title: KW-2149-induced pulmonary toxicity is not prevented by corticosteroids: a phase I and pharmacokinetic study.
abstract: KW-2149 is a new, semisynthetic, C-7-N-Substituted, mitomycin C analog showing antitumor activity both in vitro and in vivo, equal or superior to mitomycin C. In a phase I study, KW-2149 was administered as an i.v. bolus injection every 21 days and at a dose of 100 mg/m2 pulmonary toxicity was dose limiting. Animal studies have indicated since that KW-2149-induced pulmonary toxicity can be prevented by pretreatment with corticosteroids. This paper presents the results of a further phase I study of KW-2149 with corticosteroid pretreatment. Patients were treated with oral dexamethasone 8 mg every 12 h, starting 24 h before KW-2149 administration, for 5 days. KW-2149 was given as an i.v. bolus injection every 21 days. Seventeen patients were treated with a total of 48 courses. Six patients received 60 mg/m2 and 11 patients 75 mg/m2. Two courses were not evaluable for toxicity. Significant lung toxicity was observed in at least three patients treated with a dose of 75 mg/m2 KW-2149 and pulmonary toxicity was therefore considered the dose-limiting toxicity at 75 mg/m2. No other important side effects were noted. One partial response was observed in a patient with colorectal cancer. Pretreatment with dexamethasone failed to suppress KW-2149-induced lung toxicity.
authors.affiliation: Department of Medical Oncology and Laboratory of Cancer Research, Antwerp University Hospital, Belgium. Dirk.Schrijvers@uza.uia.ac.be
authors.forename: D
authors.initials: D
authors.lastname: Schrijvers
authors.forename: G
authors.initials: G
authors.lastname: Catimel
authors.forename: M
authors.initials: M
authors.lastname: Highley
authors.forename: F J
authors.initials: FJ
authors.lastname: Höppener
authors.forename: L
authors.initials: L
authors.lastname: Dirix
authors.forename: E
authors.initials: E
authors.lastname: De Bruijn
authors.forename: J P
authors.initials: JP
authors.lastname: Droz
authors.forename: A T
authors.initials: AT
authors.lastname: Van Oosterom
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D004064:Digestive System / Q000187:drug effects; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D008937:Mitomycins / Q000009:adverse effects* / Q000493:pharmacokinetics; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000305:Adrenal Cortex Hormones; D000903:Antibiotics, Antineoplastic; D008937:Mitomycins; C057625:KW 2149