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Phase I study of streptozocin- and carmustine-sequenced administration in patients with advanced cancer
K C Micetich1, B Futscher, D Koch
1Section of Hematology-Oncology, Stritch School of Medicine, Loyola University of Chicago, Maywood, Ill. 60153.
Background:
Fewer than 20% of patients with nonhematologic malignancies treated with chloroethylnitrosoureas (CENUs) respond, but streptozocin (STZ), which depletes O6-methylguanine-DNA-methyltransferase (MGMT), has been shown to reverse resistance to CENUs in vitro.
Purpose:
The purpose of this phase I study was to determine (a) the maximum tolerated dose (MTD) of carmustine (BCNU), a CENU, plus a fixed dose of STZ; (b) the toxic effects of the drugs; and (c) the effects on peripheral blood mononuclear cells (PBMC).
Methods:
A clinical phase I study of STZ followed by BCNU was designed to simulate conditions that produce maximal sensitization of CENU-resistant HT-29 cells in vitro. Patients received a 20-minute infusion of the MTD of STZ (2 g/m2) followed 1 hour later with a 60-minute infusion of BCNU (100, 125, 137.5, or 150 mg/m2). Treatment was repeated after 6 weeks. Twenty-four patients with advanced malignancies received 32 courses of therapy (range, 1-2 courses).
Results:
The MTD of BCNU was 125 mg/m2. The dose-limiting toxic effect was thrombocytopenia occurring about 22 days after treatment, with recovery between days 28 and 35. Transient hypophosphatemia and proteinuria were common, and serum creatinine was elevated in 9% of the courses. Two patients who received therapy died--one due to pulmonary toxic effects and one due to hepatic toxic effects. Two patients with previously untreated carcinoid achieved partial response. In three patients, MGMT levels in PBMC were more than 85% depleted after STZ administration and more than 90% depleted after BCNU infusion.
Conclusions:
These results show that the magnitude of MGMT depletion by STZ in PBMC is in the range necessary to produce sensitivity to CENUs in resistant cell lines but also that, when BCNU is combined with STZ, the MTD of BCNU is about 50% that of BCNU as a single agent and that platelet count suppression occurs earlier.
Implications:
We plan to conduct phase II studies of STZ plus BCNU in tumor types with low response to CENUs. One of the major goals will be to demonstrate that depletion of MGMT is greater in tumor cells than in normal cells.
Insights
This study found that combining streptozocin (STZ) with carmustine (BCNU) can deplete O6-methylguanine-DNA-methyltransferase (MGMT), potentially overcoming resistance to chloroethylnitrosoureas (CENUs). However, the maximum tolerated dose of BCNU was reduced when used with STZ.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Chloroethylnitrosoureas (CENUs) show limited efficacy in nonhematologic malignancies.
- Streptozocin (STZ) depletes O6-methylguanine-DNA-methyltransferase (MGMT), a mechanism shown to reverse CENU resistance in vitro.
Purpose of the Study:
- Determine the maximum tolerated dose (MTD) of carmustine (BCNU) combined with a fixed dose of STZ.
- Evaluate the toxic effects of the combination therapy.
- Assess the impact on peripheral blood mononuclear cells (PBMC).
Main Methods:
- Phase I clinical study involving STZ followed by BCNU.
- Patients received STZ (2 g/m2) followed 1 hour later by BCNU (100-150 mg/m2).
- Treatment cycles were repeated every 6 weeks for patients with advanced malignancies.
Main Results:
- The MTD of BCNU in combination with STZ was determined to be 125 mg/m2.
- Dose-limiting toxicity was thrombocytopenia, occurring approximately 22 days post-treatment.
- MGMT levels in PBMC were significantly depleted (>85%) after STZ and (>90%) after BCNU.
Conclusions:
- STZ effectively depletes MGMT in PBMCs to levels potentially sensitizing cells to CENUs.
- The MTD of BCNU is approximately 50% lower when combined with STZ compared to BCNU monotherapy.
- Future Phase II studies will investigate STZ plus BCNU in CENU-resistant tumors, aiming to confirm greater MGMT depletion in tumor cells.