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.

Key Words:

• ⁶⁷Gallium
• cytostatic drugs
• lymphoma
• cell cycle
• cytotoxicity
• transferrin receptor