Antitumor effects of human recombinant interleukin-6 on acute myeloid leukemia in mice and in cell cultures

Abstract

Interleukin-6 (IL-6) has been shown to inhibit growth and induce differentiation of several myeloid leukemia cell lines. In this work, two in vivo models of acute myeloid leukemia (AML) in mice have been used to test the therapeutic potential of recombinant human IL-6. In mice inoculated by a transplantable AML tumor, IL-6 injections inhibited the development of leukemia and increased survival. The effect was related to dose and length of treatment. In a model of radiation-induced leukemogenesis in SJL/J mice, administration of low- dose IL-6 for 10 days, 4 months after irradiation, reduced the incidence of leukemia observed during 1 year, whereas granulocyte- macrophage colony-stimulating factor (GM-CSF) increased the incidence of leukemia. In vitro liquid cultures of leukemic blood cells obtained from AML patients showed that IL-6 slowed growth and decreased the proportion of blasts with an increase in more mature myeloid elements in 72% of M1, M2, M4 AML cases. In contrast, GM-CSF less often produced differentiation but stimulated leukemic cell growth in liquid cultures, without synergism by IL-6.

Combined therapy with IL‐6 and inactivated tumor cells suppresses metastasis in mice bearing 3LL lung carcinomas

“…After 1 hour on ice, cells were pelleted, washed twice with 0.75 ml cold PBS-azide and transferred to a counting vial. Non-specific binding was determined for both cell lines by adding 200 ng of unlabeled murine IL-6 from Krebs ascites cells (Gothelf et al, 1991). Analysis of the binding data was performed with the LIGAND computer program (Munson, 1983;Chen et al, 1991).…”

“…IL-6 was shown to exhibit a direct anti-proliferative effect on certain tumor cells expressing IL-6 receptors (Revel, 1991;Aderka et al, 1992;Gothelf et al, 1991;Chen et al, 1991). To test whether murine carcinoma 3LL-D122 cells express highaffinity IL-6 receptors, recombinant murine IL-6 (mr-IL-6) was used for binding and competition in the presence or absence of 200-fold excess of unlabeled mIL-6 ( Fig.…”

“…Studies in our laboratory showed that the highly metastatic phenotype of D122 cells can be abrogated by transfection with H-2Kb genes, and that transfectants expressing this MHCclass-I antigen induce anti-tumor-specific CTL and are more sensitive to lysis by CTL than the parental cells (Eisenbach et al, 1984). IL-6 was shown to induce transcription factors that bind to and activate the interferon response sequence (IRS) in the promotor of (2'-5') oligoadenylate synthetase and MHCclass-I genes in myeloleukemia M1 cells (Gothelf et al, 1991), and MHC-class-I induction by IL-6 was shown recently in human colon carcinoma cells (Dansky Ullmann et al, 1992). Moreover, transfection of a hrIL-6 gene into D122 cells induced a 4-to 5-fold elevation in MHC-class-I expression FIGURE 1 -High-affinity murine-IL-6 receptor analysis of D122 cells.…”

“…In vitro IL-6 has opposing effects on the growth of different tumor cell types: it stimulates the growth of plasmacytomas and is considered as an autocrine growth factor in multiple myeloma and Kaposi sarcoma (Revel, 1991). On the other hand, IL-6 acts as a growth inhibitor on chronic lymphatic leukemia B-cells (Aderka et al, 1992), on myeloid leukemia cells, in which it can induce terminal differentiation (Gothelf et al, 1991), and on human breast-carcinoma cell lines . IL-6 can augment major-histocompatibility-complex-Class4 (MHC-Class-I) and other surface antigens on certain tumor cells (Gothelf et al, 1991;Dansky Ullman et al, 1992).…”

“…On the other hand, IL-6 acts as a growth inhibitor on chronic lymphatic leukemia B-cells (Aderka et al, 1992), on myeloid leukemia cells, in which it can induce terminal differentiation (Gothelf et al, 1991), and on human breast-carcinoma cell lines . IL-6 can augment major-histocompatibility-complex-Class4 (MHC-Class-I) and other surface antigens on certain tumor cells (Gothelf et al, 1991;Dansky Ullman et al, 1992). These host-mediated and direct cellular effects prompted us to test the anti-tumor potential of IL-6 in vivo.…”