Skip to main content
NCBI home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1991 May;34(3):143–149. doi: 10.1007/BF01742304

Cyclophosphamide modifies the induction kinetics but not cell types and cytotoxic mechanisms of antitumor cells elicited with OK-432 plus attenuated tumor cells

Kazuo Ryoyama 1,✉, Chizuko Ryoyama 1
PMCID: PMC11038439  PMID: 1756530

Abstract

The present study was designed to examine whether the antitumor cells induced by treatment with mitomycin-C-treated EL4 cells (EL4MMC) plus OK-432 plus cyclophosphamide differed from those induced by treatment with EL4MMC plus OK-432 in terms of their cell types and antitumor mechanisms. Antitumor activity of peritoneal exudate cells (PEC) from mice receiving either treatment was nonspecific, and inhibition of their target cell growth increased for up to 24 h. Macrophage toxin, silica and trypan blue abrogated the activity in vitro and in vivo, respectively. The activity of the PEC was inhibited with inhibitors of the arachidonic acid cascade, such as dexamethasone, 4-bromophenacyl bromide and nordihydroguaiaretic acid but not esculetin, ibuprofen, indomethacin and BW755C.N G-monomethyl-l-arginine, a specific competitive inhibitor of thel-arginine-dependent nitric oxide synthesis, also inhibited the activity. These results and morphological observations indicated that antitumor cells in the PEC from mice receiving either treatment were macrophages, and that their activity was closely related to the arachidonic acid cascade and to nitric oxide. Antitumor activity of the PEC spontaneously decayed in vitro and this decay was inhibited by the addition of OK-432 or lipopolysaccharide. On the other hand, cyclophosphamide sustained the appearance of antitumor cells in mice treated with EL4MMC plus OK-432. Therefore, cyclophosphamide treatment did not modify cell types and cytotoxic mechanisms of antitumor cells elicited with EL4MMC plus OK-432, but did modify the induction kinetics of such antitumor macrophages.

Key words: Antitumor macrophages, Arachidonic acid cascade, Nitric oxide, Cyclophosphamide, OK-432

References

  • 1.Balsari A, Marolda R, Gambacorti-Passerini C, Sciorelli G, Tona G, Cosulich E, Taramelli D, Fossati G, Parmiani G, Cascinelli N. Systemic administration of autologous, alloactivated helper-enriched lymphocytes to patients with metastatic melanoma of the lung. A phase I study. Cancer Immunol Immunother. 1986;21:148. doi: 10.1007/BF00199863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Braun DP, Harris JE. Effects of combination chemotherapy on immunoregulatory cells in peripheral blood of solid tumor cancer patients: correlation with rebound overshoot immune function recovery. Clin Immunol Immunopathol. 1981;20:193. doi: 10.1016/0090-1229(81)90178-1. [DOI] [PubMed] [Google Scholar]
  • 3.Dullens HFJ, Schakenraad S, Oostdijk A, Vuist W, Van Der Mass M, Den Otter W (1986) Specific tumoricidal activity of cytotoxic macrophages and cytotoxic lymphocytes, 22: 100 [DOI] [PMC free article] [PubMed]
  • 4.Eggers AE, Tarmin L, Gamboa ET. In vitro immunization against autologous glioblastoma-associated antigens. Cancer Immunol Immunother. 1985;19:43. doi: 10.1007/BF00199310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Hamburger AW, Dunn FE, Tencer KL. Separation on Percoll density gradients of cells derived from malignant ascites of mice. JNCI. 1983;70:157. [PubMed] [Google Scholar]
  • 6.Hayashi T, Arai S, Sendo F. The mechanisms of cytotoxicity to tumor cells by polymorphonuclear leukocytes stimulated with cytokines. Jpn J Cancer Res. 1988;79:375. doi: 10.1111/j.1349-7006.1988.tb01601.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Hibbs JB, Jr, Taintor RR, Vavrin Z. Macrophage cytotoxicity: role forl-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987;235:473. doi: 10.1126/science.2432665. [DOI] [PubMed] [Google Scholar]
  • 8.Hibbs JB, Jr, Vavrin Z, Taintor RR. l-Arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. J Immunol. 1987;138:550. [PubMed] [Google Scholar]
  • 9.Hogan MM, Vogel SN. Inhibition of macrophage tumoricidal activity by glucocorticoids. J Immunol. 1988;140:513. [PubMed] [Google Scholar]
  • 10.Jones B, Penfold P. Allograft cytotoxicity: critical role for adherent T cells in effector mechanism of the peritoneal population. Cell Immunol. 1979;46:259. doi: 10.1016/0008-8749(79)90415-5. [DOI] [PubMed] [Google Scholar]
  • 11.Keller R, Geiges M, Keist R. l-Arginine-dependent reactive nitrogen intermediates as mediators of tumor cell killing by activated macrophages. Cancer Res. 1990;50:1421. [PubMed] [Google Scholar]
  • 12.Lichtenstein AK, Kahle J, Berek J, Zighelboim J. Successful immunotherapy with intraperitonealCorynebacterium parvam in a murine ovarian cancer model is associated with the recruitment of tumor-lytic neutrophils into the peritoneal cavity. J Immunol. 1984;133:519. [PubMed] [Google Scholar]
  • 13.Mantovani A. The interaction of cancer chemotherapy agents with mononuclear phagocytes. Adv Pharmacol Chemother. 1982;19:35. doi: 10.1016/s1054-3589(08)60020-4. [DOI] [PubMed] [Google Scholar]
  • 14.Melioli G, Baldini E, Mingari MC, De Maria A, Sertoli MR, Badellino F, Percivale PL, Catturich A, Bertoglio S, Civalleri D, Santi L, Moretle L. Phenotypic and functional characteristics of tumor-associated lymphocytes in patients with malignant ascites receiving intraperitoneal infusions of recombinant interleukin-2 (rIL-2) Int J Cancer. 1989;43:231. doi: 10.1002/ijc.2910430210. [DOI] [PubMed] [Google Scholar]
  • 15.Moncada S, Palmer RMJ, Higgs A. Biosynthesis of nitric oxide froml-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol. 1989;38:1709. doi: 10.1016/0006-2952(89)90403-6. [DOI] [PubMed] [Google Scholar]
  • 16.Morikawa K, Takeda R, Yamazaki M, Mizuno D. Induction of tumoricidal activity of polymorphonuclear leukocytes by a linear β-1,3-d-glucan and other immunomodulators in murine cells. Cancer Res. 1985;45:1496. [PubMed] [Google Scholar]
  • 17.Nathan CF, Asofsky R, Terry WD. Characterization of the nonphagocytic adherent cell from the peritoneal cavity of normal and BCG-treated mice. J Immunol. 1977;118:1612. [PubMed] [Google Scholar]
