Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme

Henry S. Friedman, M. Eileen Dolan, Robert C. Moschel, Anthony Pegg, G. Michael Felker, Jeremy Rich, Darell D. Bigner, S. Clifford Schold

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Abstract

Background: Although chemotherapy offers promise of increased survival for children with medulloblastoma and glioblastoma multiforme, drug resistance occurs frequently, resulting in tumor progression and death. Resistance to nitrosoureas and methylating agents, which damage DNA, can be mediated by a DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGAT). Depletion of this protein with alkylguanines or methylating agents, however, restores tumor cell sensitivity to the cytotoxicity of chloroethylnitrosoureas (e.g., carmustine [BCNU]). Purpose: This study was designed to determine whether resistance to the activity of nitrosourea (the drug BCNU) in BCNU-resistant human medulloblastoma (D341 Med) and human glioblastoma multiforme (D-456 MG) can be reversed by the methylating agent streptozocin and the O6-substituted guanines O6-methylguanine and O6-benzylguanine. Methods: Xenografts were grown subcutaneously in athymic BALB/c mice. BCNU was administered as a single intraperitoneal injection at doses of 100 mg/m2, 75 mg/m2, or 38 mg/m2-i.e., 1.0, 0.75, or 0.38, respectively, of the dose lethal to 10% of treated animals (LD10). Mice were treated intraperitoneally with a single dose of O6-benzylguanine or O6-methylguanine (240 mg/m2) or with streptozocin (600 mg/m2) daily for 4 days. Response was assessed by tumor growth delay and tumor regression. AGAT activity in the xenografts was measured at 1 and 6 hours after pretreatment, at the time tumors were excised. Results: Pretreatment with O6-benzylguanine, O6-methylguanine, or streptozocin reduced AGAT activity to 4%, 25%, and 95% of control values, respectively, in D341 Med and 0%, 0%, and 25% of control values, respectively, in D-456 MG 1 hour after injection. After 6 hours, levels changed to 7%, 61%, and 116% of control values in D341 Med and 0%, 79%, and 21% of control values in D-456 MG, respectively. Both D341 Med and D-456 MG xenografts were completely resistant to BCNU at its LD10. Pretreatment with O6-benzylguanine increased BCNU sensitivity in both types of xenograft In contrast, treatment with BCNU plus O6-methylguanine or streptozocin did not produce growth delays substantially different from those produced by BCNU alone, reflecting the more efficient depletion of AGAT by O6-benzylguanine. Following therapy with BCNU plus O6-benzylguanine at 038 LD10, tumor regressions were seen in eight of 10 D341 Med and in all 10 D-456 MG xenografts. Conclusion: We recommend comprehensive clinical toxicologic evaluation of combination therapy with O6-benzylguanine plus BCNU, which would allow subsequent design of phase I clinical trials. [J Natl Cancer Inst 84:1926-1931, 1992]

Original languageEnglish (US)
Pages (from-to)1926-1931
Number of pages6
JournalJournal of the National Cancer Institute
Volume84
Issue number24
DOIs
StatePublished - Dec 16 1992

