Phase I study of streptozocin- and carmustine-sequenced administration in patients with advanced cancer.
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Micetich
K C
KC
Section of Hematology-Oncology, Stritch School of Medicine, Loyola University of Chicago, Maywood, Ill. 60153.
Futscher
B
B
Koch
D
D
Fisher
R I
RI
Erickson
L C
LC
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002330:Carmustine / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000187:drug effects; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013311:Streptozocin / Q000008:administration & dosage
D013311:Streptozocin; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine