Gallium-67 radiotoxicity in human U937 lymphoma cells

Abstract

Summary Promising clinical results have been obtained with radiolabeled antibodies in lymphoma patients. The higher uptake by lymphomas of 67Gallium (6'Ga) compared with monoclonal antibodies makes selective radiotherapy by the widely available 67Ga appealing. However, the gamma radiation of 67Ga uised in scintigraphy is considered to be almost non-toxic to lymphoma cells. However, in addition to photon radiation 67Ga emits low energy Auger electrons and 80-90 keV conversion electrons which could be cytotoxic. The objective of the present study was the assessment of radiotoxicity of 67Ga on a lymphoid cell line: U937. Proliferation (MTT-assay) and clonogenic capacity (CFU-assay) were measured after 3 and 6 days incubation with 10, 20 and 40 LCi ml -' 67Ga.Growth inhibition was 36% after 3 days incubation and 63% after 6 days incubation with 40 jICi 67Ga ml-'. Clonogenic capacity was reduced by 51% after 3 days and 72% after 6 days incubation with 40 jiCi ml-67Ga. A survival curve showed an initial shoulder and became steeper beyond 200-250 pCi cell-' (low linear energy transfer type). Iso-effect doses of 67Ga and 9'Yttrium (9Y) were determined. The iso-effect dose of 40 jICi 67Ga ml-' (cumulative dose of conversion electrons 306 cGy) was 2.5 jiCi 90Y ml-' (cumulative dose 494 cGy) and the iso-effect dose of 80 pCi 67Ga ml-was 5.0 pCi 90Y/ml. The main cytotoxic effect of 67Ga seems to be induced by the 80 keV conversion electrons. We conclude that the conversion electrons of 67Ga have a cytotoxic effect on U937 cells and that in our experiments a 16-fold higher piCi-dose of 67Ga than of 9Y was needed for the same cytotoxic effect. We believe that 67Ga holds promise for therapeutic use. 67Gallium (67Ga) In the present study we investigated the cytotoxic effect of 67Ga on a lymphoma cell line: U937. Iso-effect doses of 67Ga and 9Yttrium (90Y) were sought to relate the cytotoxic effect of 67Ga to the well known cytotoxic effect of 'Y. Materials and methodsRadionuclides 67Gallium was obtained from Mallinckrodt Diagnostics Holland B.V. as 67-Ga-chloride. 67Ga-citrate was prepared as follows: 0.1 ml GaC13 (0.7-0.8 N HCI, specific activity: 50 mCi ml -) was added to 4.0 ml Na-citrate stock solution. This stock solution was prepared as follows: 1.17 ml Nacitrate (Trisodium-citrate, C6H5Na307.2H2O), 150 gr-1') was added to 15 ml 0.1 N NaOH and the mixture diluted to 100 ml with NaCl 0.9% and the pH adjusted to 7.0. For sterilisation a micropore filter 0.2 jLm (Schleicher & Schuell) was used.9Yttrium colloidal citrate was obtained from CIS bio international, ORIS industry S.A., Gif-sur-Yvette Cedex, France. Specific activity: 4.3 mCi ml '.For purposes of convenience, activities are given as mCi, jiCi and pCi (1 mCi = 37 MBq).Cells and culture conditions U937 cells, originally derived from a patient with a diffuse histiocytic lymphoma, were purchased from ATCC (Rockville, Maryland, USA), and have been maintained in RPMI-1640-L-Glutamine (Gibco-Europe, Breda, NL) with 10% heat-inactivated foetal calf serum (FCS; Gibco, B...

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