Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program.
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).


METHODS
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.
Houghton
Peter J
PJ
St. Jude Children's Research Hospital, Memphis, Tennessee, USA. peter.houghton@stjude.org
Morton
Christopher L
CL
Kolb
E Anders
EA
Lock
Richard
R
Carol
Hernan
H
Reynolds
C Patrick
CP
Keshelava
Nino
N
Maris
John M
JM
Keir
Stephen T
ST
Wu
Jianrong
J
Smith
Malcolm A
MA
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib