RADIOTOXIC EFFECT AND DOSIMETRY OF GA-67 IN MULTICELLULAR SPHEROIDS AS COMPARED TO SINGLE CELLS OF THE LYMPHOMA CELL-LINE U715

Purpose: The purpose of the present study was to investigate if there were differences between U715 spheroids and single cells in the radiot oxic effect of Ga-67 on cell growth and clonogenic capacity ill vitro and to generate dosimetric approaches for the multicellular tumor mode l. Methods and Materials: Human lymphoma U715 cells were cultured lit vitro as single cells and multicellular spheroids, grown with the use of a combination of fibrin clot technique, spinner flasks, and liquid- overlay culture. Cells were incubated with 2.96-8.88 MBq/ml (67)Galliu m for 4 days. Spheroids were dispersed to single cells by treatment wi th plasmin. Residual proliferative and clonogenic capacity after Ga-67 incubation were assayed using the MTT-test and clonogenic test, respe ctively. Autoradiography was performed with 1 mu m sections and Ilford L4 liquid photographic emulsion. Dosimetric approaches were made, bas ed on the MIRD-approach. Results: During Ga-67 incubation proliferatio n was inhibited. The residual proliferative or clonogenic capacity was inhibited by 8.88 MBq/ml for 39 and 88%, respectively. For single cel ls with 6.66 MBq/ml these inhibitions were 64 and 96%, respectively. A utoradiography showed an homogeneous distribution of Ga-67 in spheroid s and single cells. In single cells a 2.1-3.5 times higher Ga-67 uptak e/cell than in spheroids produced an equitoxic effect. The uptake para meters were implemented in new dosimetric approaches and showed that t he efficacy of intracellular Ga-67 was two times higher in spheroid cl usters than in single cells due to energy deposition of internal conve rsion electrons within the cell clusters with a mean diameter size of nine cells. Both for proliferative and clonogenic capacity the exponen tial survival curves were superimposed. Conclusions: With the new appr oaches made in our dosimetric model the discrepancy found between Ga-6 7 accumulation and radiotoxic effect in spheroids as compared to singl e cells can be explained by additional effects of the crossfire of int ernal conversion electrons within clusters of about nine cells in diam eter in spheroids. Only twice as much Ga-67 was needed to reach equito xic absorbed doses in spheroids than was needed in single cells. Such might be important for the use of Ga-67 treatment of small metastasis of malignant lymphoma.