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

• Published in: Clinical cancer research 2002-08, Vol.8 (8), p.2488-2498
• Main Authors: SCHWARTZBERG, Lee S, PETAK, Istvan, WEIR, Alva, TAUER, Kurt, SHOPE, Steve, HOUGHTON, Janet A, STEWART, Clinton, TURNER, P. Kellie, ASHLEY, Jeri, TILLMAN, David M, DOUGLAS, Leslie, MING TAN, BILLUPS, Catherine, MIHALIK, Rudolf
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic - therapeutic use; Antimetabolites, Antineoplastic - toxicity; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Cell Separation; Colorectal Neoplasms - drug therapy; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Dose-Response Relationship, Drug; fas Receptor - metabolism; Female; Flow Cytometry; Fluorouracil - therapeutic use; Fluorouracil - toxicity; Follow-Up Studies; Humans; Interferon-gamma - pharmacokinetics; Interferon-gamma - therapeutic use; Interferon-gamma - toxicity; Leucovorin - therapeutic use; Leucovorin - toxicity; Lewis X Antigen - biosynthesis; Male; Medical sciences; Middle Aged; Models, Biological; Pharmacology. Drug treatments; Signal Transduction; Time Factors; Tumor Cells, Cultured; Up-Regulation
• ISSN: 1078-0432; 1557-3265

Potentiation of 5-fluorouracil/leucovorin (FUra/LV) cytotoxicity by IFN-γ 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-γ in the treatment of colorectal carcinoma. Based on results from our preclinical studies we designed a Phase I trial combining FUra (370 mg/m 2 ) and LV (200 mg/m 2 ), i.v. bolus daily × 5 days, with escalating doses of IFN-γ (10–100 μg/m 2 ) s.c. on days 1, 3, and 5, every 28 days. Twenty-five patients with carcinomas were enrolled; 6 patients received IFN-γ on days 1 and 3 only. The dose-limiting toxicity, stomatitis, occurred most frequently at 100 μg/m 2 IFN-γ. Minor response or SD was observed in 2 of 9 patients and in 4 of 12 patients at dose levels of ≤50 μg/m 2 and ≥75 μg/m 2 IFN-γ, respectively. Three evaluable chemonaive patients demonstrated partial response (2) or complete response (1). Serial plasma samples revealed peak FUra concentrations of >100 μ m ; at 100 μg/m 2 IFN-γ plasma concentrations >5 units/ml persisted for 6.5 h and >1 unit/ml for 28.5 h. The pharmacokinetic parameters of IFN-γ 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-γ 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-γ has shown activity in a Phase I trial in colorectal carcinoma and warrants additional evaluation in Phase II.