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Optimization of Radioimmunotherapy Using Human Malignant Melanoma Multicell Spheroids as a Model¹

Hamilton Regional Cancer Center, Ontario Cancer Foundation, and Department of Radiology, McMaster University, Hamilton, Ontario, Canada, L8V 1C3 [C. S. K., A. C., W. D. M.], and Hybritech, Inc., San Diego, California 92126 [M. W. U.]

In vitro multicell spheroids from a human melanoma cell line and the human colon cancer cell line HT29, used as control, have been established as a model of poorly vascularized micrometastases in vivo. The antimelanoma monoclonal antibody 96.5 was radiolabeled with ¹³¹I at specific radioactivities from 1.85 to 3.96 GBq/mg. Cytotoxicity of ¹³¹I-96.5 to the spheroids, at an initial size of 300 µm in diameter, was investigated as a function of concentration of ¹³¹I-96.5 in the incubation medium, specific radioactivity, and treatment time. Spheroid growth delay and clonogenic survival of cells disaggregated from the spheroids at various times after treatment were used as end points. Therapeutic effects increased with the concentration of ¹³¹I-96.5 within the range 0.2 to 2 mg/liter (0.34 to 3.4 GBq/liter) at a fixed specific radioactivity. The effects increased with specific radioactivity at a fixed concentration of ¹³¹I-96.5. Difference in therapeutic effect was also observed between treatment times of 8 and 24 h. Radiation doses to the melanoma spheroids varied from 10 to 16 Gy. Unlabeled 96.5 at 2 mg/liter or ¹³¹I-iodide at 1.7 GBq/liter did not affect the growth of the melanoma spheroids. The HT29 spheroids, however, only suffered slight cytotoxicity at 1 or 2 mg/liter of ¹³¹I-96.5 and for a treatment time of 24 h despite comparable radiosensitivity of HT29 cells and melanoma cells to high-dose-rate radiation. Similar cytotoxicity was observed in the HT29 group treated with ¹³¹I-iodide at 1.7 GBq/liter. Present findings therefore demonstrate preferential and adequate killing of the melanoma spheroids by ¹³¹I-96.5 at 0.5 mg/liter and 3.96 GBq/mg in 8 h.

¹ Research supported by the National Cancer Institute of Canada.

² To whom requests for reprints should be addressed.

Received 12/ 6/88. Revised 3/ 6/89. Accepted 3/15/89.

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