  • 18.Parmiani G, Anichini A, Fossati G. Cellular immune response against autologous human malignant melanoma: are in vitro studies providing a framework for a more effective immunotherapy? J Natl Cancer Inst. 1990;82:361. doi: 10.1093/jnci/82.5.361. [DOI] [PubMed] [Google Scholar]
  • 19.Perret TG, Lemaire G. Dexamethasone inhibits antitumor potential of activated macrophages by a receptor mediated action. Biochem Biophys Res Commun. 1986;136:130. doi: 10.1016/0006-291x(86)90886-7. [DOI] [PubMed] [Google Scholar]
  • 20.Pickaver AH, Ratcliffe NA, Williams AE, Smith H. Cytotoxic effects of peritoneal neutrophils on a syngeneic rat tumor. Nature. 1972;235:186. doi: 10.1038/newbio235186a0. [DOI] [PubMed] [Google Scholar]
  • 21.Ryoyama K, Ryoyama C. Augmented induction of antitumor cells in vivo by cyclophosphamide fails to benefit antitumor resistance of the host. Cancer Immunol Immunother. 1989;29:255. doi: 10.1007/BF00199213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Ryoyama K, Murayama T, Koshimura S. Effect of OK-432 on immunization with mitomycin-C-treated L1210 cells. Gann. 1979;70:75. [PubMed] [Google Scholar]
  • 23.Schultz RM, Nanda SKW, Altom MG. Effects of various inhibitors of arachidonic acid oxygeneation on macrophage superoxide release and tumoricidal activity. J Immunol. 1985;135:2040. [PubMed] [Google Scholar]
  • 24.Stewart CC, Stevenson AP, Hibbs J. Effector mechanisms for macrophage-induced cytostasis and cytolysis of tumor cells. In: Heppner GH, Fulton AM, editors. Macrophages and cancer. Florida: CRC press; 1988. pp. 39–59. [Google Scholar]
  • 25.Stuehr DJ, Nathan CF. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989;169:1543. doi: 10.1084/jem.169.5.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Tappel AL, Lundberg WO, Boyer PD. Effect of temperature and antioxidants upon the lipoxidase-catalyzed oxidation of sodium linoleate. Arch Biochem Biophys. 1953;42:293. doi: 10.1016/0003-9861(53)90359-2. [DOI] [PubMed] [Google Scholar]
  • 27.Tsuru S, Aiso S, Taniguchi M, Zinnaka Y, Nomoto K. Mechanisms of in vivo generation of cytotoxic activity against syngeneic tumors. I. Local differentiation of mature cytotoxic T lymphocytes in the rejection of tumors. Immunology. 1985;54:281. [PMC free article] [PubMed] [Google Scholar]
  • 28.Tzeng J-J, Barth RF, Orosz CG, James SM. Phenotype and functional activity of tumor-infiltrating lymphocytes isolated from immunogenic and nonimmunogenic rat brain tumors. Cancer Res. 1991;51:23 273. [PubMed] [Google Scholar]
  • 29.Uchida A, Kariya Y, Okamoto N, Sugia K, Fujimoto T, Yagita M. Prediction of postoperative clinical course by autologous tumor-killing activity in lung cancer patients. J Natl Cancer Inst. 1990;82:1697. doi: 10.1093/jnci/82.21.1697. [DOI] [PubMed] [Google Scholar]
  • 30.Ujiie T. OK-432-mediated augmentation of antitumor immunity and generation of cytotoxic T lymphocytes. Jpn J Exp Med. 1987;57:103. [PubMed] [Google Scholar]
  • 31.Ujiie T. Chemoimmunotherapy of L1210 leukemia with adriamycin, cyclophosphamide and OK-432, and their effects on the generation of antitumor immunity. Jpn J Cancer Res (Gann) 1987;78:737. [PubMed] [Google Scholar]
  • 32.Vanky F, Klein E, Willems J, Böök K, Ivert T, Péterffy A, Nilsonne U, Kreicberg A, Aparisi T. Lysis of autologous tumor cells by blood lymphocytes tested at the time of surgery. Cancer Immunol Immunother. 1986;21:69. doi: 10.1007/BF00199380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Watanabe S, Sendo F, Kimura S, Arai S. Activation of cytotoxic polymorphonuclear leukocytes by in vivo administration of a streptococcal preparation, OK-432. JNCI. 1984;72:1365. [PubMed] [Google Scholar]
  • 34.Yasumoto K, Miyazaki K, Nagashima A, Ishida T, Kuda T, Yano T, Sugimachi K, Nomoto K. Induction of lymphokine-activated killer cells by intrapleural instillations of recombinant interleukin-2 in patients with malignant pleurisy due to lung cancer. Cancer Res. 1987;47:2184. [PubMed] [Google Scholar]
  • 35.Zöller M. Evaluation of in vivo and in vitro effectivity of immune defense against a spontaneously arising, nonlymphoid rat tumor. Cancer Immunol Immunother. 1985;19:189. doi: 10.1007/BF00199225. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES