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Modulation of O⁶-Alkylguanine-DNA Alkyltransferase-mediated Carmustine Resistance Using Streptozotocin: A Phase I Trial¹

Department of Medicine, Division of Hematology/Oncology [T. J. P., D. C. S., M. P. R., R. L. F., E. P. W., J. C., D. L. T.], Division of Neurology [S. C. S.], Department of Child and Family Medicine, Division of Biometry and Medical Informatics [J. E. H.], Duke University Medical Center, and the Duke Comprehensive Cancer Center [S. C. S., E. P. W., R. L. F., J. C., D. L. T.], Durham, North Carolina 27710

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance may be mediated by repair of chloroethylated guaine 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 10⁹/liter; 2 patients, <25 x 10⁹/liter); neutropenia was less severe (2 patients, 2.0–3.9 x 10⁹/liter; 1 patient, 1.0–1.9 x 10⁹/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.

¹ Supported in part by grants P30-A-14236-18 and 5T32-CA-09307 from NIH, Jacob Javits Investigator Award 20581 from the National Institute of Neurological Disease and Stroke, and the P. B. Cohen Fund.

² To whom requests for reprints should be addressed, at P.O. Box 3398, Duke University Medical Center, Durham, NC 27710.

Received 10/15/91. Accepted 2/25/92.

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