Cell Cycle Dependency of Gallium Uptake and Cytotoxicity in Human Cell Lines of Hematological Malignancies

Abstract

67Gallium (67Ga) is a radionuclide which accumulates in hematological malignancies and is used for diagnostic imaging. We investigated in this in vitro study the cell cycle dependency of cellular uptake and cytotoxicity of 67Ga. Cell cycle synchronization of cells was achieved by counterflow centrifugal elutriation and the use of cytostatic drugs. The human lymphoma cell lines U-937 and U-715 were used and in elutriation experiments we also used the leukemic cell line HL-60. The transferrin receptor (CD71) expression, 67Ga uptake and cell proliferation inhibition were the parameters measured. We also studied cytotoxicity in various schedules for combination of 67Ga and drugs and the residual proliferative capacity was measured. The CD71 expression in the three cell lines increased from 106-177% on S phase cells and from 118-233% on G2M cells, as compared to the G0/G1 cell fraction. The 67Ga uptake varied from 108-127% for S cells and 128-139% for G2M cells. The drugs chosen induced cell cycle phase accumulation in S and/or G2M phase during preincubation. 67Ga preincubation induced accumulation in the G2M phase. Almost all combinations of 67Ga and drugs resulted in a non-interactive effect, except for methotrexate which resulted in an antagonistic effect. No preferential effect of any of the incubation schemes was seen. CD71 expression and 67Ga uptake were increased in S and G2M cells. Combination of 67Ga with drugs which arrest cells in these cell cycle phases did not result in a change in cytotoxicity. However, these results implicate that 67Ga and the cytostatic drugs tested except for methotrexate might be used together or sequentially in therapy.

Gas Plasma-Treated Prostate Cancer Cells Augment Myeloid Cell Activity and Cytotoxicity

“…The transferrin receptor CD71, however, usually is internalized in activated HL-60 cells [51], leading to a decrease in surface receptor expression. Nevertheless, CD71 was also reported to be associated with macrophage development [52,53]. Although not all markers were regulated in each of the settings to a similar extent, a clear tendency towards activation was seen for both the supernatant and co-culture experiments.…”

Drug‐induced suppression of phosphorylase kinase activity correlates with resolution of psoriasis as assessed by clinical, histological and immunohistochemical parameters

“…The localization of Ki‐67 to the nucleolus has been shown to be phosphorylation‐dependent, as dephosphorylation causes its movement to cytoplasmic sites 58 . TRR expression is also cell‐cycle‐dependent, increasing from 106–177% on S phase cells to 118–233% on G 2 M cells 59 . PhK may affect the expression of TRR in several ways.…”

“…58 TRR expression is also cell-cycle-dependent, increasing from 106±177% on S phase cells to 118± 233% on G 2 M cells. 59 PhK may affect the expression of TRR in several ways. First, by enhancing inositol phosphorylation PhK affects the activity of phosphatidylinositol 3 H kinases; antibodies blocking the activity of these kinases have been shown to block cycling of TRR and growth factor receptors and to inhibit both the actin cytoskeletal functions and growth factordependent DNA synthesis.…”