Related Experiment Video
Updated: Jul 15, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program
Peter J Houghton1, Christopher L Morton, E Anders Kolb
1St. Jude Children's Research Hospital, Memphis, Tennessee, USA. peter.houghton@stjude.org
Insights
Bortezomib showed activity against childhood acute lymphoblastic leukemia (ALL) preclinical models. Further research is needed to explore bortezomib combination therapies for pediatric ALL.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Cancer Research
Background:
- Bortezomib, a proteasome inhibitor, is FDA-approved for multiple myeloma.
- Phase 1 trials of bortezomib in children have been completed.
Purpose of the Study:
- To evaluate the antitumor activity of bortezomib.
- To test bortezomib against in vitro and in vivo preclinical models of childhood cancer.
Main Methods:
- Bortezomib was tested in vitro against the Pediatric Preclinical Testing Program (PPTP) panel.
- In vivo testing involved a dose of 1 mg/kg for 6 weeks.
Main Results:
- Bortezomib exhibited uniform in vitro activity with a median IC50 of 23 nM.
- Activity was notable against acute lymphoblastic leukemia (ALL) cell lines.
- Limited in vivo activity was observed against solid tumors, but significant responses were seen in the ALL panel.
Conclusions:
- Bortezomib demonstrated activity against selected ALL lines in vivo at its maximum tolerated dose.
- Further studies should investigate bortezomib combination therapies for childhood ALL.
Background:
Bortezomib is a proteasome inhibitor that has been approved by FDA for the treatment of multiple myeloma and that has completed phase 1 testing in children. The purpose of the current study was to evaluate the antitumor activity of bortezomib against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP).
Procedures:
Bortezomib was tested against the PPTP in vitro panel at concentrations ranging from 0.1 nM to 1.0 microM and was tested in vivo at a dose of 1 mg/kg for a planned duration of 6 weeks.
Results:
Bortezomib was uniformly active against the PPTP's in vitro panel, with a median IC(50) of 23 nM and with a steep dose-response curve. The four acute lymphoblastic leukemia (ALL) cell lines had significantly lower IC(50) values compared to the remaining lines of the in vitro panel. Limited in vivo activity was observed for bortezomib against the solid tumor xenografts tested, with one line meeting criteria for intermediate activity for the time to event measure and with the remaining lines showing low activity for this measure. Bortezomib demonstrated in vivo activity against the ALL panel, inducing two complete and two partial responses among seven evaluable lines.
Conclusions:
Administered at its MTD in mice, bortezomib demonstrated activity against selected lines of the PPTP's ALL in vivo panel. Further studies are indicated to determine the activity of bortezomib when combined with standard agents to treat childhood ALL.
Related Concept Videos
01:28Preclinical Development: Overview
01:16In vitro Mutagenesis
01:24Pharmacokinetics in Pediatric Patients: Drug Metabolism