title: Phase I clinical and pharmacological study of O6-benzylguanine followed by carmustine in patients with advanced cancer.
abstract: O6-benzylguanine (BG) is a potent inactivator of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) that enhances sensitivity to nitrosoureas in tumor cell lines and tumor-bearing animals. The major objectives of this study were to define the optimal modulatory dose and associated toxicities of benzylguanine administered alone and in combination with carmustine; to define the maximally tolerated dose and associated toxicities of carmustine administered with benzylguanine and to describe the pharmacokinetics of BG in humans and its effects on AGT depletion and recovery in peripheral blood mononuclear cells. Patients with histologically confirmed advanced solid tumors or lymphoma that had failed to respond to standard therapy or for which no standard therapy was available were eligible to participate in this study. Patients initially received BG as a 1-h i.v. infusion without carmustine. After a 14-day washout (ie., without therapy) period, patients received BG as a 1-h i.v. infusion followed, 1 h later, by a 15-min i.v. infusion of carmustine. Cycles of chemotherapy were repeated every 6 weeks. Cohorts of patients received BG doses ranging from 10 to 120 mg/m2 and carmustine doses ranging from 13 to 50 mg/m2. Plasma and urine samples were collected and analyzed for BG, and O6-benzyl-8-oxoguanine concentrations and AGT activity was determined in peripheral blood mononuclear cells. There was no toxicity attributable to BG alone at any dose tested. Bone marrow suppression was the primary and dose-limiting toxicity of BG combined with carmustine and was cumulative in some patients. The neutrophil nadir occurred at a median of day 27, with complete recovery in most patients by day 43. Nonhematological toxicity included fatigue, anorexia, increased bilirubin, and transaminase elevation. Recommended doses for Phase II testing are 120 mg/m2 BG given with carmustine at 40 mg/m2. BG rapidly disappeared from plasma and was converted to a major metabolite, O6-benzyl-8-oxoguanine, which has a 2.4-fold higher maximal concentration and 20-fold higher area under the concentration versus time curve than BG. AGT activity in peripheral blood mononuclear cells was rapidly and completely suppressed at all of the BG doses. The rate of AGT regeneration was more rapid for patients treated with the lowest dose of BG but was similar for BG doses ranging from 20-120 mg/m2. In conclusion, coadministration of BG and carmustine is feasible in cancer patients, but the maximal dose of carmustine that can be safely administered with BG is approximately one-third of the standard clinical dose. Bone marrow suppression, which may be cumulative, is the dose-limiting toxicity of the combination. Prolonged AGT suppression is likely attributable primarily to the effect of O6-benzyl-8-oxoguanine.
authors.affiliation: Department of Medicine, Cancer Research Center and Committee on Clinical Pharmacology, University of Chicago, Illinois 60637, USA. rschilsk@medicine.bsd.uchicago.edu
authors.forename: R L
authors.initials: RL
authors.lastname: Schilsky
authors.forename: M E
authors.initials: ME
authors.lastname: Dolan
authors.forename: D
authors.initials: D
authors.lastname: Bertucci
authors.forename: R B
authors.initials: RB
authors.lastname: Ewesuedo
authors.forename: N J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: S
authors.initials: S
authors.lastname: Mani
authors.forename: L R
authors.initials: LR
authors.lastname: Wilson
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002330:Carmustine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C064976:O(6)-benzylguanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine