Lymphokines, interleukins, and other immunological hormones, i.e., the secretory bioregulatory macromolecules of lymphocytes, macrophages, and other leukocytes, are being studied to define their effective anticarcinogenic and tumor cell growth inhibitory activities. Leukoregulin, a lymphokine recently isolated during the course of this project, can prevent carcinogenesis and inhibit tumor cell growth. Anticarcinogenic action is direct, irreversible and occurs without cytotoxicity. Inhibition of tumor cell growth is primarily reversible but can become irreversible due to increased susceptibility of preneoplastic and neoplastic cells to cytolytic destruction by natural killer cells resulting from leukoregulin target cell interaction. Leukoregulin at very high concentrations is also directly cytolytic for tumor cells. The direct-acting anticarcinogenic activity of leukoregulin is more potent than the tumor cell inhibitory activity; but by also being able to increase target cell sensitivity to the cytoreductive action of naturally cytotoxic lymphocytes, leukoregulin can be an effective homeostatic mechanism for control of carcinogenesis at its later stages of development. Leukoregulin-induced changes in plasma membrane permeability are partially dependent upon extracellular ionic calcium and are accompanied by increased calcium flux, the rapid opening and closing of plasma membrane single ion channels and translocation of protein kinase C from the cytosol to the plasma membrane which may be important events in the molecular pathway resulting in inhibition of tumor and other abnormal cell proliferation by this immunologic hormone. Leukoregulin induces identical changes in target cell plasma membrane permeability as occur during natural killer lymphocyte cytotoxicity, providing strong evidence that it is an intrinsic mediator or element of the natural cytotoxicity reaction and possibly signifying its central role in immunological homeostasis.
