title: Phase I trial of exisulind (sulindac sulfone, FGN-1) as a chemopreventive agent in patients with familial adenomatous polyposis.
abstract: Exisulind (sulindac sulfone; FGN-1), a metabolite of sulindac without known effects on prostaglandin synthesis, can promote apoptosis and inhibit tumorigenesis in preclinical systems. We performed a Phase I trial of this compound in patients with familial adenomatous polyposis (FAP) to examine the tolerability and safety of this drug in the cancer chemoprevention setting. Six patients each were treated with exisulind at doses of 200, 300, and 400 mg p.o. twice a day. Reversible hepatic dysfunction was noted in four of six patients treated at the 400-mg p.o., twice-a-day dose level, but in only one to two of six patients treated at each of the lower dose levels. The serum half-life of exisulind was 6-9 h; little drug accumulation was noted over time. A nonsignificant trend toward increased apoptosis in polyps was noted at the maximum tolerated dose, but no decrease in polyp numbers or significant effects on cellular proliferation was noted. After treatment, polyps tended to display a "halo" appearance grossly and mucinous differentiation histologically. The maximum safe dose of exisulind is 300 mg p.o. twice a day in patients with subtotal colectomies. Reversible hepatic dysfunction limits further dose escalation. A decrease in polyp numbers could not be demonstrated, but the trend toward increased apoptosis at the MTD and the observation of mucinous change histologically suggest that further investigation of drugs of this class might be warranted.
authors.affiliation: The Taussig Cancer Center, Department of Gastroenterology, Cleveland Clinic Foundation, Ohio 44195, USA.
authors.forename: R
authors.initials: R
authors.lastname: van Stolk
authors.forename: G
authors.initials: G
authors.lastname: Stoner
authors.forename: W L
authors.initials: WL
authors.lastname: Hayton
authors.forename: K
authors.initials: K
authors.lastname: Chan
authors.forename: B
authors.initials: B
authors.lastname: DeYoung
authors.forename: L
authors.initials: L
authors.lastname: Kresty
authors.forename: B H
authors.initials: BH
authors.lastname: Kemmenoe
authors.forename: P
authors.initials: P
authors.lastname: Elson
authors.forename: L
authors.initials: L
authors.lastname: Rybicki
authors.forename: J
authors.initials: J
authors.lastname: Church
authors.forename: K
authors.initials: K
authors.lastname: Provencher
authors.forename: D
authors.initials: D
authors.lastname: McLain
authors.forename: E
authors.initials: E
authors.lastname: Hawk
authors.forename: B
authors.initials: B
authors.lastname: Fryer
authors.forename: G
authors.initials: G
authors.lastname: Kelloff
authors.forename: R
authors.initials: R
authors.lastname: Ganapathi
authors.forename: G T
authors.initials: GT
authors.lastname: Budd
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000473:pathology; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D017209:Apoptosis; D005260:Female; D006207:Half-Life; D006801:Humans; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D013467:Sulindac / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; D013467:Sulindac; C025463:sulindac sulfone