Initial testing (stage 1) of temozolomide by the pediatric preclinical testing program

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: The DNA methylating agent temozolomide was developed primarily for treatment of glioblastoma. However, preclinical data have suggested a broader application for treatment of childhood cancer. Temozolomide was tested against the PPTP solid tumor and ALL models. Procedures: Temozolomide was tested against the PPTP in vitro panel at concentrations ranging from 0.1 to 1,000μM and was tested against the PPTP in vivo panels at doses from 22 to 100mg/kg administered orally daily for 5 days, repeated at day 21. Results: In vitro temozolomide showed cytotoxicity with a median relative IC50 (rIC50) value of 380μM against the PPTP cell lines (range 1 to >1,000μM). The three lines with rIC50 values lesser than 10μM had low MGMT expression compared to the remaining cell lines. In vivo temozolomide demonstrated significant toxicity at 100mg/kg, but induced tumor regressions in 15 of 23 evaluable solid tumor models (13 maintained CR [MCR], 2 CR) and 5 of 8 ALL models (3 MCR, 2 CR). There was a steep dose response curve, with lower activity at 66mg/kg temozolomide and with tumor regressions at 22 and 44mg/kg restricted to models with low MGMT expression. Conclusions: Temozolomide demonstrated high level antitumor activity against both solid tumor and leukemia models, but also elicited significant toxicity at the highest dose level. Lowering the dose of TMZ to more closely match clinical exposures markedly reduced the antitumor activity for many xenograft lines with responsiveness at lower doses closely related to low MGMT expression.

Original languageEnglish (US)
Pages (from-to)783-790
Number of pages8
JournalPediatric Blood and Cancer
Volume60
Issue number5
DOIs
StatePublished - May 2013

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temozolomide
Pediatrics
Neoplasms
Inhibitory Concentration 50
Cell Line
Glioblastoma
Heterografts
Leukemia

Keywords

  • Developmental therapeutics
  • Preclinical testing
  • Temodar

ASJC Scopus subject areas

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

Cite this

Keir, S. T., Maris, J. M., Reynolds, C. P., Kang, M. H., Kolb, E. A., Gorlick, R., ... Smith, M. A. (2013). Initial testing (stage 1) of temozolomide by the pediatric preclinical testing program. Pediatric Blood and Cancer, 60(5), 783-790. https://doi.org/10.1002/pbc.24368

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

In: Pediatric Blood and Cancer, Vol. 60, No. 5, 05.2013, p. 783-790.

Research output: Contribution to journalArticle

Keir, ST, Maris, JM, Reynolds, CP, Kang, MH, Kolb, EA, Gorlick, R, Lock, R, Carol, H, Morton, CL, Wu, J, Kurmasheva, RT, Houghton, PJ & Smith, MA 2013, 'Initial testing (stage 1) of temozolomide by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 60, no. 5, pp. 783-790. https://doi.org/10.1002/pbc.24368
Keir, Stephen T. ; Maris, John M. ; Reynolds, C. Patrick ; Kang, Min H. ; Kolb, E. Anders ; Gorlick, Richard ; Lock, Richard ; Carol, Hernan ; Morton, Christopher L. ; Wu, Jianrong ; Kurmasheva, Raushan T. ; Houghton, Peter J. ; Smith, Malcolm A. / Initial testing (stage 1) of temozolomide by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2013 ; Vol. 60, No. 5. pp. 783-790.
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abstract = "Background: The DNA methylating agent temozolomide was developed primarily for treatment of glioblastoma. However, preclinical data have suggested a broader application for treatment of childhood cancer. Temozolomide was tested against the PPTP solid tumor and ALL models. Procedures: Temozolomide was tested against the PPTP in vitro panel at concentrations ranging from 0.1 to 1,000μM and was tested against the PPTP in vivo panels at doses from 22 to 100mg/kg administered orally daily for 5 days, repeated at day 21. Results: In vitro temozolomide showed cytotoxicity with a median relative IC50 (rIC50) value of 380μM against the PPTP cell lines (range 1 to >1,000μM). The three lines with rIC50 values lesser than 10μM had low MGMT expression compared to the remaining cell lines. In vivo temozolomide demonstrated significant toxicity at 100mg/kg, but induced tumor regressions in 15 of 23 evaluable solid tumor models (13 maintained CR [MCR], 2 CR) and 5 of 8 ALL models (3 MCR, 2 CR). There was a steep dose response curve, with lower activity at 66mg/kg temozolomide and with tumor regressions at 22 and 44mg/kg restricted to models with low MGMT expression. Conclusions: Temozolomide demonstrated high level antitumor activity against both solid tumor and leukemia models, but also elicited significant toxicity at the highest dose level. Lowering the dose of TMZ to more closely match clinical exposures markedly reduced the antitumor activity for many xenograft lines with responsiveness at lower doses closely related to low MGMT expression.",
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AU - Maris, John M.

AU - Reynolds, C. Patrick

AU - Kang, Min H.

AU - Kolb, E. Anders

AU - Gorlick, Richard

AU - Lock, Richard

AU - Carol, Hernan

AU - Morton, Christopher L.

AU - Wu, Jianrong

AU - Kurmasheva, Raushan T.

AU - Houghton, Peter J.

AU - Smith, Malcolm A.

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N2 - Background: The DNA methylating agent temozolomide was developed primarily for treatment of glioblastoma. However, preclinical data have suggested a broader application for treatment of childhood cancer. Temozolomide was tested against the PPTP solid tumor and ALL models. Procedures: Temozolomide was tested against the PPTP in vitro panel at concentrations ranging from 0.1 to 1,000μM and was tested against the PPTP in vivo panels at doses from 22 to 100mg/kg administered orally daily for 5 days, repeated at day 21. Results: In vitro temozolomide showed cytotoxicity with a median relative IC50 (rIC50) value of 380μM against the PPTP cell lines (range 1 to >1,000μM). The three lines with rIC50 values lesser than 10μM had low MGMT expression compared to the remaining cell lines. In vivo temozolomide demonstrated significant toxicity at 100mg/kg, but induced tumor regressions in 15 of 23 evaluable solid tumor models (13 maintained CR [MCR], 2 CR) and 5 of 8 ALL models (3 MCR, 2 CR). There was a steep dose response curve, with lower activity at 66mg/kg temozolomide and with tumor regressions at 22 and 44mg/kg restricted to models with low MGMT expression. Conclusions: Temozolomide demonstrated high level antitumor activity against both solid tumor and leukemia models, but also elicited significant toxicity at the highest dose level. Lowering the dose of TMZ to more closely match clinical exposures markedly reduced the antitumor activity for many xenograft lines with responsiveness at lower doses closely related to low MGMT expression.

AB - Background: The DNA methylating agent temozolomide was developed primarily for treatment of glioblastoma. However, preclinical data have suggested a broader application for treatment of childhood cancer. Temozolomide was tested against the PPTP solid tumor and ALL models. Procedures: Temozolomide was tested against the PPTP in vitro panel at concentrations ranging from 0.1 to 1,000μM and was tested against the PPTP in vivo panels at doses from 22 to 100mg/kg administered orally daily for 5 days, repeated at day 21. Results: In vitro temozolomide showed cytotoxicity with a median relative IC50 (rIC50) value of 380μM against the PPTP cell lines (range 1 to >1,000μM). The three lines with rIC50 values lesser than 10μM had low MGMT expression compared to the remaining cell lines. In vivo temozolomide demonstrated significant toxicity at 100mg/kg, but induced tumor regressions in 15 of 23 evaluable solid tumor models (13 maintained CR [MCR], 2 CR) and 5 of 8 ALL models (3 MCR, 2 CR). There was a steep dose response curve, with lower activity at 66mg/kg temozolomide and with tumor regressions at 22 and 44mg/kg restricted to models with low MGMT expression. Conclusions: Temozolomide demonstrated high level antitumor activity against both solid tumor and leukemia models, but also elicited significant toxicity at the highest dose level. Lowering the dose of TMZ to more closely match clinical exposures markedly reduced the antitumor activity for many xenograft lines with responsiveness at lower doses closely related to low MGMT expression.

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