title: Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.
abstract: OBJECTIVE
  The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma.
  
  
  METHODS
  Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration.
  
  
  RESULTS
  Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG.
  
  
  CONCLUSIONS
  These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.
authors.affiliation: Departments of Surgery, Medicine, Pathology, Radiology, and Community and Family Medicine, Duke University Medical Center, Durham, NC 27710, USA. fried003@nc.duke.edu
authors.forename: H S
authors.initials: HS
authors.lastname: Friedman
authors.forename: J
authors.initials: J
authors.lastname: Pluda
authors.forename: J A
authors.initials: JA
authors.lastname: Quinn
authors.forename: R B
authors.initials: RB
authors.lastname: Ewesuedo
authors.forename: L
authors.initials: L
authors.lastname: Long
authors.forename: A H
authors.initials: AH
authors.lastname: Friedman
authors.forename: I
authors.initials: I
authors.lastname: Cokgor
authors.forename: O M
authors.initials: OM
authors.lastname: Colvin
authors.forename: M M
authors.initials: MM
authors.lastname: Haglund
authors.forename: D M
authors.initials: DM
authors.lastname: Ashley
authors.forename: J N
authors.initials: JN
authors.lastname: Rich
authors.forename: J
authors.initials: J
authors.lastname: Sampson
authors.forename: A E
authors.initials: AE
authors.lastname: Pegg
authors.forename: R C
authors.initials: RC
authors.lastname: Moschel
authors.forename: R E
authors.initials: RE
authors.lastname: McLendon
authors.forename: J M
authors.initials: JM
authors.lastname: Provenzale
authors.forename: E S
authors.initials: ES
authors.lastname: Stewart
authors.forename: S
authors.initials: S
authors.lastname: Tourt-Uhlig
authors.forename: A M
authors.initials: AM
authors.lastname: Garcia-Turner
authors.forename: J E
authors.initials: JE
authors.lastname: Herndon
authors.forename: D D
authors.initials: DD
authors.lastname: Bigner
authors.forename: M E
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001254:Astrocytoma / Q000097:blood / Q000188:drug therapy*; D002330:Carmustine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016543:Central Nervous System Neoplasms / Q000097:blood / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy*; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy
chemical_list: C110997:8-oxo-O(6)-benzylguanine; C064976:O(6)-benzylguanine; C024829:8-hydroxyguanine; D006147:Guanine; D002330:Carmustine