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Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program
Author(s) -
Houghton Peter J.,
Morton Christopher L.,
Kolb E. Anders,
Lock Richard,
Carol Hernan,
Reynolds C. Patrick,
Keshelava Nino,
Maris John M.,
Keir Stephen T.,
Wu Jianrong,
Smith Malcolm A.
Publication year - 2008
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.21214
Subject(s) - bortezomib , in vivo , medicine , proteasome inhibitor , multiple myeloma , pharmacology , in vitro , oncology , biology , biochemistry , microbiology and biotechnology
Abstract 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 µM 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. Pediatr Blood Cancer 2008;50:37–45. © 2007 Wiley‐Liss, Inc.