title: Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program.
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).
  
  
  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.
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee, USA. peter.houghton@stjude.org
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Nino
authors.initials: N
authors.lastname: Keshelava
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib