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

Depletion of the DNA-repair protein O-6-alkylguanine-DNA alkyltransfer ase (AGT) increases the sensitivity of cells in culture and of human t umor xenografts to chloroethylnitrosoureas such as carmustine (BCNU). We have previously demonstrated that dacarbazine (DTIC) can deplete AG T activity in cells in culture and in human tumor xenografts. A phase I trial of DTIC followed immediately by BCNU was conducted to determin e the DTIC dose resulting in maximal depletion of AGT in the periphera l blood mononuclear cells (PBMC) of cancer patients and to determine t he maximally tolerated dose of DTIC given as a 4-h infusion immediatel y 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 tu mors. Complete depletion of AGT activity was not achieved at DTIC dose s of up to 750 mg/m(2). The dose-limiting toxicity was hematologic, al though 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 acti vity 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 in fusion. 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. The re was no direct correlation between the DTIC dose and the extent of A GT depletion. Baseline PBMC AGT levels varied widely among patients.