Activity of Temozolomide in the Treatment of Central Nervous System Tumor Xenografts

Henry S. Friedman, M. Eileen Dolan, Anthony E. Pegg, Susan Marcelli, Stephen Keir, Joseph J. Catino, Darell D. Bigner, S. Clifford Schold

Research output: Contribution to journalArticle

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Abstract

The activity of 8-carbamoyl-3-methylimidazo[5,1-d]-l,2,3,5-tetrazin-4(3H)-one (temozolomide) in the treatment of a panel of xenografts derived from ependymoma, medulloblastoma, and childhood and adult high-grade glioma was evaluated in athymic nude mice bearing s.c. and intracranial tumors. Temozolomide administered daily for a total of five doses demonstrated marked activity against a panel of Mer+ xenografts despite marginal to moderate activity of 13-bis(2-chloroethyl)-l-nitrosourea. The growth delays produced by temozolomide in these xenografts were 1.8–7.5-fold greater than those produced by procarbazine. Although temozolomide demonstrated marginal activity against the Mer+ cell line D341 Med when a 5-day schedule was used, a high-dose 1-day schedule resulted in moderate activity. Temozolomide produced increases in median survival of 1285% (adult glioma D-54 MG), 323% (childhood glioma D-456 MG), and 68% (ependymoma D612 EP). Pretreatment of mice with O6-benzylguanine increased temozolomide-induced mortality, requiring reduction of the dosage from 1200 to 750 mg/m2 on the single-day regimen. O6-Benzylguanine pretreatment of mice bearing Mer+ D341 Med increased the growth delay of temozolomide, in duplicate experiments, from —3.1 to 4.8 and 1.1 to 4.9 days. These studies suggest that temozolomide may be active in the treatment of a broad spectrum of central nervous system cancers, including Mer+ tumors resistant to l,3-bis(2-chloroethyl)-l-nitrosourea.

Original languageEnglish (US)
Pages (from-to)2853-2857
Number of pages5
JournalCancer Research
Volume55
Issue number13
StatePublished - Jul 1 1995

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temozolomide
Central Nervous System Neoplasms
Heterografts
Glioma
Medulloblastoma
Nude Mice
Appointments and Schedules
Procarbazine
Ependymoma
Neoplasms
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Friedman, H. S., Dolan, M. E., Pegg, A. E., Marcelli, S., Keir, S., Catino, J. J., ... Schold, S. C. (1995). Activity of Temozolomide in the Treatment of Central Nervous System Tumor Xenografts. Cancer Research, 55(13), 2853-2857.
Friedman, Henry S. ; Dolan, M. Eileen ; Pegg, Anthony E. ; Marcelli, Susan ; Keir, Stephen ; Catino, Joseph J. ; Bigner, Darell D. ; Schold, S. Clifford. / Activity of Temozolomide in the Treatment of Central Nervous System Tumor Xenografts. In: Cancer Research. 1995 ; Vol. 55, No. 13. pp. 2853-2857.
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abstract = "The activity of 8-carbamoyl-3-methylimidazo[5,1-d]-l,2,3,5-tetrazin-4(3H)-one (temozolomide) in the treatment of a panel of xenografts derived from ependymoma, medulloblastoma, and childhood and adult high-grade glioma was evaluated in athymic nude mice bearing s.c. and intracranial tumors. Temozolomide administered daily for a total of five doses demonstrated marked activity against a panel of Mer+ xenografts despite marginal to moderate activity of 13-bis(2-chloroethyl)-l-nitrosourea. The growth delays produced by temozolomide in these xenografts were 1.8–7.5-fold greater than those produced by procarbazine. Although temozolomide demonstrated marginal activity against the Mer+ cell line D341 Med when a 5-day schedule was used, a high-dose 1-day schedule resulted in moderate activity. Temozolomide produced increases in median survival of 1285{\%} (adult glioma D-54 MG), 323{\%} (childhood glioma D-456 MG), and 68{\%} (ependymoma D612 EP). Pretreatment of mice with O6-benzylguanine increased temozolomide-induced mortality, requiring reduction of the dosage from 1200 to 750 mg/m2 on the single-day regimen. O6-Benzylguanine pretreatment of mice bearing Mer+ D341 Med increased the growth delay of temozolomide, in duplicate experiments, from —3.1 to 4.8 and 1.1 to 4.9 days. These studies suggest that temozolomide may be active in the treatment of a broad spectrum of central nervous system cancers, including Mer+ tumors resistant to l,3-bis(2-chloroethyl)-l-nitrosourea.",
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Friedman, HS, Dolan, ME, Pegg, AE, Marcelli, S, Keir, S, Catino, JJ, Bigner, DD & Schold, SC 1995, 'Activity of Temozolomide in the Treatment of Central Nervous System Tumor Xenografts', Cancer Research, vol. 55, no. 13, pp. 2853-2857.

Activity of Temozolomide in the Treatment of Central Nervous System Tumor Xenografts. / Friedman, Henry S.; Dolan, M. Eileen; Pegg, Anthony E.; Marcelli, Susan; Keir, Stephen; Catino, Joseph J.; Bigner, Darell D.; Schold, S. Clifford.

In: Cancer Research, Vol. 55, No. 13, 01.07.1995, p. 2853-2857.

Research output: Contribution to journalArticle

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AU - Dolan, M. Eileen

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AU - Schold, S. Clifford

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Friedman HS, Dolan ME, Pegg AE, Marcelli S, Keir S, Catino JJ et al. Activity of Temozolomide in the Treatment of Central Nervous System Tumor Xenografts. Cancer Research. 1995 Jul 1;55(13):2853-2857.