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Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1995 Nov;41(6):389–396. doi: 10.1007/BF01526559

Prophylactic intervention in radiation-leukemia-virus-induced murine lymphoma by the biological response modifier polysaccharide K

E Yefenof 1,, I Gafanovitch 1, E Oron 1, M Bar 1, E Klein 2
PMCID: PMC11037824  PMID: 8635197

Abstract

Polysaccharide K (PSK) is a biological response modifier used for adjuvant immunotherapy of malignant diseases. We studied the potential applicability of PSK for preventing tumor progression using an experimental model of murine lymphoma. Mice inoculated with the radiation leukemia virus (RadLV) develop thymic lymphomas after a latency of 3–6 months. However, 2 weeks after virus inoculation, prelymphoma cells can already be detected in the thymus. We found that PSK treatment induced hyperresponsiveness to concanavalin A and heightened production of interleukin-2 (IL-2) and IL-4 in spleen cells of both control and prelymphoma mice. The response was transient and was accompanied with a dominant usage of T cells expressing Vβ8, but other T cell subsets were also stimulated by PSK. T lymphoma cells expressing Vβ8.2 underwent apoptosis when incubated with PSK. Treatment of RadLV-inoculated mice with PSK delayed the onset of overt lymphoma (and mortality) but could not protect the mice from the disease. Combined treatment with PSK and a RadLV-specific immunotoxin prevented synergistically the progression of the prelymphoma cells to frank lymphoma. The results suggest that PSK contains a superantigen-like component that selectively activates Vβ8+ T cells. Its administration prelymphoma mice interfered with the process of lymphoma progression.

Key words: RadLV, Lymphoma, PSK, Superantigen, Prevention

References

  • 1.Tsukagoshi S, Hashimoto Y, Fujii G, Kobayashi H, Nomoto K, Orita K. Krestin (PSK) Cancer Treat Rev. 1984;11:131. doi: 10.1016/0305-7372(84)90005-7. [DOI] [PubMed] [Google Scholar]
  • 2.Ebihara K, Minamishima Y. Protective effect of biological response modifiers on murine cytomegalovirus infection. J Virol. 1984;51:117. doi: 10.1128/jvi.51.1.117-122.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Enrke MJ, Reino JM, Eppolito C, Mihich E. The effect of PSK, a protein bound polysaccharide on immune responses against allogeneic antigens. Int J Immunopharmacol. 1983;5:35. doi: 10.1016/0192-0561(83)90069-3. [DOI] [PubMed] [Google Scholar]
  • 4.Hosokawa M, Mizukoshi T, Sugawara M, Kobayashi H. Therapeutic effects of PSK and busulfan on the recurrent and metastatic diseases after the surgical removal of 3-methylcholanthrene-induced autochtonous tumors in C57BL/6 mice. Gann. 1985;76:61. [PubMed] [Google Scholar]
  • 5.Kondo M, Kato H, Yokoe N, Matsumura N, Hotta T, Masasuke M. Activation of the complement by immunostimulants, BCG, OK-432 (Picibani), and PS-K (Krestin) in vitro. Gann. 1978;69:699. [PubMed] [Google Scholar]
  • 6.Mizushima Y, Yuhki N, Hosokawa M, Kobayashi H. Diminution of cyclophosphamide-induced suppression of antitumor immunity by an immunomodulator PSK and combined therapeutic effects of PSK and cyclophosphamide on transplanted tumor in rats. Cancer Res. 1982;42:5176. [PubMed] [Google Scholar]
  • 7.Nomoto K, Yoshikumi C, Matsunaga K, Fujii T, Takeya K. Restoration of antibody-forming capacities by PS-K in tumorbearing mice. Gann. 1975;66:365. [PubMed] [Google Scholar]
  • 8.Tsurku S, Nomoto K. Effects of PSK on specific tumor immunity to syngeneic tumor cells. J Clin Lab Immunol. 1983;4:215. [PubMed] [Google Scholar]
  • 9.Torisu M, Hayashi Y, Ishimitsu T, Fujimura T, Iwasaki K, Katano M, Yamamoto H, Kimura Y, Takesue M, Motoharu K, Nomoto K. Significant prolongation of disease-free period gained by oral polysaccharide K (PSK) administration after curative surgical operation of colorectal cancer. Cancer Immunol Immunother. 1990;31:261. doi: 10.1007/BF01740932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Nakazato H, Koike A, Saji S, Ogawa N, Sakamoto J. Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Lancet. 1994;343:1122. doi: 10.1016/s0140-6736(94)90233-x. [DOI] [PubMed] [Google Scholar]
  • 11.Mitomi T. Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. Dis Colon Rectum. 1992;35:123. doi: 10.1007/BF02050666. [DOI] [PubMed] [Google Scholar]
  • 12.Fujii T, Saito K, Oguchi Y, Matsunaga K, Kobayashi Y, Yoshikumi C, Taguchi T. Effects of the protein-bound polysacharide preparation, PSK on spontaneous breast cancer in mice. J Int Med Res. 1988;16:286. doi: 10.1177/030006058801600406. [DOI] [PubMed] [Google Scholar]
  • 13.Yamane T, Fujita Y, Sagara Y, Okuzumi J, Kuwata K, Tanaka M, Takahashi T. The effect of a protein-bound polysaccharide preparation, PS-K, on carcinogenesis in the glandular stomach of rats induced byN-methyl-N'-nitro-N-nitrosoguanidine. J Kyoto Prefect Univ Med. 1989;98:307. [Google Scholar]
  • 14.Nakajima T, Ichikawa S, Uchida S, Komada T. Effects of a protein-bound polysaccharide from a basidiomycetes against hepatocarcinogenesis induced by ′3-methyl-4-dimethylaminoazobenzene in rats. Clin Ther. 1990;12:385. [PubMed] [Google Scholar]
  • 15.Henderson BE, Ross RK, Pike MC. Towards the primary prevention of cancer. Science. 1991;254:1131. doi: 10.1126/science.1957166. [DOI] [PubMed] [Google Scholar]
  • 16.Baum M, Ziv Y, Colletta AA. Can we prevent breast cancer? Br J Cancer. 1991;66:205. doi: 10.1038/bjc.1991.276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Klein G, Klein E. Evolution of tumors and the impact of molecular oncology. Nature. 1985;315:190. doi: 10.1038/315190a0. [DOI] [PubMed] [Google Scholar]
  • 18.Weinberg RA. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res. 1989;49:3713. [PubMed] [Google Scholar]
  • 19.Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet. 1993;9:138. doi: 10.1016/0168-9525(93)90209-z. [DOI] [PubMed] [Google Scholar]
  • 20.Wakefield LA, Sporn MB. Suppression of carcinogenesis: a role for TGF-β and related molecules in prevention of cancer. In: Klein G, editor. Tumor suppressor genes. New York: Dekker; 1990. p. 217. [PubMed] [Google Scholar]
  • 21.Haran-Ghera N. Spontaneous and induced preleukemia cells in C57BL/6 mice. J Natl Cancer Inst. 1978;60:707. doi: 10.1093/jnci/60.3.707. [DOI] [PubMed] [Google Scholar]
  • 22.Haran-Ghera N, Peled A. Induction of leukemia in mice by irradiation and radiation leukemia virus variants. Adv Cancer Res. 1979;30:45. doi: 10.1016/s0065-230x(08)60894-5. [DOI] [PubMed] [Google Scholar]
  • 23.Ben-David Y, Kotler M, Yefenof E. Leukemogenic, immunogenic and genetic properties of a thymotropic radiation leukemia virus. Int J Cancer. 1987;39:492. doi: 10.1002/ijc.2910390415. [DOI] [PubMed] [Google Scholar]
  • 24.Ben-David Y, Yefenof E, Kotler M. Clonal analysis of radiation leukemia virus (RadLV) induced leukemic and preleukemic cells. Cancer Res. 1987;47:6590. [PubMed] [Google Scholar]
  • 25.Yefenof E, Epsztein S, Kotler M. Quantitation, in vitro propagation and characterization of preleukemic cells induced by radiation leukemia virus. Cancer Res. 1991;51:2179. [PubMed] [Google Scholar]
  • 26.Yefenof E, Ela C, Kotler M, Vitetta ES. Induction of IL-4 secretion by the radiation leukemia virus (RadLV): role in autocrine growth stimulation of RadLV infected pre-leukemic cells. Int J Cancer. 1992;50:481. doi: 10.1002/ijc.2910500325. [DOI] [PubMed] [Google Scholar]
