title: Phase I pharmacokinetic study of the novel antitumor agent SR233377.
abstract: SR233377 is a novel thioxanthenone analogue that demonstrated solid tumor selectivity in vitro with activity confirmed in vivo against several murine tumors including those of colon, pancreas, and mammary origin. Its primary preclinical dose-limiting toxicities included myelosuppression and neurological toxicity. The neurological toxicity was acute and could be ameliorated in mice when the drug was administered as a 1-h infusion instead of rapid i.v. injection. As a result of its preclinical efficacy profile, SR233377 entered Phase I clinical investigation. The compound was administered i.v. over 2 h on day 1 repeated every 28 days. The starting dose was 33 mg/m2 (one-tenth the mouse LD10). Escalations continued to 445 mg/m2 (six escalations), where dose-limiting toxicity was observed. At this dose, acute ventricular arrhythmias, including one patient with torsades de pointes and transient cardiac arrest, occurred. Because this toxicity might have been related to the plasma peak, the protocol was amended to a 24-h infusion beginning at 225 mg/m2. With this dose, prolongation of the corrected QT interval (QTc) over the pretreatment levels resulted. Because prolonged QTc is a known forerunner to acute ventricular arrhythmias, clinical development of SR233377 was stopped. However, preclinical antitumor and toxicity studies with analogues are underway with hopes of identifying a new clinical candidate with similar antitumor effects that is devoid of cardiac toxic effects.
authors.affiliation: Karmanos Cancer Institute, Department of Internal Medicine, Detroit, Michigan 48201, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: B J
authors.initials: BJ
authors.lastname: Foster
authors.forename: A
authors.initials: A
authors.lastname: Wozniak
authors.forename: L K
authors.initials: LK
authors.lastname: Heilbrun
authors.forename: J I
authors.initials: JI
authors.lastname: McCormick
authors.forename: P E
authors.initials: PE
authors.lastname: Ruble
authors.forename: M A
authors.initials: MA
authors.lastname: Graham
authors.forename: J
authors.initials: J
authors.lastname: Purvis
authors.forename: J
authors.initials: J
authors.lastname: Rake
authors.forename: M
authors.initials: M
authors.lastname: Drozd
authors.forename: G F
authors.initials: GF
authors.lastname: Lockwood
authors.forename: T H
authors.initials: TH
authors.lastname: Corbett
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013892:Thioxanthenes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D013449:Sulfonamides; D013892:Thioxanthenes; C096974:WIN 33377