Phase I Trial of Exisulind (Sulindac Sulfone, FGN-1) as a Chemopreventive Agent in Patients with Familial Adenomatous Polyposis
2000
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.
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