PMID- 16204693
OWN - NLM
STAT- MEDLINE
DCOM- 20051014
LR  - 20201222
IS  - 1460-2105 (Electronic)
IS  - 0027-8874 (Linking)
VI  - 97
IP  - 19
DP  - 2005 Oct 5
TI  - 5-fluorouracil-based chemotherapy enhances the antitumor activity of a 
      thymidylate synthase-directed polyepitopic peptide vaccine.
PG  - 1437-45
AB  - 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.
FAU - Correale, Pierpaolo
AU  - Correale P
AD  - Siena University School of Medicine, Viale Bracci 1, 53100 Siena, Italy.
FAU - Del Vecchio, Maria Teresa
AU  - Del Vecchio MT
FAU - Di Genova, Giuseppa
AU  - Di Genova G
FAU - Savellini, Gianni Gori
AU  - Savellini GG
FAU - La Placa, Marco
AU  - La Placa M
FAU - Terrosi, Chiara
AU  - Terrosi C
FAU - Vestri, Marzio
AU  - Vestri M
FAU - Urso, Renato
AU  - Urso R
FAU - Lemonnier, Francois
AU  - Lemonnier F
FAU - Aquino, Angelo
AU  - Aquino A
FAU - Bonmassar, Enzo
AU  - Bonmassar E
FAU - Giorgi, Giorgio
AU  - Giorgi G
FAU - Francini, Guido
AU  - Francini G
FAU - Cusi, Maria Grazia
AU  - Cusi MG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Cancer Vaccines)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-A Antigens)
RN  - 0 (Peptides)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
CIN - J Natl Cancer Inst. 2005 Oct 5;97(19):1396-7. PMID: 16204684
MH  - Animals
MH  - Antimetabolites, Antineoplastic/*pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology
MH  - Breast Neoplasms/drug therapy
MH  - Cancer Vaccines/immunology/*pharmacology
MH  - Carcinoma/drug therapy
MH  - Cell Culture Techniques
MH  - Colonic Neoplasms/drug therapy
MH  - Cytotoxicity, Immunologic/*drug effects
MH  - Dendritic Cells
MH  - Epitopes, T-Lymphocyte/*pharmacology
MH  - Female
MH  - Flow Cytometry
MH  - Fluorouracil/*pharmacology
MH  - HLA-A Antigens
MH  - Humans
MH  - Immunohistochemistry
MH  - Lymphoma/drug therapy
MH  - Mice
MH  - Mice, Transgenic
MH  - Peptides/pharmacology
MH  - T-Lymphocytes, Cytotoxic/*drug effects/immunology
MH  - Thymidylate Synthase/*metabolism
MH  - Transfection
MH  - Transplantation, Isogeneic
EDAT- 2005/10/06 09:00
MHDA- 2005/10/15 09:00
CRDT- 2005/10/06 09:00
PHST- 2005/10/06 09:00 [pubmed]
PHST- 2005/10/15 09:00 [medline]
PHST- 2005/10/06 09:00 [entrez]
AID - 97/19/1437 [pii]
AID - 10.1093/jnci/dji188 [doi]
PST - ppublish
SO  - J Natl Cancer Inst. 2005 Oct 5;97(19):1437-45. doi: 10.1093/jnci/dji188.