Phase I clinical and pharmacological study of O-6-benzylguanine followed by carmustine in patients with advanced cancer

O-6-benzylguanine (BG) is a potent inactivator of the DNA repair protein O- 6-alkylguanine-DNA alkyltransferase (AGT) that enhances sensitivity to nitr osoureas in tumor cell lines and tumor-bearing animals. The major objective s of this study were to define the optimal modulatory dose and associated t oxicities of benzylguanine administered alone and in combination with carmu stine; to define the maximally tolerated dose and associated toxicities of carmustine administered with benzylguanine and to describe the pharmacokine tics of BG in humans and its effects on AGT depletion and recovery in perip heral blood mononuclear cells, Patients with histologically confirmed advan ced solid tumors or lymphoma that had failed to respond to standard therapy or for which no standard therapy was available were eligible to participat e in this study. Patients initially received BG as a 1-h i.v. infusion with out carmustine, After a 14-day washout (i.e., without therapy) period, pati ents 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 wee ks. Cohorts of patients received BG doses ranging from 10 to 120 mg/m(2) an d carmustine doses ranging from 13 to 50 mg/m(2). Plasma and urine samples were collected and analyzed for BG, and O-6-benzyl-8-oxoguanine concentrati ons and AGT activity was determined in peripheral blood mononuclear cells, There was no toxicity attributable to BG alone at any dose tested. Bone mar row suppression was the primary and dose-limiting toxicity of BG combined w ith carmustine and was cumulative in some patients. The neutrophil nadir oc curred at a median of day 27, with complete recovery in most patients by da y 43, Nonhematological toxicity included fatigue, anorexia, increased bilir ubin, and transaminase elevation. Recommended doses for Phase II testing ar e 120 mg/m(2) BG given with carmustine at 40 mg/m(2). BG rapidly disappeare d from plasma and was converted to a major metabolite, O-6-benzyl-8-oxoguan ine, which has a 2.4-fold higher maximal concentration and 20-fold higher a rea under the concentration versus time curve than BG, AGT activity in peri pheral 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 fro m 20-120 mg/m(2). In conclusion, coadministration of BG and carmustine is f easible in cancer patients, but the maximal dose of carmustine that can be safely administered with BG is approximately one-third of the standard clin ical dose. Bone marrow suppression, which may be cumulative, is the dose-li miting toxicity of the combination. Prolonged AGT suppression is likely att ributable primarily to the effect of O-6-benzyl-8-oxoguanine.