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Sequential therapy with dacarbazine and carmustine: a phase I study
R B Mitchell1, M E Dolan, L Janisch
1Department of Medicine, University of Chicago, Illinois 60637.
Abstract:
Depletion of the DNA-repair protein O6-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/m2. The dose-limiting toxicity was hematologic, although at higher doses of BCNU (> or = 100 mg/m2) we observed significant nonhematologic toxicity. Our recommended phase II doses are 1,000 mg/m2 DTIC followed by 75 mg/m2 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.
Insights
Dacarbazine (DTIC) combined with carmustine (BCNU) aims to deplete DNA-repair protein AGT in cancer patients. Recommended Phase II doses are 1,000 mg/m2 DTIC and 75 mg/m2 BCNU, though complete AGT depletion was not achieved.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- O6-alkylguanine-DNA alkyltransferase (AGT) depletion enhances sensitivity to chloroethylnitrosoureas like carmustine (BCNU).
- Dacarbazine (DTIC) has demonstrated potential in depleting AGT activity in preclinical models.
Purpose of the Study:
- To determine the DTIC dose for maximal AGT depletion in patient PBMCs.
- To establish the maximally tolerated dose of DTIC when infused before BCNU.
Main Methods:
- A Phase I trial involving 42 patients with refractory solid tumors.
- DTIC was administered as a 4-hour infusion, followed by a 2-hour BCNU infusion.
- AGT activity in peripheral blood mononuclear cells (PBMCs) was measured at various time points.
Main Results:
- Complete AGT depletion was not achieved even at DTIC doses up to 750 mg/m2.
- Recommended Phase II doses are 1,000 mg/m2 DTIC followed by 75 mg/m2 BCNU.
- AGT activity decreased to approximately 62-65% of baseline by 4-24 hours post-DTIC initiation; no dose-response correlation was observed.
Conclusions:
- The combination of DTIC and BCNU shows potential for AGT modulation in cancer patients.
- Hematologic toxicity was dose-limiting, with non-hematologic toxicity observed at higher BCNU doses.
- Further investigation is warranted to optimize DTIC and BCNU dosing for maximal therapeutic benefit and minimal toxicity.