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

Peter J Houghton, Christopher L. Morton, E. Anders Kolb, Richard Lock, Hernan Carol, C. Patrick Reynolds, Nino Keshelava, John M. Maris, Stephen T. Keir, Jianrong Wu, Malcolm A. Smith

Research output: Contribution to journalArticle

92 Citations (Scopus)

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 IC50 of 23 nM and with a steep dose-response curve. The four acute lymphoblastic leukemia (ALL) cell lines had significantly lower IC50 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.

Original languageEnglish (US)
Pages (from-to)37-45
Number of pages9
JournalPediatric Blood and Cancer
Volume50
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

Fingerprint

Proteasome Inhibitors
Pediatrics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Inhibitory Concentration 50
Bortezomib
Multiple Myeloma
Heterografts
Neoplasms
Cell Line
In Vitro Techniques

Keywords

  • Bortezomib
  • Developmental therapeutics
  • Preclinical testing

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

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

In: Pediatric Blood and Cancer, Vol. 50, No. 1, 01.01.2008, p. 37-45.

Research output: Contribution to journalArticle

Houghton, PJ, Morton, CL, Kolb, EA, Lock, R, Carol, H, Reynolds, CP, Keshelava, N, Maris, JM, Keir, ST, Wu, J & Smith, MA 2008, 'Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 50, no. 1, pp. 37-45. https://doi.org/10.1002/pbc.21214
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. / Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2008 ; Vol. 50, No. 1. pp. 37-45.
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AU - Reynolds, C. Patrick

AU - Keshelava, Nino

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N2 - 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 IC50 of 23 nM and with a steep dose-response curve. The four acute lymphoblastic leukemia (ALL) cell lines had significantly lower IC50 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.

AB - 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 IC50 of 23 nM and with a steep dose-response curve. The four acute lymphoblastic leukemia (ALL) cell lines had significantly lower IC50 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.

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