas, one glioblastoma, one neuroblastoma) alone or combined with cyclophosphamide (two models), vincristine (three models) or cisplatin (one model), each administered at its maximum tolerated dose, or rapamycin (six models).
Results:
The combination of cediranib with standard cytotoxic agents was superior to the cytotoxic agent used alone for a single xenograft (one of the three xenografts evaluated for the vincristine-cediranib combination). The cediranib-cyclophosphamide combination was inferior to single agent cyclophosphamide in time to event for both models studied and was significantly inferior for one of the models. Cediranib combined with rapamycin was superior to each of the agents used alone in two of the six models and was determined to be additive or supra-additive with rapamycin in four models, although the effects were not large.
Conclusions:
Cediranib combined with cytotoxic chemotherapy agents demonstrated little or no benefit (and in one case was significantly inferior) compared to chemotherapy alone for the six pediatric cancer xenografts studied. By contrast, the combination of cediranib with rapamycin was additive or supra-additive in four of the six models in terms of prolongation of time to event, though tumor regressions were not observed for this combination.
Insights
Cediranib combined with chemotherapy showed limited benefit in pediatric cancer models. However, combining cediranib with rapamycin demonstrated additive or supra-additive effects in several models, suggesting potential for pediatric cancer treatment.
Area of Science:
- Oncology
- Pharmacology
Background:
- Cediranib is a potent inhibitor of vascular endothelial growth factor (VEGF) receptors.
- It has shown activity in adult cancers and is being investigated in combination therapies.
Purpose of the Study:
- To evaluate the efficacy of cediranib in combination with cytotoxic agents and rapamycin in pediatric cancer xenograft models.
Main Methods:
- Cediranib was tested alone and in combination with cyclophosphamide, vincristine, cisplatin, or rapamycin in six pediatric tumor xenograft models.
- Maximum tolerated doses of agents were used.
Main Results:
- Cediranib plus cytotoxic agents showed minimal to no benefit, and was inferior in one case, compared to chemotherapy alone.
- Cediranib plus rapamycin showed additive or supra-additive effects in four of six models, but no tumor regressions were observed.
Conclusions:
- Combination of cediranib with cytotoxic chemotherapy offers little benefit in pediatric xenografts.
- Cediranib combined with rapamycin shows potential additive/supra-additive effects, warranting further investigation in pediatric cancers.
