title: Modulation of O6-alkylguanine-DNA alkyltransferase-mediated carmustine resistance using streptozotocin: a phase I trial.
abstract: 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance may be mediated by repair of chloroethylated guanine before stable cross-linking occurs. Guanine adducts may be repaired by the enzyme O6-alkylguanine-DNA alkyltransferase (O6-AGAT). Such repair irreversibly inactivates O6-AGAT. Streptozotocin (STZ) forms adducts at the O6 position of guanine; repair of these adducts consumes O6-AGAT. In vivo STZ potentiates BCNU cytotoxicity. The purpose of this trial was to determine the maximum tolerated dose of BCNU that can be administered together with STZ. The STZ dose was 500 mg/m2/day for 4 days and was not escalated. BCNU was given 4 h after the third dose of STZ at a starting dose of 75 mg/m2. A total of 43 patients were entered in the study. There were 4 dose escalations, reaching a maximum tolerated BCNU dose of 175 mg/m2. At this dose, thrombocytopenia was the dose-limiting toxicity (one patient, 25-49 x 10(9)/liter; 2 patients, less than 25 x 10(9)/liter); neutropenia was less severe (2 patients, 2.0-3.9 x 10(9)/liter, 1 patient, 1.0-1.9 x 10(9)/liter). Two other commonly seen toxicities were elevations in the serum alkaline phosphatase and mild elevations in the serum creatinine. Peripheral blood lymphocyte O6-AGAT levels decreased from a mean of 212 fmol/mg protein pretherapy to 8.2 fmol/mg protein on day 3 prior to BCNU (P = 0.03). Three partial responses were seen. There were no therapy-related fatalities, and toxicity was easily managed. This study established that 150 mg of BCNU can be administered safely together with STZ, 500 mg/m2/day for 4 days. Additional studies are required to determine whether O6-AGAT-mediated BCNU resistance is suppressed.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: T J
authors.initials: TJ
authors.lastname: Panella
authors.forename: D C
authors.initials: DC
authors.lastname: Smith
authors.forename: S C
authors.initials: SC
authors.lastname: Schold
authors.forename: M P
authors.initials: MP
authors.lastname: Rogers
authors.forename: E P
authors.initials: EP
authors.lastname: Winer
authors.forename: R L
authors.initials: RL
authors.lastname: Fine
authors.forename: J
authors.initials: J
authors.lastname: Crawford
authors.forename: J E
authors.initials: JE
authors.lastname: Herndon
authors.forename: D L
authors.initials: DL
authors.lastname: Trump
mesh_terms: D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D002330:Carmustine / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D004351:Drug Resistance; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D008780:Methyltransferases / Q000096:biosynthesis*; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013311:Streptozocin / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D013311:Streptozocin; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000469:Alkaline Phosphatase; D002330:Carmustine