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/m2) and LV (200 mg/m2), i.v. bolus daily x 5 days, with escalating doses of IFN-γ (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-γ on days 1 and 3 only. The dose-limiting toxicity, stomatitis, occurred most frequently at 100 μg/m2 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/m2 and ≥75 μg/m2 IFN-γ 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-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.
|Number of pages||11|
|Journal||Clinical Cancer Research|
|Publication status||Published - 2002|
ASJC Scopus subject areas
- Cancer Research