Leukoregulin, a direct-acting anticancer immunological hormone that is distinct from lymphotoxin and interferon

Human lymphokine preparations can directly lyse or suppress proliferation of human tumor cells or can enhance the susceptibility of human tumor cells to lysis mediated by natural killer lymphocytes. In the past, these antitumor activities were attributed to lymphotoxin. This study demonstrates, however, that these human lymphokine antitumor cell activities are biochemically separable from lymphotoxin and are properties of a lymphokine which was named leukoregulin because it is produced by lymphocytes and it regulates target cell physiology and growth. Leukoregulin obtained by high-performance liquid chromatography and isoelectric focusing was free of detectable lymphotoxin, interferon, interleukins 1 and 2, and macrophage-activating factor activities. Leukoregulin has an apparent molecular weight of 135,000 as measured by linear gradient polyacrylamide gel electrophoresis and gel filtration chromatography and has isoelectric pHs of approximately 5.3 and 7.5. The molecular weight of leukoregulin, determined in the dissociating conditions of sodium dodecyl sulfate polyacrylamide gel electrophoresis, was 32,000. Flow cytometric analysis showed that tumor cell lysis, growth inhibition, and enhancement of susceptibility to natural killer cell-mediated cytotoxicity by leukoregulin were accompanied by rapid alterations in tumor cell membrane permeability. Lymphotoxin from human peripheral blood leukocytes and highly purified lymphotoxin from RPMI 1788 human lymphoblastoid cells lysed murine alpha-L929 tumor cells but did not possess any of the direct acting antihuman tumor cell cytostatic, cytolytic, or natural killer cell enhancing activities that leukoregulin exhibited against a broad spectrum of human tumor cell lines. The dual modes of the anticancer actions of leukoregulin, direct cytotoxicity and indirect enhancement of natural killer cell cytotoxicity, make leukoregulin a unique-acting lymphokine and suggest several ways in which leukoregulin may be used as a therapeutic agent against cancer.