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

Lee Schwartzberg, Istvan Petak, Clinton Stewart, P. Kellie Turner, Jeri Ashley, David M. Tillman, Leslie Douglas, Ming Tan, Catherine Billups, Rudolf Mihalik, Alva Weir, Kurt Tauer, Steve Shope, Janet A. Haughton

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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 x 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 μM; 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.

Original languageEnglish (US)
Pages (from-to)2488-2498
Number of pages11
JournalClinical Cancer Research
Volume8
Issue number8
StatePublished - Jan 1 2002

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Leucovorin
Fluorouracil
Colonic Neoplasms
Carcinoma
Colorectal Neoplasms
Colon
CD95 Antigens
Therapeutics
Death Domain Receptors
Stomatitis
DNA Damage
Up-Regulation
Pharmacokinetics
RNA

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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. / Schwartzberg, Lee; Petak, Istvan; Stewart, Clinton; Turner, P. Kellie; Ashley, Jeri; Tillman, David M.; Douglas, Leslie; Tan, Ming; Billups, Catherine; Mihalik, Rudolf; Weir, Alva; Tauer, Kurt; Shope, Steve; Haughton, Janet A.

In: Clinical Cancer Research, Vol. 8, No. 8, 01.01.2002, p. 2488-2498.

Research output: Contribution to journalArticle

Schwartzberg, L, Petak, I, Stewart, C, Turner, PK, Ashley, J, Tillman, DM, Douglas, L, Tan, M, Billups, C, Mihalik, R, Weir, A, Tauer, K, Shope, S & Haughton, JA 2002, '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', Clinical Cancer Research, vol. 8, no. 8, pp. 2488-2498.
Schwartzberg, Lee ; Petak, Istvan ; Stewart, Clinton ; Turner, P. Kellie ; Ashley, Jeri ; Tillman, David M. ; Douglas, Leslie ; Tan, Ming ; Billups, Catherine ; Mihalik, Rudolf ; Weir, Alva ; Tauer, Kurt ; Shope, Steve ; Haughton, Janet A. / 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. In: Clinical Cancer Research. 2002 ; Vol. 8, No. 8. pp. 2488-2498.
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abstract = "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 x 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 μM; 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.",
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AU - Ashley, Jeri

AU - Tillman, David M.

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AU - Tan, Ming

AU - Billups, Catherine

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