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Carmustine
Medulloblastoma
Glioblastoma
Heterografts
Streptozocin
Neoplasms
Clinical Trials, Phase I
Guanine
Growth
O(6)-benzylguanine
Intraperitoneal Injections
Drug Resistance
DNA Repair
DNA Damage
Proteins
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Friedman, H. S., Dolan, M. E., Moschel, R. C., Pegg, A., Felker, G. M., Rich, J., ... Schold, S. C. (1992). Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme. Journal of the National Cancer Institute, 84(24), 1926-1931. https://doi.org/10.1093/jnci/84.24.1926
Friedman, Henry S. ; Dolan, M. Eileen ; Moschel, Robert C. ; Pegg, Anthony ; Felker, G. Michael ; Rich, Jeremy ; Bigner, Darell D. ; Schold, S. Clifford. / Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme. In: Journal of the National Cancer Institute. 1992 ; Vol. 84, No. 24. pp. 1926-1931.
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title = "Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme",
abstract = "Background: Although chemotherapy offers promise of increased survival for children with medulloblastoma and glioblastoma multiforme, drug resistance occurs frequently, resulting in tumor progression and death. Resistance to nitrosoureas and methylating agents, which damage DNA, can be mediated by a DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGAT). Depletion of this protein with alkylguanines or methylating agents, however, restores tumor cell sensitivity to the cytotoxicity of chloroethylnitrosoureas (e.g., carmustine [BCNU]). Purpose: This study was designed to determine whether resistance to the activity of nitrosourea (the drug BCNU) in BCNU-resistant human medulloblastoma (D341 Med) and human glioblastoma multiforme (D-456 MG) can be reversed by the methylating agent streptozocin and the O6-substituted guanines O6-methylguanine and O6-benzylguanine. Methods: Xenografts were grown subcutaneously in athymic BALB/c mice. BCNU was administered as a single intraperitoneal injection at doses of 100 mg/m2, 75 mg/m2, or 38 mg/m2-i.e., 1.0, 0.75, or 0.38, respectively, of the dose lethal to 10{\%} of treated animals (LD10). Mice were treated intraperitoneally with a single dose of O6-benzylguanine or O6-methylguanine (240 mg/m2) or with streptozocin (600 mg/m2) daily for 4 days. Response was assessed by tumor growth delay and tumor regression. AGAT activity in the xenografts was measured at 1 and 6 hours after pretreatment, at the time tumors were excised. Results: Pretreatment with O6-benzylguanine, O6-methylguanine, or streptozocin reduced AGAT activity to 4{\%}, 25{\%}, and 95{\%} of control values, respectively, in D341 Med and 0{\%}, 0{\%}, and 25{\%} of control values, respectively, in D-456 MG 1 hour after injection. After 6 hours, levels changed to 7{\%}, 61{\%}, and 116{\%} of control values in D341 Med and 0{\%}, 79{\%}, and 21{\%} of control values in D-456 MG, respectively. Both D341 Med and D-456 MG xenografts were completely resistant to BCNU at its LD10. Pretreatment with O6-benzylguanine increased BCNU sensitivity in both types of xenograft In contrast, treatment with BCNU plus O6-methylguanine or streptozocin did not produce growth delays substantially different from those produced by BCNU alone, reflecting the more efficient depletion of AGAT by O6-benzylguanine. Following therapy with BCNU plus O6-benzylguanine at 038 LD10, tumor regressions were seen in eight of 10 D341 Med and in all 10 D-456 MG xenografts. Conclusion: We recommend comprehensive clinical toxicologic evaluation of combination therapy with O6-benzylguanine plus BCNU, which would allow subsequent design of phase I clinical trials. [J Natl Cancer Inst 84:1926-1931, 1992]",
author = "Friedman, {Henry S.} and Dolan, {M. Eileen} and Moschel, {Robert C.} and Anthony Pegg and Felker, {G. Michael} and Jeremy Rich and Bigner, {Darell D.} and Schold, {S. Clifford}",
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Friedman, HS, Dolan, ME, Moschel, RC, Pegg, A, Felker, GM, Rich, J, Bigner, DD & Schold, SC 1992, 'Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme', Journal of the National Cancer Institute, vol. 84, no. 24, pp. 1926-1931. https://doi.org/10.1093/jnci/84.24.1926

Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme. / Friedman, Henry S.; Dolan, M. Eileen; Moschel, Robert C.; Pegg, Anthony; Felker, G. Michael; Rich, Jeremy; Bigner, Darell D.; Schold, S. Clifford.

In: Journal of the National Cancer Institute, Vol. 84, No. 24, 16.12.1992, p. 1926-1931.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme

AU - Friedman, Henry S.

AU - Dolan, M. Eileen

AU - Moschel, Robert C.

AU - Pegg, Anthony

AU - Felker, G. Michael

AU - Rich, Jeremy

AU - Bigner, Darell D.

