PLATELET FACTOR-4 AND OTHER CXC CHEMOKINES SUPPORT THE SURVIVAL OF NORMAL HEMATOPOIETIC-CELLS AND REDUCE THE CHEMOSENSITIVITY OF CELLS TO CYTOTOXIC AGENTS

The effects of platelet factor 4 (PF4) on the viability and chemosensi tivity of normal hematopoietic cells and cancer cell lines were studie d to determine the mechanisms whereby PF4 functions as either an inhib itor or a protector and to evaluate its clinical significance. Two oth er chemokines, interleukin-8 (IL-8) and neutrophil-activating peptide- 2 (NAP-2), were also studied in comparison to PF4. Using a tetrazolium salt assay for cell viability, we observed that PF4 at 1 to 50 mu g/m L supported the viability of normal human bone marrow cells. Approxima tely 45% of cells cultured for 48 hours survived, whereas 80% or more survived in the presence of PF4 5 mu g/mL. PF4 also supported the viab ility of CD34(+) cord blood (CB) cells and protected them from apoptos is induced by transforming growth factor beta 1 (TGF beta 1) and cytot oxic drugs. Pretreatment of CD34(+) cells by PF4, but not by TGF beta 1, caused an increase in the number of megakaryocyte colonies after th ese cells were replated in secondary cultures. Flow cytometry analysis showed that when CD34(+) cells were preincubated with PF4 or TGF beta 1 for 12 days in hematopoietic growth factor-rich medium, an increase d number of remaining CD34(+) cells was observed only for PF4-treated cells. Furthermore, PF4 significantly reduced the chemosensitivity of bone marrow cells, as shown by its ability to increase the 50% inhibit ion concentration (IC50) of several cytotoxic agents. Like PF4, IL-8 a nd NAP-P at 0.1, 0.6, and 1 mu g/mL supported the survival of myeloid progenitors, including colony-forming units granulocyte, erythroblast, monocyte, megakaryocyte (CFU-GEMM), CFU-megakaryocyte (CFU-MK), CFU-g ranulocyte/macrophage (CFU-GM), and burst-forming units-erythroblast ( BFU-E), and reduced their sensitivity to the toxicity of etoposide (ET P). Protamine sulfate at 1 to 100 mu g/mL showed no such activity of P F4. Interestingly, the three chemokines failed to affect significantly the viability and chemosensitivity of three leukemic and two other tu mor cell lines. Based on these results, we conclude for the first time that PF4 and IL-8 and NAP-2 support the survival of normal hematopoie tic precursors and protect them from the toxicity of chemotherapeutic agents. Because such activities are unique to normal hematopoietic cel ls but not to the cancer cell lines evaluated, a potential clinical ap plication of these molecules in the treatment of cancer is suggested. (C) 1997 by The American Society of Hematology.