Leukemia cells and the cytokine network: therapeutic prospects

The network and balance of cytokines is of major importance in maintaining proper homeostasis of hematopoiesis. Abnormalities in this network may result in a variety of blood disorders; however, the role of this network is not clear in leukemia. The use of antineoplastic agents has improved the survival rate of some types of leukemia, and adjunctive therapy with cytokines may be helpful. Chemotherapeutic approaches are no longer the best choice because cytotoxicity may affect normal and leukemic cells, and leukemic cells may develop resistance to the chemotherapeutic agent. Induction of differentiation to a mature phenotype and the control of apoptotic-gene expression have provided other possible alternative therapies. Combined effects of cytokines and vitamin derivatives such as retinoic acid (RA) and 1,25 dihydroxyvitamin D3 (VD3) were found more beneficial than any of these agents individually. These agents exhibit cooperative effects, potentiate each other's effects, or both. Therefore, understanding the hematopoietic actions of these agents, their interactions with their receptors, and their differentiation signaling pathways may result in the design of new therapies. However, the role of cytokines in apoptosis is controversial because in some cases they were found to increase tumor cell resistance to apoptosis-inducing agents. Recent studies in the molecular biology of gene regulation, transcription factors, and repressors have led to new possible approaches such as differentiation therapy for the treatment of leukemia. In addition, the development of drugs that act on the molecular level such as imatinib is just the beginning of a new era in molecular targeted therapy in which the drug acts specifically on the leukemic cell. There are many possible combinations of cytokines, retinoids, and VD3, and perhaps the best therapeutic combination is yet to be described. This minireview is an update on the role of cytokines and the therapeutic potential of combinations with agents such as RA, VD3, and other chemotherapeutic agents.