Direct and Indirect Effects of Human Interferon Alpha on Renal Cell Carcinoma: a New in Vitro Assay System for Evaluating Cytokine-mediated Antitumor Effects

Overview

Journal Cancer Immunol Immunother

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 1993 Jul 1

PMID 8319245

Citations 1

Authors

H Matsuyama

S Yoshihiro

Y Ohmoto

N Yamamoto

K Naito

Affiliations

Soon will be listed here.

Abstract

A highly purified natural alpha-interferon (nIFN alpha) was tested in vitro for direct and indirect antiproliferative activity against renal cell carcinoma (RCC), using a modified human tumor clonogenic assay and clinically achievable concentrations. In preclinical experiments, the indirect (cytokine-mediated) antiproliferative activity of nIFN alpha was investigated using ACHN cells (established human RCC cell line). Continuous exposure to nIFN alpha at concentrations of more than 5 IU/ml in the presence of feeder cells (a mixture of 5 x 10(4) monocytes/dish and 5 x 10(5) lymphocytes/dish, obtained from healthy donors) significantly inhibited colony formation of ACHN cells in comparison with growth inhibition in the absence of feeder cells (P < 0.05). Various cytokines were measured in the supernatants lying over the medium on the feeder-layer agarose containing the same conditioned feeder cells. With IFN alpha at 500 IU/ml, tumor necrosis factor alpha (TNF alpha) and IFN gamma were detected at markedly high levels for 2-24 h. Neutralizing anti-TNF alpha monoclonal antibody significantly reduced the indirect antiproliferative activity. Using our modified human tumor clonogenic assay technique, sufficient numbers of colonies for drug testing were observed in 19 of 31 surgical specimens (61.3%). In these clinical materials, nIFN alpha at a clinically achievable concentration (50 IU/ml) significantly inhibited colony growth in the presence of feeder cells consisting of 5 x 10(4) monocytes/dish and 5 x 10(5) lymphocytes/dish, obtained from the patient whose tumor was examined (P < 0.05). In colony-forming cases, a significant correlation between the percentage colony survival and TNF alpha concentration in the supernatant was observed (r = -0.95, P < 0.01). These results suggest that this assay system may be an appropriate technique for evaluating the antiproliferative activities of nIFN alpha involving cytokine-mediated action, and that TNF alpha may play an important role in this cytokine-mediated activity.

Citing Articles

Cytokine-mediated antitumor effect of bacillus Calmette-Guérin on tumor cells in vitro.

Kurisu H, Matsuyama H, Ohmoto Y, Shimabukuro T, Naito K Cancer Immunol Immunother. 1994; 39(4):249-53.

PMID: 7954527 PMC: 11038674. DOI: 10.1007/BF01525988.

References

Hamburger A, Salmon S . Primary bioassay of human tumor stem cells. Science. 1977; 197(4302):461-3. DOI: 10.1126/science.560061. View

Salmon S, Durie B, Young L, Liu R, TROWN P, Stebbing N . Effects of cloned human leukocyte interferons in the human tumor stem cell assay. J Clin Oncol. 1983; 1(3):217-25. DOI: 10.1200/JCO.1983.1.3.217. View

Jett J, Mantovani A, Herberman R . Augmentation of human monocyte-mediated cytolysis by interferon. Cell Immunol. 1980; 54(2):425-34. DOI: 10.1016/0008-8749(80)90222-1. View

Rockwell S . Effects of clumps and clusters on survival measurements with clonogenic assays. Cancer Res. 1985; 45(4):1601-7. View

Saito T, Berens M, Welander C . Direct and indirect effects of human recombinant gamma-interferon on tumor cells in a clonogenic assay. Cancer Res. 1986; 46(3):1142-7. View

Ernstoff M, Fusi S, Kirkwood J . Parameters of interferon action: I. Immunological effects of whole cell leukocyte interferon (IFN-alpha) in phase I-II trials. J Biol Response Mod. 1983; 2(6):528-39. View

Paucker K, Cantell K, Henle W . Quantitative studies on viral interference in suspended L cells. III. Effect of interfering viruses and interferon on the growth rate of cells. Virology. 1962; 17:324-34. DOI: 10.1016/0042-6822(62)90123-x. View

Minato N, Reid L, CANTOR H, Lengyel P, Bloom B . Mode of regulation of natural killer cell activity by interferon. J Exp Med. 1980; 152(1):124-37. PMC: 2185902. DOI: 10.1084/jem.152.1.124. View

CARSWELL E, Old L, Kassel R, Green S, Fiore N, Williamson B . An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975; 72(9):3666-70. PMC: 433057. DOI: 10.1073/pnas.72.9.3666. View

10.

Urban J, Shepard H, Rothstein J, Sugarman B, Schreiber H . Tumor necrosis factor: a potent effector molecule for tumor cell killing by activated macrophages. Proc Natl Acad Sci U S A. 1986; 83(14):5233-7. PMC: 323925. DOI: 10.1073/pnas.83.14.5233. View

11.

Pace J, RUSSELL S, Schreiber R, Altman A, Katz D . Macrophage activation: priming activity from a T-cell hybridoma is attributable to interferon-gamma. Proc Natl Acad Sci U S A. 1983; 80(12):3782-6. PMC: 394136. DOI: 10.1073/pnas.80.12.3782. View

12.

Herberman R, Ortaldo J . Natural killer cells: their roles in defenses against disease. Science. 1981; 214(4516):24-30. DOI: 10.1126/science.7025208. View

13.

Matsuyama H . [The in vitro assessment of various types of interferons for urological tumors by the human tumor clonogenic assay]. Hinyokika Kiyo. 1986; 32(4):503-11. View

14.

Sadlik J, Hoyer M, Leyko M, Horvat R, Parmely M, Whitacre C . Lymphocyte supernatant-induced human monocyte tumoricidal activity: dependence on the presence of gamma-interferon. Cancer Res. 1985; 45(5):1940-5. View

15.

Saito T, Berens M, Welander E . Characterization of the indirect antitumor effect of gamma-interferon using ascites-associated macrophages in a human tumor clonogenic assay. Cancer Res. 1987; 47(3):673-9. View

16.

Bitterlich G, Szabo G, Werner E, Larcher C, Fuchs D, Hausen A . Selective induction of mononuclear phagocytes to produce neopterin by interferons. Immunobiology. 1988; 176(3):228-35. DOI: 10.1016/S0171-2985(88)80055-X. View

17.

Balch C, Riley L, Bae Y, Salmeron M, Platsoucas C, von Eschenbach A . Patterns of human tumor-infiltrating lymphocytes in 120 human cancers. Arch Surg. 1990; 125(2):200-5. DOI: 10.1001/archsurg.1990.01410140078012. View

18.

Leary P, GRESSER I . Interferon inhibits DNA synthesis induced in mouse lymphocyte suspensions by phytohaemagglutinin or by allogeneic cells. Nat New Biol. 1972; 237(73):120-1. DOI: 10.1038/newbio237120a0. View

19.

Epstein L, Shen J, Abele J, Reese C . Sensitivity of human ovarian carcinoma cells to interferon and other antitumor agents as assessed by an in vitro semi-solid agar technique. Ann N Y Acad Sci. 1980; 350:228-44. DOI: 10.1111/j.1749-6632.1980.tb20624.x. View

20.

Zarling J, Eskra L, Borden E, Horoszewicz J, CARTER W . Activation of human natural killer cells cytotoxic for human leukemia cells by purified interferon. J Immunol. 1979; 123(1):63-70. View