SEQUENTIAL THERAPY WITH DACARBAZINE AND CARMUSTINE - A PHASE-I STUDY

Depletion of the DNA-repair protein O-6-alkylguanine-DNA alkyltransferase (AGT) increases the sensitivity of cells in culture and of human tumor xenografts to chloroethylnitrosoureas such as carmustine (BCNU). We have previously demonstrated that dacarbazine (DTIC) can deplete AGT activity in cells in culture and in human tumor xenografts. A phase I trial of DTIC followed immediately by BCNU was conducted to determine the DTIC dose resulting in maximal depletion of AGT in the peripheral blood mononuclear cells (PBMC) of cancer patients and to determine the maximally tolerated dose of DTIC given as a 4-h infusion immediately prior to a fixed dose of BCNU. A 4-h infusion of DTIC followed by a 2-h infusion of BCNU was given to 42 patients with refractory solid tumors. Complete depletion of AGT activity was not achieved at DTIC doses of up to 750 mg/m(2). The dose-limiting toxicity was hematologic, although at higher doses of BCNU (greater than or equal to 100 mg/m(2)) we observed significant nonhematologic toxicity. Our recommended phase II doses are 1,000 mg/m(2) DTIC followed by 75 mg/m(2) BCNU. AGT activity in PBMC of the 28 patients studied decreased to a mean of 62% +/- 11% (SE) of the baseline value at 4 h after initiation of the DTIC infusion. At 24 h after initiation of the DTIC infusion, AGT activity in PBMC was depleted to a mean of 65% +/- 14% of the baseline value. There was no direct correlation between the DTIC dose and the extent of AGT depletion. Baseline PBMC AGT levels varied widely among patients.