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Recombinant human interleukin-4 inhibits growth of some human lung tumor
cell lines in vitro and in vivo
MS Topp, M Koenigsmann, A Mire-Sluis, D Oberberg, F Eitelbach, Z von Marschall, M Notter, B Reufi, H Stein and E Thiel
Department of Hematology/Oncology, Klinikum Steglitz, Freie Universitaet
Berlin, Germany.
Cytokines play an important role in activating the immune system against
malignant cells. One of these cytokines, interleukin-4 (IL-4) has entered
clinical phase I trials because of its immunoregulatory potency. In the
present study we report that recombinant human (rh) IL- 4 has major direct
antiproliferative effects on one human lung cancer cell line (CCL 185) in
vitro as measured by a human tumor cloning assay (HTCA), tritiated
thymidine uptake, and counting cell numbers and marginal activity in a
second cell line (HTB 56) in the HTCA. This activity could be abolished by
neutralizing antibody against rhIL-4. The biological response of the tumor
cells to the cytokine is correlated with expression of receptors for human
IL-4 on both the mRNA level and the protein level. The responsive cell
line, CCL 185, secretes IL-6 after being incubated with rhIL-4. On the
other hand, neutralizing antibodies against IL-6 showed no influence on the
growth modulatory efficacy of rhIL-4 in this cell line. Furthermore, CCL
185 does not show detectable production of IL-1, tumor necrosis factor
alpha or interferon gamma after incubation with rhIL-4. Thus, the response
to rhIL-4 is not mediated through autocrine production of these cytokines
triggered by rhIL-4. In a next series of experiments some of the cell lines
were xenotransplanted to BALB/c nu/nu mice. Subsequently, the mice were
treated for 12 days with two doses of 0.5 mg/m2 rhIL-4 or control vehicle
subcutaneously per day. Treatment with rhIL-4 yielded a significant
inhibition of tumor growth versus control in two of the non-small cell lung
cancer cell lines being responsive in vitro (CCL 185, HTB 56). Histology of
the tumors in both groups showed no marked infiltration of the tumors with
murine hematopoietic and lymphocytic cells consistent with the species
specificity of IL-4. In contrast, no tumor growth inhibition was found in
the small cell lung cancer cell lines (HTB 119, HTB 120) being
nonresponsive in vitro. We conclude that rhIL-4 has direct
antiproliferative effects on the growth of some human non-small cell lung
cancer cell lines in vitro and in vivo, which together with its regulatory
effects on various effector cell populations makes this cytokine an
interesting candidate for further investigation in experimental cancer
treatment.
Volume 82,
Issue 9,
pp. 2837-2844,
11/01/1993
Copyright © 1993 by The American Society of Hematology
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