title: Phase I trial of dihydrolenperone in lung cancer patients: a novel compound with in vitro activity against lung cancer.
abstract: 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.
authors.affiliation: National Cancer Institute-Navy Medical Oncology Branch, Bethesda, MD 20889-5105.
authors.forename: B E
authors.initials: BE
authors.lastname: Johnson
authors.forename: R
authors.initials: R
authors.lastname: Parker
authors.forename: C M
authors.initials: CM
authors.lastname: Tsai
authors.forename: J
authors.initials: J
authors.lastname: Baltz
authors.forename: M J
authors.initials: MJ
authors.lastname: Miller
authors.forename: R
authors.initials: R
authors.lastname: Shoemaker
authors.forename: R
authors.initials: R
authors.lastname: Phelps
authors.forename: A
authors.initials: A
authors.lastname: Bastian
authors.forename: J
authors.initials: J
authors.lastname: Stocker
authors.forename: J
authors.initials: J
authors.lastname: Phares
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D002090:Butyrophenones / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D015507:Drugs, Investigational / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006220:Haloperidol / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002090:Butyrophenones; D015507:Drugs, Investigational; C048020:dihydrolenperone; D006220:Haloperidol