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 32 kDa lymphokine first identified and isolated during the course of this project can prevent carcinogenesis and inhibit tumor cell growth. The molecular actions of leukoregulin are rapid as indicated by an increase in intracellular ionic calcium, activation of plasma membrane cation channels, and an increase in plasma membrane permeability within minutes of leukoregulin-cell interaction and transmembrane signalling. The increase in membrane permeability is accompanied by an increased sensitivity of the cell to destruction by natural killer and lymphokine-activated killer lymphocytes together with an enhancement of drug uptake and concomitant down-regulation of the pl7O intracellular glycoprotein associated with multiple drug resistance A synergistic decrease in proliferation is observed in human K562 leukemia cells treated for 30 minutes with leukoregulin and doxorubicin in comparison to cells treated with either agent alone. This indicates that leukoregulin enhances both the cellular uptake and the tumor inhibitory action of doxorubicin. Leukoregulin also increases the membrane permeability and the anti-viral action of acyclovir in human WISH cells 2 hours after infection of the cells with herpes simplex type I virus. Identification of cytokines that increase the entry of pharmacologically active molecules into the desired target cells will greatly facilitate the pharmacotherapeutic goal of achieving sufficient intracellular uptake of the pharmacologically active agent to obtain the desired cellular action. The increased permeability of the plasma membrane and concurrent enhanced uptake of metabolic inhibitors into leukoregulin-treated target cells constitute a new approach in this direction.
