Antitumor activity of the butyrophenone
dihydrolenperone in
non-small cell lung cancer was initially suggested by in vitro screening against
tumor cells derived from fresh surgical samples using the human
tumor colony-forming assay. We have completed a directed phase I trial in patients with
lung cancer. Thirty-two patients with
lung cancer have completed 25 courses of
therapy at doses of 10 to 60 mg/square meter orally on a twice daily schedule. Twenty-three men and 9 women with a median age of 55 (range 24-69) were entered. Twenty-four were performance status 0 or 1 and 8 were 2. The maximum tolerated dose was 50 mg/square meter orally twice daily and the dose limiting toxicity was
somnolence. Of the 32 patients, 18 developed symptomatic
hypotension (grade 1 or 2). There was no significant hematologic, renal, or hepatic toxicity. In vitro
drug testing using the MTT [3-(4,5- dimethylthiazol-2-yl)-2,5-
diphenyl-tetrazolium
bromide (
thiazolyl blue)] assay confirmed 50% inhibition of non-small cell and
small cell lung cancer cell line growth at 70-450 micromolar concentrations. Plasma
dihydrolenperone levels were at least 75-fold less than levels at which in vitro activity was observed. We conclude: 1) the maximum tolerated dose in our study is 50 mg/square meter orally twice daily, 2) the dose-limiting side effect of
dihydrolenperone is
somnolence, and 3) the concentrations of
dihydrolenperone observed in plasma are significantly lower than those associated with in vitro activity.