  • 27.Yefenof E, Abboud G, Epsztein S, Vitetta ES. Treatment of premalignancy: prevention of lymphoma in radiation leukemia virus inoculated mice by cyclosporin A and immunotoxin. Proc Natl Acad Sci USA. 1992;89:728. doi: 10.1073/pnas.89.2.728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Haas M. Continuous production of radiation leukemia virus in C57BL thymona tissue culture lines: purification of the leukemogenic virus. Cell. 1974;1:79. [Google Scholar]
  • 29.Haran-Ghera N, Ben-Yaakov M, Peled A. Immunologic characteristics in relation to high and low leukemogenic activity of radiation leukemia virus variants. J Immunol. 1977;118:600. [PubMed] [Google Scholar]
  • 30.Yefenof E, Meidav A, Kedar E. In vitro generation of cytotoxic lymphocytes against radiation and radiation leukemia virus (RadLV) induced tumors: III. Suppression of anti-tumor immunity in vitro by lymphocytes of mice undergoing RadLV induced leukemogenesis. J Exp Med. 1980;152:1473. doi: 10.1084/jem.152.6.1473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Fulton RJ, Uhr JW, Vitetta ES. In vitro therapy of the BCL1 tumor: Effect of immunotoxin valency and deglycosylation of the ricin A chain. Cancer Res. 1988;48:2626. [PubMed] [Google Scholar]
  • 32.Pullen AM, Marrack P, Kappler JW. The T cell repertoire is heavily influenced by tolerance to polymorphic self antigens. Nature. 1988;335:796. doi: 10.1038/335796a0. [DOI] [PubMed] [Google Scholar]
  • 33.Tomonari K, Lovering E, Spencer S. Correlation between the Vβ4+CD8+ T cell population and the H-2d haplotype. Immunogenetics. 1990;31:333. doi: 10.1007/BF02115007. [DOI] [PubMed] [Google Scholar]
  • 34.MacDonald HR, Schneider R, Less RK, Howe RC, Acha-Orbea H, Festenstein H, Zinkernagel RM, Hengartner H. T-cell receptor Vβ use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature. 1988;332:40. doi: 10.1038/332040a0. [DOI] [PubMed] [Google Scholar]
  • 35.Staerz U, Rammensee H, Benedetto J, Bevan M. Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor. J Immunol. 1985;134:3994. [PubMed] [Google Scholar]
  • 36.Haskins K, Hannum C, White J, Roehm N, Kubo R, Kappler J, Marrack P. The antigen specific, major histocompatibility complex-restricted receptor on T cells. VI. An antibody to a receptor allotype. J Exp Med. 1984;160:452. doi: 10.1084/jem.160.2.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Kappler JW, Staerz U, White J, Marrack PC. Self-tolerance eliminates T cells specific for M1s-modified products of the major histocompatibility complex. Nature. 1988;332:35. doi: 10.1038/332035a0. [DOI] [PubMed] [Google Scholar]
  • 38.Tomonari K, Lovering E. T cell receptor specific monoclonal antibodies against a Vβ11 positive mouse T cell clones. Immunogenetics. 1988;28:445. doi: 10.1007/BF00355377. [DOI] [PubMed] [Google Scholar]
  • 39.Kappler JW, Wade T, White J, Kushner E, Blackman M, Bill J, Roehm N, Marrack P. A T cell receptor Vβ segment that imparts reactivity to a class II major histocompatibility complex product. Cell. 1987;49:263. doi: 10.1016/0092-8674(87)90567-8. [DOI] [PubMed] [Google Scholar]
  • 40.Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980;284:555. doi: 10.1038/284555a0. [DOI] [PubMed] [Google Scholar]
  • 41.Reference deleted
  • 42.Fleischer B. Superantigens. Curr Opin Immunol. 1992;4:392. doi: 10.1016/s0952-7915(06)80028-2. [DOI] [PubMed] [Google Scholar]
  • 43.Yefenof E, Einat E, Klein E. Potentiation of T cell immunity against radiation-leukemia-virus-induced lymphoma by polysaccharide K. Cancer Immunol Immunother. 1991;34:133. doi: 10.1007/BF01741348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Boccoli G, Masciulli R, Ruggeri EM, Carlini P, Giannella G, Mongtesoro E, Mastroberardino G, Isacchi G, Testa U, Calabresi F, Peschle C. Adoptive immunotherapy of human cancer: the cytokine cascade and monocyte activation following high-dose Interleukin 2 Bolus treatment. Cancer Res. 1990;50:5795. [PubMed] [Google Scholar]
  • 45.Dupere S, Obiri N, Lackey A, Emma D, Yannelli J, Orr D, Birch R, O'Conner TE. Patterns of cytokines released by peripheral blood leukocytes of normal donors and cancer patients during interleukin-2 activation in vitro. J Biol Responses Mod. 1990;9:140. [PubMed] [Google Scholar]
  • 46.Economou JS, Hoban M, Lee JD, Essner R, Swisher S, McBride W, Hoon DB, Morton DL. Production of tumor necrosis factor α and interferon γ in interleukin-2-treated melanoma patients: correlation with clinical toxicity. Cancer Immunol Immunother. 1991;34:49. doi: 10.1007/BF01741324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Vetto JT, Papa MZ, Lotze MT, Chang AE, Rosenberg SA. Reduction of toxicity of interleukin-2 and lymphokine-activated killer cells in humans by the administration of corticosteroids. J Clin Oncol. 1987;5:496. doi: 10.1200/JCO.1987.5.3.496. [DOI] [PubMed] [Google Scholar]
  • 48.Margolin KA, Rayner AA, Hawkins MJ, Atkins MB, Dutcher JP, Fisher RI, Weiss GR, Doroshow JH, Jaffe HS, Roper M, Parkinson DR, Wiernik PH, Creekmore SP, Boldt DH. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J Clin Oncol. 1989;7:486. doi: 10.1200/JCO.1989.7.4.486. [DOI] [PubMed] [Google Scholar]
  • 49.Bukowski RM, Murthy S, Sergi J, Budd GT, McKeever S, Medendorp SV, Tubbs R, Gibson V, Finke J. Phase I trial of continuous infusion recombinant interleukin-2 and intermittent recombinant interferon-α2a: Clinical effects. J Biol Response Mod. 1990;9:538. [PubMed] [Google Scholar]

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