Experimental basis for the use of recombinant human granulocyte-macrophage colony-stimulating factor in patients with...

Granulocyte-macrophage colony-stimulating factor (GM-CSF) not only stimulates hematopoiesis, but also induces the proliferation and differentiation of leukemic myeloid cells. The observation that clonogenic growth of malignant cells can be induced in vitro has led to the development of therapeutic concepts that aim to increase the sensitivity of cells to cytostatic and cytotoxic agents by priming them with GM-CSF. In in vitro experiments, preincubating leukemic cells with recombinant cytokines including GM-CSF led to a consistent, dose-dependent increase in the cytotoxicity of cytosine arabinoside (Ara-C). This effect has since been observed in patients with acute myeloid leukemia (AML) although its mechanism is not yet entirely clear. It seems that GM-CSF increases the relative number of cells in the S phase of the cell cycle and enhances the activity of DNA polymerases, enzymes that are essential to nucleotide incorporation into DNA. Based on these experimental results, numerous clinical trials have investigated the role of GM-CSF in priming leukemic blasts before chemotherapy. These studies will allow us to determine whether our in vitro observations of increased cytotoxicity translate into higher remission rates and durations, and will help us to identify the patient subgroups most likely to benefit from this therapeutic approach.