Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma.
OBJECTIVE
The major mechanism of resistance to alkylnitrosourea therapy is the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which removes chlorethylation or methylation damage from the O6-position of guanine. O6-benzylguanine (O6-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial to define the presurgical dose required for depletion of tumor AGT activity in patients with malignant glioma.


METHODS
Patients were to be treated 18 hours before craniotomy with intravenous doses that ranged between 40 and 100 mg/m2 given over 1 hour. Resected tumor was snap-frozen in liquid nitrogen and AGT activity analyzed by high-pressure liquid chromatography (HPLC). Up to 13 patients were treated at a specific dose of O6-BG, with a target end point of > or = 11 of 13 patients with undetectable tumor AGT levels (< 10 fmol/mg protein).


RESULTS
Thirty patients with malignant gliomas were enrolled, with 11 of 11 patients treated at 100 mg/m2 O6-BG demonstrating tumor AGT levels less than 10 fmol/mg protein. No toxicity was noted in any patient treated.


CONCLUSIONS
These results indicate that 100 mg/m2 of O6-BG can maintain tumor AGT levels less than 10 fmol/mg protein for at least 18 hours after treatment, a time interval in which bis(2-chloroethyl)nitrosourea (BCNU)-induced chloroethyl adducts are fully converted into interstrand cross-links. A 100-mg/m2 dose of O6-BG will be used in combination with BCNU in another phase I trial designed to determine the maximal-tolerated dose of BCNU.
Friedman
H S
HS
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Kokkinakis
D M
DM
Pluda
J
J
Friedman
A H
AH
Cokgor
I
I
Haglund
M M
MM
Ashley
D M
DM
Rich
J
J
Dolan
M E
ME
Pegg
A E
AE
Moschel
R C
RC
McLendon
R E
RE
Kerby
T
T
Herndon
J E
JE
Bigner
D D
DD
Schold
S C
SC
D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000601:surgery*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000601:surgery*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D011300:Preoperative Care
D004791:Enzyme Inhibitors; C064976:O(6)-benzylguanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase