Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program

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

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Background. ABT-263 is a potent (Ki < 1 nM) small-molecule BH3 mimetic that inhibits the antiapoptotic proteins Bcl-2, Bcl-xL and Bcl-w. The structurally related Bcl-2 inhibitor ABT-737 exhibits single-agent preclinical activity against lymphoma, small-cell lung carcinoma, and chronic lymphocytic leukemia and displays synergistic cytotoxicity with chemotherapeutics and radiation. Methods. ABT-263 was tested at concentrations ranging from 1.0 nM to 10.0 μM using 23 cell lines from the PPTP in vitro panel and was tested in 44 xenograft models representing nine distinct histologies using daily gavage administration of ABT-263 (100 mg/kg) or vehicle for 21 days. Results. ABT-263 was active against approximately one-half of the cell lines of the PPTP in vitro panel. The median IC50 for all of the lines in the panel was 1.91 μM. ABT-263 induced significant prolongation of the EFS distribution in 9 of 35 (26%) of the solid tumor xenografts, and in 5 of 6 (83%) of the evaluable ALL xenografts. ABT-263 induced no objective responses in the solid tumor panels, but induced CRs in 3 of 6 evaluable xenografts in the ALL panel, including two that were maintained for an additional 3 weeks following treatment cessation. Conclusions. ABT-263 demonstrated in vitro activity against a range of cell lines, with the ALL cell lines showing the greatest sensitivity. ABT-263 demonstrated limited single agent in vivo activity against the PPTP's solid tumor panels but showed significant activity against xenografts in the ALL panel.

Original languageEnglish (US)
Pages (from-to)1181-1189
Number of pages9
JournalPediatric Blood and Cancer
Volume50
Issue number6
DOIs
StatePublished - Jun 2008

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Pediatrics
Heterografts
Cell Line
Neoplasms
Withholding Treatment
navitoclax
Small Cell Lung Carcinoma
B-Cell Chronic Lymphocytic Leukemia
Inhibitory Concentration 50
Lymphoma
Histology
Radiation
In Vitro Techniques
N-propyl-4-phenyl-1,2,3,6-tetrahydropyridine
Proteins

Keywords

  • ABT-263
  • Bcl-2
  • Developmental therapeutics
  • Preclinical testing

ASJC Scopus subject areas

  • Cancer Research
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Lock, R., Carol, H., Houghton, P. J., Morton, C. L., Anders Kolb, E., Gorlick, R., ... Smith, M. A. (2008). Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. Pediatric Blood and Cancer, 50(6), 1181-1189. https://doi.org/10.1002/pbc.21433

Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. / Lock, Richard; Carol, Hernan; Houghton, Peter J.; Morton, Christopher L.; Anders Kolb, E.; Gorlick, Richard; Patrick Reynolds, C.; Maris, John M.; Keir, Stephen T.; Wu, Jianrong; Smith, Malcolm A.

In: Pediatric Blood and Cancer, Vol. 50, No. 6, 06.2008, p. 1181-1189.

Research output: Contribution to journalArticle

Lock, R, Carol, H, Houghton, PJ, Morton, CL, Anders Kolb, E, Gorlick, R, Patrick Reynolds, C, Maris, JM, Keir, ST, Wu, J & Smith, MA 2008, 'Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 50, no. 6, pp. 1181-1189. https://doi.org/10.1002/pbc.21433
Lock, Richard ; Carol, Hernan ; Houghton, Peter J. ; Morton, Christopher L. ; Anders Kolb, E. ; Gorlick, Richard ; Patrick Reynolds, C. ; Maris, John M. ; Keir, Stephen T. ; Wu, Jianrong ; Smith, Malcolm A. / Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2008 ; Vol. 50, No. 6. pp. 1181-1189.
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abstract = "Background. ABT-263 is a potent (Ki < 1 nM) small-molecule BH3 mimetic that inhibits the antiapoptotic proteins Bcl-2, Bcl-xL and Bcl-w. The structurally related Bcl-2 inhibitor ABT-737 exhibits single-agent preclinical activity against lymphoma, small-cell lung carcinoma, and chronic lymphocytic leukemia and displays synergistic cytotoxicity with chemotherapeutics and radiation. Methods. ABT-263 was tested at concentrations ranging from 1.0 nM to 10.0 μM using 23 cell lines from the PPTP in vitro panel and was tested in 44 xenograft models representing nine distinct histologies using daily gavage administration of ABT-263 (100 mg/kg) or vehicle for 21 days. Results. ABT-263 was active against approximately one-half of the cell lines of the PPTP in vitro panel. The median IC50 for all of the lines in the panel was 1.91 μM. ABT-263 induced significant prolongation of the EFS distribution in 9 of 35 (26{\%}) of the solid tumor xenografts, and in 5 of 6 (83{\%}) of the evaluable ALL xenografts. ABT-263 induced no objective responses in the solid tumor panels, but induced CRs in 3 of 6 evaluable xenografts in the ALL panel, including two that were maintained for an additional 3 weeks following treatment cessation. Conclusions. ABT-263 demonstrated in vitro activity against a range of cell lines, with the ALL cell lines showing the greatest sensitivity. ABT-263 demonstrated limited single agent in vivo activity against the PPTP's solid tumor panels but showed significant activity against xenografts in the ALL panel.",
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AU - Lock, Richard

