In vitro generation of cytotoxic T lymphocytes against HLA-A2.1-restricted peptides derived from human thymidylate synthase.
J Chemother
; 13(5): 519-26, 2001 Oct.
Article
in En
| MEDLINE
| ID: mdl-11760216
ABSTRACT
5-Fluorouracil (5-FU) is a pyrimidine antimetabolite active against colorectal carcinoma and other malignancies of the digestive tract. Over-expression or mutation of thymidylate synthase (TS), the target enzyme of the 5-FU metabolite, 5-fluorodeoxyuridine monophosphate, is strictly correlated with cancer cell resistance to 5-FU. On this basis we investigated whether TS is a potential target for active specific immunotherapy of human colon carcinoma, which acquires resistance to 5-FU. Three TS-derived epitope peptides which fit defined amino acid consensus motifs for HLA-A2.1 binding were synthesized and investigated for their ability to induce human TS-specific cytotoxic T cell (CTL) responses in vitro. CTL lines specific for each peptide were established by stimulating peripheral blood mononuclear cells (PBMC) from an HLA-A2.1+ healthy donor with autologous dendritic cells loaded with TS peptide. Specific CTL lines showed HLA-A2.1-restricted cytotoxicity in vitro to HLA-A2.1+ target cells pulsed with the specific TS peptide and to HLA-class I matching colon carcinoma target cells over-expressing TS enzyme after exposure to 5-FU. Recognition by CTL lines suggests that these TS peptides may be potential candidates for use in a peptide-based vaccine against 5-FU resistant colon carcinoma.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thymidylate Synthase
/
Carcinoma
/
T-Lymphocytes, Cytotoxic
/
HLA-A2 Antigen
/
Colonic Neoplasms
/
Fluorouracil
/
Antimetabolites, Antineoplastic
Limits:
Humans
Language:
En
Journal:
J Chemother
Journal subject:
ANTINEOPLASICOS
/
TERAPIA POR MEDICAMENTOS
Year:
2001
Document type:
Article
Affiliation country:
Italy