AU - Schold, S. Clifford

PY - 1992/12/16

Y1 - 1992/12/16

N2 - Background: Although chemotherapy offers promise of increased survival for children with medulloblastoma and glioblastoma multiforme, drug resistance occurs frequently, resulting in tumor progression and death. Resistance to nitrosoureas and methylating agents, which damage DNA, can be mediated by a DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGAT). Depletion of this protein with alkylguanines or methylating agents, however, restores tumor cell sensitivity to the cytotoxicity of chloroethylnitrosoureas (e.g., carmustine [BCNU]). Purpose: This study was designed to determine whether resistance to the activity of nitrosourea (the drug BCNU) in BCNU-resistant human medulloblastoma (D341 Med) and human glioblastoma multiforme (D-456 MG) can be reversed by the methylating agent streptozocin and the O6-substituted guanines O6-methylguanine and O6-benzylguanine. Methods: Xenografts were grown subcutaneously in athymic BALB/c mice. BCNU was administered as a single intraperitoneal injection at doses of 100 mg/m2, 75 mg/m2, or 38 mg/m2-i.e., 1.0, 0.75, or 0.38, respectively, of the dose lethal to 10% of treated animals (LD10). Mice were treated intraperitoneally with a single dose of O6-benzylguanine or O6-methylguanine (240 mg/m2) or with streptozocin (600 mg/m2) daily for 4 days. Response was assessed by tumor growth delay and tumor regression. AGAT activity in the xenografts was measured at 1 and 6 hours after pretreatment, at the time tumors were excised. Results: Pretreatment with O6-benzylguanine, O6-methylguanine, or streptozocin reduced AGAT activity to 4%, 25%, and 95% of control values, respectively, in D341 Med and 0%, 0%, and 25% of control values, respectively, in D-456 MG 1 hour after injection. After 6 hours, levels changed to 7%, 61%, and 116% of control values in D341 Med and 0%, 79%, and 21% of control values in D-456 MG, respectively. Both D341 Med and D-456 MG xenografts were completely resistant to BCNU at its LD10. Pretreatment with O6-benzylguanine increased BCNU sensitivity in both types of xenograft In contrast, treatment with BCNU plus O6-methylguanine or streptozocin did not produce growth delays substantially different from those produced by BCNU alone, reflecting the more efficient depletion of AGAT by O6-benzylguanine. Following therapy with BCNU plus O6-benzylguanine at 038 LD10, tumor regressions were seen in eight of 10 D341 Med and in all 10 D-456 MG xenografts. Conclusion: We recommend comprehensive clinical toxicologic evaluation of combination therapy with O6-benzylguanine plus BCNU, which would allow subsequent design of phase I clinical trials. [J Natl Cancer Inst 84:1926-1931, 1992]

AB - Background: Although chemotherapy offers promise of increased survival for children with medulloblastoma and glioblastoma multiforme, drug resistance occurs frequently, resulting in tumor progression and death. Resistance to nitrosoureas and methylating agents, which damage DNA, can be mediated by a DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGAT). Depletion of this protein with alkylguanines or methylating agents, however, restores tumor cell sensitivity to the cytotoxicity of chloroethylnitrosoureas (e.g., carmustine [BCNU]). Purpose: This study was designed to determine whether resistance to the activity of nitrosourea (the drug BCNU) in BCNU-resistant human medulloblastoma (D341 Med) and human glioblastoma multiforme (D-456 MG) can be reversed by the methylating agent streptozocin and the O6-substituted guanines O6-methylguanine and O6-benzylguanine. Methods: Xenografts were grown subcutaneously in athymic BALB/c mice. BCNU was administered as a single intraperitoneal injection at doses of 100 mg/m2, 75 mg/m2, or 38 mg/m2-i.e., 1.0, 0.75, or 0.38, respectively, of the dose lethal to 10% of treated animals (LD10). Mice were treated intraperitoneally with a single dose of O6-benzylguanine or O6-methylguanine (240 mg/m2) or with streptozocin (600 mg/m2) daily for 4 days. Response was assessed by tumor growth delay and tumor regression. AGAT activity in the xenografts was measured at 1 and 6 hours after pretreatment, at the time tumors were excised. Results: Pretreatment with O6-benzylguanine, O6-methylguanine, or streptozocin reduced AGAT activity to 4%, 25%, and 95% of control values, respectively, in D341 Med and 0%, 0%, and 25% of control values, respectively, in D-456 MG 1 hour after injection. After 6 hours, levels changed to 7%, 61%, and 116% of control values in D341 Med and 0%, 79%, and 21% of control values in D-456 MG, respectively. Both D341 Med and D-456 MG xenografts were completely resistant to BCNU at its LD10. Pretreatment with O6-benzylguanine increased BCNU sensitivity in both types of xenograft In contrast, treatment with BCNU plus O6-methylguanine or streptozocin did not produce growth delays substantially different from those produced by BCNU alone, reflecting the more efficient depletion of AGAT by O6-benzylguanine. Following therapy with BCNU plus O6-benzylguanine at 038 LD10, tumor regressions were seen in eight of 10 D341 Med and in all 10 D-456 MG xenografts. Conclusion: We recommend comprehensive clinical toxicologic evaluation of combination therapy with O6-benzylguanine plus BCNU, which would allow subsequent design of phase I clinical trials. [J Natl Cancer Inst 84:1926-1931, 1992]

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