Background and Methods: It has been shown that T-cell dysfunction, including apoptosis of peripheral blood T cells, commonly occurs in patients receiving chemotherapy. In order to evaluate whether concomitant administration of the oral biological response modifier protein-bound polysaccharide K (PSK) could induce anti-apoptotic effects in patients treated with the anti-cancer drug, S-1, peripheral blood T cells were analyzed for induction of apoptosis, caspase-3 activities and expression of proapoptotic protein Bax and anti-apoptotic protein Bcl-2 in patients with curatively resected stage III gastric cancer, who were randomly assigned to postoperative adjuvant therapy with S-1 alone (n = 10) or S-1 combined with PSK (n = 10). Results: T-cell apoptosis 5 weeks after adjuvant therapy was significantly higher in the S-1 group (24.1 ± 5.0%) than in the S-1 + PSK group (19.1 ± 3.9%). S-1 induced T-cell apoptosis and concomitantly elevated caspase-3 activities and Bax expression in peripheral blood T cells. In addition, PSK partially prevented the T-cell apoptosis induced by S-1. Conclusion: PSK could partially prevent the T-cell apoptosis induced by S-1.

1.
Pawelec G, Heinzel S, Kiessling R, Muller L, Ouyang Q, Zeuthen J: Escape mechanisms in tumor immunity: a year 2000 update. Crit Rev Oncog 2000;11:97–133.
2.
Muller L, Kiessling R, Rees RC, Pawelec G: Escape mechanisms in tumor immunity: an update. J Environ Pathol Toxicol Oncol 2002;21:277–330.
3.
Garrido F, Cabrera T, Concha A, Glew S, Ruiz-Cabello F, Stern PL: Natural history of HLA expression during tumour development. Immunol Today 1993;14:491–499.
4.
Kiessling R, Kono K, Petersson M, Wasserman K: Immunosuppression in human tumor-host interaction: role of cytokines and alterations in signal-transducing molecules. Springer Semin Immunopathol 1996;18:227–242.
5.
Tanaka Y, Tevethia SS: In vitro selection of SV40 T antigen epitope loss variants by site-specific cytotoxic T lymphocyte clones. J Immunol 1988;140:4348–4354.
6.
Restifo NP, Esquivel F, Kawakami Y, Yewdell JW, Mule JJ, Rosenberg SA, Bennink JR: Identification of human cancers deficient in antigen processing. J Exp Med 1993;177:265–272.
7.
Tada T, Ohzeki S, Utsumi K, Takiuchi H, Muramatsu M, Li XF, Shimizu J, Fujiwara H, Hamaoka T: Transforming growth factor-beta-induced inhibition of T cell function. Susceptibility difference in T cells of various phenotypes and functions and its relevance to immunosuppression in the tumor-bearing state. J Immunol 1991;146:1077–1082.
8.
Finke JH, Zea AH, Stanley J, Longo DL, Mizoguchi H, Tubbs RR, Wiltrout RH, O’Shea JJ, Kudoh S, Klein E, Bukowski RM, Ochoa AC: Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Res 1993;53:5613–5616.
9.
Zea AH, Curti BD, Longo DL, Alvord WG, Strobl SL, Mizoguchi H, Creekmore SP, O’Shea JJ, Powers GC, Urba WJ, Ochoa AC: Alterations in T cell receptor and signal transduction molecules in melanoma patients. Clin Cancer Res 1995;1:1327–1335.
10.
Kono K, Ressing ME, Brandt RM, Melief CJ, Potkul RK, Andersson B, Petersson M, Kast WM, Kiessling R: Decreased expression of signal-transducing zeta chain in peripheral T cells and natural killer cells in patients with cervical cancer. Clin Cancer Res 1996;2:1825–1828.
11.
Nakagomi H, Petersson M, Magnusson I, Juhlin C, Matsuda M, Mellstedt H, Taupin JL, Vivier E, Anderson P, Kiessling R: Decreased expression of the signal-transducing zeta chains in tumor- infiltrating T-cells and NK cells of patients with colorectal carcinoma. Cancer Res 1993;53:5610–5612.
12.
Lai P, Rabinowich H, Crowley-Nowick PA, Bell MC, Mantovani G, Whiteside TL: Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. Clin Cancer Res 1996;2:161–173.
13.
Reichert TE, Day R, Wagner EM, Whiteside TL: Absent or low expression of the zeta chain in T cells at the tumor site correlates with poor survival in patients with oral carcinoma. Cancer Res 1998;58:5344–5347.
14.
Gastman BR, Johnson DE, Whiteside TL, Rabinowich H: Caspase-mediated degradation of T-cell receptor zeta-chain. Cancer Res 1999;59:1422–1427.
15.
Saito T, Kuss I, Dworacki G, Gooding W, Johnson JT, Whiteside TL: Spontaneous ex vivo apoptosis of peripheral blood mononuclear cells in patients with head and neck cancer. Clin Cancer Res 1999;5:1263–1273.
