Cytokinetic Resistance in Acute Leukemia: Recombinant Human Granulocyte Colony-Stimulating Factor, Granulocyte Macrophage Colony-Stimulating Factor, Interleukin-3 and Stem Cell Factor Effects In Vitro and Clinical Trials with Granulocyte Macrophage Colony-Stimulating Factor

Human leukemia has been extensively investigated over the last 25 years regarding its cell kinetics, cytokine regulation, and molecular defects. It has been postulated that leukemic cells proliferate at variable rates, with DNA synthesis times as short as 6, cell cycle times as long as 200 h, and that cell kinetic parameters can be of prognostic importance [1–4]. In addition to the marked heterogeneity observed in cycling cells, seminal experiments conducted over 25 years ago demonstrated the presence of noncycling, quiescent leukemic cells [5]. It is believed that these cells are less sensitive to chemotherapy and thus constitute the residual cells which lead to clinical relapse at different time intervals after initial induction of remission. We have previously demonstrated that cell kinetic measure-ments are correlated with remission incidence, remission duration, and survival in AML [6]. The most predictive parameter was found to be cellular RNA content, as determined by acridine orange flow cytometry. This cellular feature is asssociated with a quiescent state (“G0”-low RNA content, and “G1”-high RNA content). More refined measurements of genes expressed when cells enter the division cycle, including Ki67, PCNA, and c-myc, were also found to be useful in dissecting cell cycle kinetics, in particular, the important G0-G1 transition.