5-Fluorouracil–Based Chemotherapy Enhances the Antitumor Activity of a Thymidylate Synthase–Directed Polyepitopic Peptide Vaccine

Autor: Marzio Vestri, Enzo Bonmassar, Gianni Gori Savellini, Marco La Placa, Angelo Aquino, Guido Francini, Giorgio Giorgi, François Lemonnier, Giuseppa Di Genova, Renato Urso, Maria Teresa Del Vecchio, Pierpaolo Correale, Chiara Terrosi, Maria Grazia Cusi
Rok vydání: 2005
Předmět:
Cytotoxic
Cytotoxicity
medicine.medical_treatment
animal cell
colon carcinoma
cancer cell culture
Thymidylate synthase
Transgenic
Epitope
fluorouracil
Epitopes
Mice
Antineoplastic Combined Chemotherapy Protocols
Cytotoxic T cell
Isogeneic
antineoplastic antimetabolite
target cell
epitope
drug effect
Settore BIO/14
Flow Cytometry
Antineoplastic
Immunohistochemistry
peptide
priority journal
Oncology
mouse strain
Antimetabolites
Antineoplastic
Transfection
in vivo study
Humans
human
protein expression
mouse
drug potentiation
human cell
Dendritic Cells
Immunotherapy
culture technique
transgenic mouse
Transplantation
Isogeneic
CTL
T-Lymphocyte
Cancer cell
Immunology
Peptide vaccine
genetic transfection
Peptides
T-Lymphocytes
Cytotoxic
Cytotoxicity
Immunologic
Cancer Research
peripheral blood mononuclear cell
Lymphoma
Antimetabolites
Settore MED/06 - Oncologia Medica
T-Lymphocytes
Cell Culture Techniques
Epitopes
T-Lymphocyte
major histocompatibility antigen class 1
cytotoxic T lymphocyte
carcinoma
immunology
thymidylate synthase directed polyepitopic peptide vaccine
Immunologic
antigen binding
animal
breast carcinoma
antineoplastic agent
HLA A antigen
breast tumor
apoptosis
article
colon tumor
unclassified drug
enzyme activity
female
Colonic Neoplasms
cancer vaccine
dendritic cell
Mice
Transgenic
Breast Neoplasms
thymidylate synthase
antineoplastic activity
cellular immunity
isograft
Biology
interleukin 2
Cancer Vaccines
Immune system
medicine
Animals
concentration response
immunohistochemistry
nonhuman
cytotoxicity
flow cytometry
lymphoma
metabolism
Carcinoma
Female
Fluorouracil
HLA-A Antigens
Thymidylate Synthase
Transplantation
Cancer research
biology.protein
Zdroj: JNCI: Journal of the National Cancer Institute. 97:1437-1445
ISSN: 1460-2105
0027-8874
DOI: 10.1093/jnci/dji188
Popis: Background: Thymidylate synthase (TS), a key enzyme in DNA synthesis, is often overexpressed in cancer cells. Some chemotherapeutic agents, such as 5-fluorouracil (5-FU), act by inhibiting TS expression. We evaluated whether a novel 28-amino acid multiepitope peptide, TS/PP, that contains the sequences of three TS-derived epitopes with binding motifs for HLA-A(*)02.01 could induce a TS-directed cytotoxic T-lymphocyte (CTL) response with antitumor activity. Methods: TS/PP peptide immunologic activity in CTL lines derived from human leukocyte antigen (HLA)-A(*)02.01 + peripheral blood mononuclear cells (PBMCs) was tested in the presence of interleukin-2 and autologous TS/PP peptide-loaded dendritic cells. Immunologic and antitumor activities of TS/PP and its toxicity were also evaluated in vivo in HLA-A(*)02.01 transgenic (HHD) mice that were vaccinated with TS/PP, control, or TS-peptide cocktail and treated with or without 5-FU chemotherapy. The mice were also inoculated subcutaneously with TS-expressing EL-4/HHD lymphoma cells to assess immune response against these tumor cells. Results: TS/PP-specific CTL lines showed a TS-multiepitopic specificity and were able to kill TS + /HLA-A(*)02.01 + breast and colon carcinoma cells. The killing ability against target cells previously exposed to sublethal doses of 5-FU was statistically significantly greater than against untreated target cells (43.5% versus 26.5% at 25/1 effector to target ratio [Difference {diff} = 17.0]; 95% confidence interval [CI] = 12.6 to 20.4) for MDA-MB-231 breast carcinoma cells and 73.5 versus 48.5 (diff = 25.0; 95% CI = 16.2 to 33.8) for the SW-1463 colon carcinoma cells. HHD mice vaccinated with TS/PP manifested a TS-peptide-specific CTL response with no sign of autoimmunity or toxicity. Furthermore, treatment of these mice with 5-FU delayed or prevented the occurrence of tumors formed by inoculation with autologous (TS + )EL-4/HHD lymphoma cells. Conclusions: The multiepitopic TS/PP vaccine induces a tumor-specific immune response in mice and is especially potent when used in combination with 5-FU-based chemotherapy.
Databáze: OpenAIRE
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