Toxicity of intracranial and intraperitoneal O6-benzyl guanine in combination with BCNU delivered locally in a mouse model

Michael Guarnieri, Ann Biser-Rohrbaugh, Betty Mae Tyler, Patrik Gabikian, Tracie E. Bunton, Qing Ze Wu, Jon David Weingart, Benjamin Solomon

Research output: Contribution to journalArticle

Abstract

Purpose: The DNA-repair protein, O6-alkylguanine-DNA alkyl transferase, may account for resistance of CNS tumors to DNA-alkylating drugs, such as bis-(2-chloroethyl)-1-nitrosourea (BCNU). The therapeutic effects of BCNU can be potentiated by inhibiting the repair protein with an alkylated guanine analog, O6-benzyl guanine (O6BG). To investigate potential toxicity of this inhibition, we examined the effects of O6BG in mice treated with intracranial (i.c.) BCNU given via a biodegradable polymer. Methods: Mice were treated with escalating doses of BCNU chronically delivered i.c., and with chronically delivered O6BG. The O6BG was delivered via a 7-day intraperitoneal (i.p.) or i.c. osmotic minipump. Toxicity of the combination therapies was measured from survival data. Bone marrow response was estimated from white blood cell counts. Results: Combining systemic (i.p.) O6BG with locally (i.c.) delivered BCNU resulted in a decrease in the maximum tolerated dose (MTD) of local BCNU. With local delivery of O6BG, the MTD of BCNU in combination with O6BG was increased. Conclusions: Based on the results of this study, a dose escalation study will be necessary when combining systemic O6BG with the higher doses of i.c. BCNU.

Original languageEnglish (US)
Pages (from-to)392-396
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume50
Issue number5
DOIs
StatePublished - 2002

Fingerprint

Carmustine
Guanine
Toxicity
Maximum Tolerated Dose
DNA
Repair
Biodegradable polymers
Therapeutic Uses
Transferases
Leukocyte Count
DNA Repair
Tumors
Polymers
Bone
Proteins
Blood
Bone Marrow
Cells

Keywords

  • Bis-chloroethyl nitrosourea (BCNU)
  • O6-alkylguanine-DNA alkyl transferase (AGAT, MGMT)
  • O6-benzyl guanine (O6BG)

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Toxicity of intracranial and intraperitoneal O6-benzyl guanine in combination with BCNU delivered locally in a mouse model. / Guarnieri, Michael; Biser-Rohrbaugh, Ann; Tyler, Betty Mae; Gabikian, Patrik; Bunton, Tracie E.; Ze Wu, Qing; Weingart, Jon David; Solomon, Benjamin.

In: Cancer Chemotherapy and Pharmacology, Vol. 50, No. 5, 2002, p. 392-396.

Research output: Contribution to journalArticle

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