Effect of the combined treatment with 5-fluorouracil, gamma-interferon or folinic acid on carcinoembryonic antigen expression in colon cancer cells.
5-Fluorouracil (5-FU) and human recombinant gamma-interferon (gamma-IFN) were found to increase the expression of carcinoembryonic antigen (CEA) in human cancer cells in vitro. In the present study, the antimetabolite was associated with gamma-IFN or folinic acid (FA), a biochemical modulator of cellular metabolism of 5-FU, able to increase its antineoplastic activity. Treatment of two human colon cancer cell lines (HT-29 and WiDr) with 5-FU + gamma-IFN resulted in an increase of CEA expression higher than that obtainable with both agents alone, although no synergistic effects were obtained. This was demonstrated in terms of: (a) mRNA transcripts (HT-29); (b) cytoplasm and membrane CEA protein levels detected by Western blot analysis (HT-29); and (c) plasma membrane reactivity determined by flow cytometry analysis (HT-29 and WiDr). Moreover, 5-FU + gamma-IFN increased HLA class I molecules in the HT-29 cell membrane over that obtainable with gamma-IFN alone. In contrast, both agents did not induce the expression of the costimulatory molecule B7-1. Treatment with FA enhanced the antitumor effect of 5-FU but not its ability to augment CEA expression. This suggests that the FA-sensitive biochemical mechanism of action of 5-FU is not involved in its effect on CEA expression. In vivo studies showed, for the first time, that 5-FU, alone or combined with gamma-IFN, increases the amount of CEA protein over controls, either in cancer cells or in peripheral blood of nude mice bearing HT-29 cells. These results could be of potential diagnostic and/or therapeutic value when CEA protein is the target of humoral or cell-mediated immunity.
Aquino
A
A
Department of Neuroscience, University of Rome, Tor Vergata, Italy. Aquino@UniRoma2.it
Prete
S P
SP
Greiner
J W
JW
Giuliani
A
A
Graziani
G
G
Turriziani
M
M
De Filippi
R
R
Masci
G
G
Bonmassar
E
E
De Vecchis
L
L
D000818:Animals; D018122:B7-1 Antigen / Q000032:analysis; D015153:Blotting, Western; D002272:Carcinoembryonic Antigen / Q000032:analysis* / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D019073:HT29 Cells; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage*; D002955:Leucovorin / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000032:analysis; D014183:Transplantation, Heterologous
D018122:B7-1 Antigen; D002272:Carcinoembryonic Antigen; D015395:Histocompatibility Antigens Class I; D012333:RNA, Messenger; D007371:Interferon-gamma; D002955:Leucovorin; D005472:Fluorouracil