Inhibition of Growth of Melanoma Cells by CD95 (Fas/APO-1) Gene Transfer In Vivo

Interaction of CD95 ligand with its cognate receptor CD95 induces apoptotic cell death. Alterations in this pathway within tumor cells can result in escape from apoptosis and from immune surveillance. Melanoma cells recently were found to escape an immune attack via high expression of CD95 ligand, thereby inducing apoptosis of activated T lymphocytes. When screening four human melanoma cell lines for expression of CD95 and CD95 ligand, respectively, an inverse correlation was found, i.e., cells expressing high levels for CD95 ligand (CD95Lhigh) were almost negative for CD95 and vice versa. Since coexpression of CD95 and CD95 ligand may lead to apoptosis by autocrine suicide or fratricide, it was tested whether overexpression of CD95 in CD95Lhigh melanoma cells results in apoptotic cell death. Upon transfection with a cytomegalovirus-promoter-driven expression vector encoding the CD95 gene, CD95Lhigh melanoma cells underwent apoptosis at a much higher level than CD95Llow melanoma cells. Apoptosis appeared to be due to the activation of CD95 as cell death was inhibited by cotransfection with a dominant negative mutant for the CD95 signaling protein, Fas-associated protein with death domain. Tumor progression of CD95Lhigh melanoma cells transplanted into nude mice was significantly reduced when recipient animals were injected with liposomes containing the CD95 expression vector. As demonstrated by immunohistochemistry and TUNEL staining, in vivo transfected tumor cells expressed CD95 and underwent apoptotic cell death. Hence, this study indicates that delivery of the CD95 gene inhibits tumor growth in vivo and thus might be a therapeutic strategy to treat tumor cells that express high levels of CD95 ligand

[Reviews] Free radicals, antioxidants and cancer chemotherapy

[Abstract] Free radicals play a dual role as both beneficial and deleterious species, since they can be either helpful or harmful to the organism. They are products from normal cellular metabolism, or from external sources like pollution, medication, and radiation. The accumulation of excessive amount of free radicals in the body generates redox imbalance, a phenomenon referred to as oxidative stress. This deleterious process is involved in development of chronic and degenerative diseases such as cancer, rheumatoid arthritis, cardiovascular and neurodegenerative illnesses. In order to check the activities of free radicals in vivo, antioxidant systems have evolved, either naturally generated (endogenous antioxidants), or externally supplied through foods (exogenous antioxidants). This review deals with free radicals and their beneficial and deleterious effect on cellular activities, role of antioxidants (glutathione) in the maintenance of cellular redox homeostasis ; atention is focused on free radical-linked pathogenesis of cancer, and a discussion is also devoted to antioxidant supplementation in cancer patients undergoing chemotherapy