[Role of cytokines in differentiation therapy with retinoic acid]

It is now clear that retinoic acid (RA) can induce complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). The remission is apparently induced via the differentiating effects of RA, based on the appearance of increasing differentiated cells in the circulation and bone marrow. However, sometimes transient hyperleukocytosis develops after 1 to 2 weeks of therapy. To understand the hyperleukocytosis, we examined effects of some growth-promoting cytokines on proliferation of RA-treated APL cells in primary culture. Effect of negative regulators was also examined. These results indicate that proliferation of APL cells is greatly modulated by several cytokines even in the presence of RA. Enhanced RA-induced differentiation, when used in combination with other agents, has been shown with several cytokines, including granulocyte colony-stimulating factor and interferon alpha. The potential therapeutic use for RA in combination with interferon alpha is discussed.