Modulation of the Fas signaling pathway by IFN-gamma in therapy of colon cancer: phase I trial and correlative studies of IFN-gamma, 5-fluorouracil, and leucovorin.
Potentiation of 5-fluorouracil/leucovorin (FUra/LV) cytotoxicity by IFN-gamma 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-gamma 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-gamma (10-100 micro g/m2) s.c. on days 1, 3, and 5, every 28 days. Twenty-five patients with carcinomas were enrolled; 6 patients received IFN-gamma on days 1 and 3 only. The dose-limiting toxicity, stomatitis, occurred most frequently at 100 micro g/m2 IFN-gamma. Minor response or SD was observed in 2 of 9 patients and in 4 of 12 patients at dose levels of < or =50 micro g/m2 and > or =75 micro g/m2 IFN-gamma, respectively. Three evaluable chemonaive patients demonstrated partial response (2) or complete response (1). Serial plasma samples revealed peak FUra concentrations of >100 micro M; at 100 micro g/m2 IFN-gamma plasma concentrations >5 units/ml persisted for 6.5 h and >1 unit/ml for 28.5 h. The pharmacokinetic parameters of IFN-gamma 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-gamma 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-gamma has shown activity in a Phase I trial in colorectal carcinoma and warrants additional evaluation in Phase II.
Schwartzberg
Lee S
LS
The West Clinic, Memphis, Tennessee 38120, USA.
Petak
Istvan
I
Stewart
Clinton
C
Turner
P Kellie
PK
Ashley
Jeri
J
Tillman
David M
DM
Douglas
Leslie
L
Tan
Ming
M
Billups
Catherine
C
Mihalik
Rudolf
R
Weir
Alva
A
Tauer
Kurt
K
Shope
Steve
S
Houghton
Janet A
JA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002469:Cell Separation; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000627:therapeutic use* / Q000633:toxicity; D005500:Follow-Up Studies; D006801:Humans; D007371:Interferon-gamma / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D002955:Leucovorin / Q000627:therapeutic use* / Q000633:toxicity; D016256:Lewis X Antigen / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D016256:Lewis X Antigen; D019014:fas Receptor; D007371:Interferon-gamma; D002955:Leucovorin; D005472:Fluorouracil