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Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea.

Publication ,  Journal Article
Kurpad, SN; Dolan, ME; McLendon, RE; Archer, GE; Moschel, RC; Pegg, AE; Bigner, DD; Friedman, HS
Published in: Cancer Chemother Pharmacol
1997

The prognosis for patients with malignant gliomas continues to be dismal. The high degree of resistance of gliomas to nitrosourea-based chemotherapy is one major factor in poor treatment outcome. The identification of O6-alkylguanine-DNA alkyltransferase (AGAT) as a major determinant of nitrosourea resistance has resulted in the development of several agents to inactivate this repair protein and counteract tumor cell resistance. However, a major problem in preclinical trials has been the marked nitrosourea dose limitations imposed by the prior administration of AGAT-depleting agents. We investigated the AGAT depletion and selective enhancement of BCNU activity of intraarterial (i.a.) O6-benzylguanine (O6BG) in the human malignant glioma xenograft D-456 MG growing intracranially (i.e.) in athymic rats. Whereas i.a. O6BG at 2.5 mg/kg produced 100% inhibition of D-456 MG AGAT i.e. activity 8 h after administration, intraperitoneal (i.p.) O6BG at this dose produced only 40% inhibition, requiring dose escalation to 10 mg/kg to produce 100% AGAT depletion. Prior administration of i.p. O6BG (10 mg/kg) and i.a. O6BG (2.5 mg/kg) limited maximum tolerated intravenous (i.v.) BCNU doses (37.5 mg/kg when given alone) to 6.25 and 25 mg/kg, respectively. Higher doses of BCNU alone or in combination with O6BG produced histopathologic evidence of cerebral and hepatic toxicity. Therapy experiments revealed a significantly improved median survival for rats treated with O6BG i.a. (2.5 mg/kg) plus BCNU i.v. (25 mg/kg, days 61 and 59 in duplicate experiments) compared with saline (day 21. P = 0.001). O6BG i.a. or i.p. (days 22 and 23, P = 0.001), BCNU i.v. (37.5 mg/kg, day 29, P = 0.001), and O6BG i.p. (10 mg/kg), plus BCNU i.v. (6.25 mg/kg, day 37, P < 0.001). Therefore, O6BG i.a., by virtue of rapid AGAT depletion and selective uptake into i.c. tumors, offers significant potential for regional chemomodulation of AGAT-mediated nitrosourea resistance in malignant human gliomas with concomitant reduction of systemic toxicity.

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Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

1997

Volume

39

Issue

4

Start / End Page

307 / 316

Location

Germany

Related Subject Headings

  • Transplantation, Heterologous
  • Transferases
  • Rats, Nude
  • Rats
  • Oncology & Carcinogenesis
  • Injections, Intra-Arterial
  • Humans
  • Guanine
  • Glioblastoma
  • Drug Resistance, Neoplasm
 

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Kurpad, S. N., Dolan, M. E., McLendon, R. E., Archer, G. E., Moschel, R. C., Pegg, A. E., … Friedman, H. S. (1997). Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Chemother Pharmacol, 39(4), 307–316. https://doi.org/10.1007/s002800050577
Kurpad, S. N., M. E. Dolan, R. E. McLendon, G. E. Archer, R. C. Moschel, A. E. Pegg, D. D. Bigner, and H. S. Friedman. “Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea.Cancer Chemother Pharmacol 39, no. 4 (1997): 307–16. https://doi.org/10.1007/s002800050577.
Kurpad SN, Dolan ME, McLendon RE, Archer GE, Moschel RC, Pegg AE, et al. Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Chemother Pharmacol. 1997;39(4):307–16.
Kurpad, S. N., et al. “Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea.Cancer Chemother Pharmacol, vol. 39, no. 4, 1997, pp. 307–16. Pubmed, doi:10.1007/s002800050577.
Kurpad SN, Dolan ME, McLendon RE, Archer GE, Moschel RC, Pegg AE, Bigner DD, Friedman HS. Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Chemother Pharmacol. 1997;39(4):307–316.
Journal cover image

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

1997

Volume

39

Issue

4

Start / End Page

307 / 316

Location

Germany

Related Subject Headings

  • Transplantation, Heterologous
  • Transferases
  • Rats, Nude
  • Rats
  • Oncology & Carcinogenesis
  • Injections, Intra-Arterial
  • Humans
  • Guanine
  • Glioblastoma
  • Drug Resistance, Neoplasm