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Modulation of the Fas Signaling Pathway by IFN- in Therapy of Colon Cancer: Phase I Trial and Correlative Studies of IFN-, 5-Fluorouracil, and Leucovorin¹

The West Clinic, Memphis, Tennessee 38120 [L. S. S., J. A., A. W., K. T., S. S.]; Division of Molecular Therapeutics, Department of Hematology-Oncology [I. P., D. M. T., L. D., J. A. H.], Department of Pharmaceutical Sciences [C. S., P. K. T.], and Department of Biostatistics [M. T., C. B.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105; and First Institute of Pathology and Experimental Cancer Research, Semmelweiss University of Medicine, Budapest, Hungary 1085 [R. M.]

Potentiation of 5-fluorouracil/leucovorin (FUra/LV) cytotoxicity by IFN- in colon carcinoma cells is dependent on FUra-induced DNA damage, the Fas death receptor, and independent of p53 and RNA-mediated FUra toxicity, which occurs in normal gastrointestinal tissues. This provides a rationale for enhancing the selective action of FUra/LV by IFN- in the treatment of colorectal carcinoma.

Based on results from our preclinical studies we designed a Phase I trial combining FUra (370 mg/m²) and LV (200 mg/m²), i.v. bolus daily x 5 days, with escalating doses of IFN- (10–100 µg/m²) s.c. on days 1, 3, and 5, every 28 days. Twenty-five patients with carcinomas were enrolled; 6 patients received IFN- on days 1 and 3 only.

The dose-limiting toxicity, stomatitis, occurred most frequently at 100 µg/m² IFN-. Minor response or SD was observed in 2 of 9 patients and in 4 of 12 patients at dose levels of 50 µg/m² and 75 µg/m² IFN-, respectively. Three evaluable chemonaive patients demonstrated partial response (2) or complete response (1). Serial plasma samples revealed peak FUra concentrations of >100 µM; at 100 µg/m² IFN- plasma concentrations >5 units/ml persisted for 6.5 h and >1 unit/ml for 28.5 h. The pharmacokinetic parameters of IFN- correlated with a 2–3-fold up-regulation of Fas expression at 24 h in CD15⁺ cells in peripheral blood samples. Furthermore, clinically relevant IFN- concentrations up-regulated Fas expression and sensitized HT29 colon carcinoma cells in vitro to FUra/LV cytotoxicity.

On the basis of the modulation of Fas signaling, FUra/LV combined with IFN- has shown activity in a Phase I trial in colorectal carcinoma and warrants additional evaluation in Phase II.

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