Immunobiology of Carcinogenesis
In 1975 Dr. Evans first demonstrated that normal leukocyte cytokine preparations are preferentially cytotoxic for syngeneic chemical carcinogen induced tumor cells (Evans CH et al. 1975). Subsequently he showed that carcinogen exposed cells can become susceptible during the preneoplastic stages of carcinogenesis to the growth inhibitory activity of lymphokines (Evans CH et al. 1977, DiPaolo JA et al. 1984). In 1983 his laboratory discovered and isolated a 32 kD anticarcinogenic lymphokine (Ransom JH and Evans CH 1983) which has been named leukoregulin to denote its anatomic origin and modulatory action(Ransom JH et al. 1985). Other unique leukoregulin activities are the ability of the cytokine to permeabilize tumor cells (Barnett SC and Evans CH 1986), upregulate sensitivity of tumor cells to lymphocyte killing (Furbert-Harris PM and Evans CH 1989, Slingluff CL Jr et al. 1990), increase the uptake of pharmacologically active molecules (Evans CH and Baker PD 1988, Hooks JJ et al. 1991, Evans CH et al. 1993) and downregulate viral gene expression (Hooks JJ et al. 1991, Woodworth CD et al. 1992) and multidrug resistance in tumor cells (Evans CH and Baker PD 1992). Bio-technological investigations are in progress to define the chemical structure of leukoregulin, to clone the gene directing synthesis of leukoregulin and to produce the cytokine and its biologically active segments by use of recombinant DNA directed biosynthesis. Cell biology studies are focused on definition of the transmembrane signals by which leukoregulin destablizes the target cell plasma membrane resulting in an increased sensitivity to lymphocytotoxicity and an increased uptake of pharmacologically active molecules. Three U.S. patents have been awarded for leukoregulin discoveries in the laboratory.
Current investigations are focused on purification and characterization of the biological activity of native and recombinant proteins to define bioactive leukoregulin gene segments. Comparison of the membrane permeabilizing, drug uptake enhancing and enhancement to lymphocyte killing specific activities are underway. Other activities of interest are tumor growth inhibition, anti-virus transcription and modulation of glycosaminoglycan synthesis. The latter is of particular interest in terms of defining whether leukoregulin has a role in pathologic processes. Collaborative studies with Dr. Terry J. Smith in the Department of Medicine at Albany Medical College are investigating the effects of leukoregulin on the synthesis of glycosaminoglycans and cyclooxygenases in human orbital fibroblasts. The increase in hyaluronan and prostaglandin synthase 2 (COX2) synthesis in leukoregulin stimulated orbital fibroblasts is substantially greater than that observed with other cytokines, making leukoregulin a candidate molecular trigger in the excessive orbital tissue hyperplasia characteristic of Grave's ophthalmopathy. This is the first indication that high local concentrations of leukoregulin may adversely affect growth and/or function of some normal tissues. It will be important to observe whether recombinant proteins with leukoregulin anti-cancer activity also affect selected normal tissues.