16.
Takahashi A, Kono K, Amemiya H, Iizuka H, Fujii H, Matsumoto Y: Elevated caspase-3 activity in peripheral blood T cells coexists with increased degree of T-cell apoptosis and down-regulation of TCR zeta molecules in patients with gastric cancer. Clin Cancer Res 2001;7:74–80.
17.
Takahashi A, Hanson MG, Norell HR, Havelka AM, Kono K, Malmberg KJ, Kiessling RV: Preferential cell death of CD8+ effector memory (CCR7-CD45RA-) T cells by hydrogen peroxide-induced oxidative stress. J Immunol 2005;174:6080–6087.
18.
Kim JW, Tsukishiro T, Johnson JT, Whiteside TL: Expression of pro- and antiapoptotic proteins in circulating CD8+ T cells of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 2004;10:5101–5110.
19.
Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K; ACTS-GC Group: Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810–1820.
20.
Koizumi W, Kurihara M, Nakano S, Hasegawa K: Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. For the S-1 Cooperative Gastric Cancer Study Group. Oncology 2000;58:191–197.
21.
Nio Y, Imai S, Shiraishi T, Ohgaki K, Tobe T: Lymphocytes anticancer chemosensitivity testing in vitro – an approach to predict immunosuppressive effect of anticancer agents. J Clin Lab Immunol 1989;29:141–145.
22.
Kiessling R, Wasserman K, Horiguchi S, Kono K, Sjoberg J, Pisa P, Petersson M: Tumor-induced immune dysfunction. Cancer Immunol Immunother 1999;48:353–362.
23.
Fisher M, Yang LX: Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy. Anticancer Res 2002;22:1737–1754.
24.
Kato M, Hirose K, Hakozaki M, Ohno M, Saito Y, Izutani R, Noguchi J, Hori Y, Okumoto S, Kuroda D, et al: Induction of gene expression for immunomodulating cytokines in peripheral blood mononuclear cells in response to orally administered PSK, an immunomodulating protein-bound polysaccharide. Cancer Immunol Immunother 1995;40:152–156.
25.
Noguchi K, Tanimura H, Yamaue H, Tsunoda T, Iwahashi M, Tani M, Mizobata S, Hotta T, Arii K, Tamai M, et al: Polysaccharide preparation PSK augments the proliferation and cytotoxicity of tumor-infiltrating lymphocytes in vitro. Anticancer Res 1995;15:255–258.
26.
Habelhah H, Okada F, Nakai K, Choi SK, Hamada J, Kobayashi M, Hosokawa M: Polysaccharide K induces Mn superoxide dismutase (Mn-SOD) in tumor tissues and inhibits malignant progression of QR-32 tumor cells: possible roles of interferon alpha, tumor necrosis factor alpha and transforming growth factor beta in Mn-SOD induction by polysaccharide K. Cancer Immunol Immunother 1998;46:338–344.
27.
Nakazato H, Koike A, Saji S, Ogawa N, Sakamoto J: Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Study Group of Immunochemotherapy with PSK for Gastric Cancer. Lancet 1994;343:1122–1126.
28.
Ohwada S, Ikeya T, Yokomori T, Kusaba T, Roppongi T, Takahashi T, Nakamura S, Kakinuma S, Iwazaki S, Ishikawa H, Kawate S, Nakajima T, Morishita Y: Adjuvant immunochemotherapy with oral Tegafur/Uracil plus PSK in patients with stage II or III colorectal cancer: a randomised controlled study. Br J Cancer 2004;90:1003–1010.
29.
Sakamoto J, Morita S, Oba K, Matsui T, Kobayashi M, Nakazato H, Ohashi Y; Meta-Analysis Group of the Japanese Society for Cancer of the Colon Rectum: efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curatively resected colorectal cancer: a meta-analysis of centrally randomized controlled clinical trials. Cancer Immunol Immunother 2006;55:404–411.
30.
Alexandre J, Nicco C, Chereau C, Laurent A, Weill B, Goldwasser F, Batteux F: Improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic mangafodipir. J Natl Cancer Inst 2006;98:236–244.
31.
Cheng H, Liu Y, Liu S, Zheng D: 5-Fluorouracil enhances apoptosis sensitivity of T lymphocytes mediated by CD3 epsilon. Cell Biochem Funct 2004;22:187–195.
32.
Ueda Y, Fujimura T, Kinami S, Hirono Y, Yamaguchi A, Naitoh H, Tani T, Kaji M, Yamagishi H, Miwa K; Hokuriku-Kinki Immunochemo-Therapy Study Group-Gastric Cancer (HKIT-GC): A randomized phase III trial of postoperative adjuvant therapy with S-1 alone versus S-1 plus PSK for stage II/IIIA gastric cancer: Hokuriku-Kinki Immunochemo-Therapy Study Group-Gastric Cancer (HKIT-GC). Jpn J Clin Oncol 2006;36:519–522.
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