Determination of the optimal modulatory dose of O6-benzylguanine in patients with surgically resectable tumors.
OBJECTIVE
O6-benzylguanine (BG) provides a means to effectively inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) and increase the chemotherapeutic effectiveness of chloroethylating and methylating agents in preclinical and clinical studies. Two different doses of BG have been reported as the optimal biochemical modulatory dose for patients (i.e., 100 and 120 mg/m2). The objective of our study was to compare these doses by measuring AGT in surgically removed specimens after treatment with BG.


METHODS
BG was administered to patients as an i.v. infusion 16 +/- 4 h before surgical resection of their systemic tumor. AGT activity was measured in the tumor using a methylated DNA substrate. The target end point was defined as > or =11 of 13 patients with undetectable tumor AGT levels (<10 fmol/mg protein).


RESULTS
Of the 28 patients enrolled, 25 of whom were analyzed for AGT activity, the most common primary sites of cancer included the colon (n = 11), bladder (n = 3), rectum (n = 4), and stomach (n = 3). Positive (DaOY cells) and negative (Chinese hamster ovary cells) control cell lines were included in each assay. Seven of the 12 patients treated with 100 mg/m2 BG had AGT activity of >10 fmol/mg protein (15-147 fmol/mg protein). Only 2 of the 13 patients treated with 120 mg/m2 BG had AGT activity of >10 fmol/mg protein (11 and 12 fmol/mg protein).


CONCLUSIONS
From our surgically removed tissue data, a dose of 120 mg/m2 BG is recommended to deplete systemic tumors of AGT activity.
Dolan
M Eileen
ME
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. edolan@medicine.bsd.uchicago.edu
Posner
Mitchell
M
Karrison
Theodore
T
Radosta
Jonathan
J
Steinberg
Gary
G
Bertucci
Donna
D
Vujasin
Lucky
L
Ratain
Mark J
MJ
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016466:CHO Cells; D006224:Cricetinae; D019175:DNA Methylation; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000601:surgery*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C064976:O(6)-benzylguanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase