Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.
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.
Friedman
H S
HS
Departments of Surgery, Medicine, Pathology, Radiology, and Community and Family Medicine, Duke University Medical Center, Durham, NC 27710, USA. fried003@nc.duke.edu
Pluda
J
J
Quinn
J A
JA
Ewesuedo
R B
RB
Long
L
L
Friedman
A H
AH
Cokgor
I
I
Colvin
O M
OM
Haglund
M M
MM
Ashley
D M
DM
Rich
J N
JN
Sampson
J
J
Pegg
A E
AE
Moschel
R C
RC
McLendon
R E
RE
Provenzale
J M
JM
Stewart
E S
ES
Tourt-Uhlig
S
S
Garcia-Turner
A M
AM
Herndon
J E
JE
Bigner
D D
DD
Dolan
M E
ME
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
C110997:8-oxo-O(6)-benzylguanine; C064976:O(6)-benzylguanine; C024829:8-hydroxyguanine; D006147:Guanine; D002330:Carmustine