AU - Carol, Hernan

AU - Houghton, Peter J.

AU - Morton, Christopher L.

AU - Anders Kolb, E.

AU - Gorlick, Richard

AU - Patrick Reynolds, C.

AU - Maris, John M.

AU - Keir, Stephen T.

AU - Wu, Jianrong

AU - Smith, Malcolm A.

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N2 - Background. ABT-263 is a potent (Ki < 1 nM) small-molecule BH3 mimetic that inhibits the antiapoptotic proteins Bcl-2, Bcl-xL and Bcl-w. The structurally related Bcl-2 inhibitor ABT-737 exhibits single-agent preclinical activity against lymphoma, small-cell lung carcinoma, and chronic lymphocytic leukemia and displays synergistic cytotoxicity with chemotherapeutics and radiation. Methods. ABT-263 was tested at concentrations ranging from 1.0 nM to 10.0 μM using 23 cell lines from the PPTP in vitro panel and was tested in 44 xenograft models representing nine distinct histologies using daily gavage administration of ABT-263 (100 mg/kg) or vehicle for 21 days. Results. ABT-263 was active against approximately one-half of the cell lines of the PPTP in vitro panel. The median IC50 for all of the lines in the panel was 1.91 μM. ABT-263 induced significant prolongation of the EFS distribution in 9 of 35 (26%) of the solid tumor xenografts, and in 5 of 6 (83%) of the evaluable ALL xenografts. ABT-263 induced no objective responses in the solid tumor panels, but induced CRs in 3 of 6 evaluable xenografts in the ALL panel, including two that were maintained for an additional 3 weeks following treatment cessation. Conclusions. ABT-263 demonstrated in vitro activity against a range of cell lines, with the ALL cell lines showing the greatest sensitivity. ABT-263 demonstrated limited single agent in vivo activity against the PPTP's solid tumor panels but showed significant activity against xenografts in the ALL panel.

AB - Background. ABT-263 is a potent (Ki < 1 nM) small-molecule BH3 mimetic that inhibits the antiapoptotic proteins Bcl-2, Bcl-xL and Bcl-w. The structurally related Bcl-2 inhibitor ABT-737 exhibits single-agent preclinical activity against lymphoma, small-cell lung carcinoma, and chronic lymphocytic leukemia and displays synergistic cytotoxicity with chemotherapeutics and radiation. Methods. ABT-263 was tested at concentrations ranging from 1.0 nM to 10.0 μM using 23 cell lines from the PPTP in vitro panel and was tested in 44 xenograft models representing nine distinct histologies using daily gavage administration of ABT-263 (100 mg/kg) or vehicle for 21 days. Results. ABT-263 was active against approximately one-half of the cell lines of the PPTP in vitro panel. The median IC50 for all of the lines in the panel was 1.91 μM. ABT-263 induced significant prolongation of the EFS distribution in 9 of 35 (26%) of the solid tumor xenografts, and in 5 of 6 (83%) of the evaluable ALL xenografts. ABT-263 induced no objective responses in the solid tumor panels, but induced CRs in 3 of 6 evaluable xenografts in the ALL panel, including two that were maintained for an additional 3 weeks following treatment cessation. Conclusions. ABT-263 demonstrated in vitro activity against a range of cell lines, with the ALL cell lines showing the greatest sensitivity. ABT-263 demonstrated limited single agent in vivo activity against the PPTP's solid tumor panels but showed significant activity against xenografts in the ALL panel.

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