| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2005 Oxford University Press
ARTICLE |
5-Fluorouracil–Based Chemotherapy Enhances the Antitumor Activity of a Thymidylate Synthase–Directed Polyepitopic Peptide Vaccine
Affiliations of authors: Medical Oncology Section (PC, MLP, GF), Pathology Section, Department of Human Pathology and Oncology (MTDV, MV), Virology Section, Department of Molecular Biology (GDG, GGS, CT, MGC), "Giorgio Segre" Department of Pharmacology (RU, GG), Siena University School of Medicine, Siena, Italy; Immunité Cellulaire Antivirale, Institut Pasteur, Paris Cedex, France (FL); Medical Oncology and Pharmacology Section, Department of Neuroscience, University of Roma "Tor Vergata," Rome, Italy (AA, EB)
Correspondence to: Maria Grazia Cusi, PhD, Department of Molecular Biology, Virology Section, Siena University School of Medicine, Viale Bracci 1, 53100 Siena, Italy (e-mail: cusi{at}unisi.it) or Pierpaolo Correale, PhD, Department of Human Pathology and Oncology, Medical Oncology Section, Siena University School of Medicine, Viale Bracci 1, 53100 Siena, Italy (e-mail: correale{at}unisi.it).
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.
CiteULike 
Connotea 
Del.icio.us What's this?
Editorial about this Article
- Cytotoxins and Cancer Immunotherapy: The Dance of the Macabre?
- Carmen J. Allegra and Richard W. Childs
J Natl Cancer Inst 2005 97: 1396-1397.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
|
|
 |
|
  C. J. Allegra and R. W. Childs Cytotoxins and Cancer Immunotherapy: The Dance of the Macabre? J Natl Cancer Inst, October 5, 2005; 97(19): 1396 - 1397. [Full Text] [PDF]
|
|