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Increased MIBG Uptake After Transfer of the Human Norepinephrine Transporter Gene in Rat Hepatoma

¹ Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany
² Clinical Cooperation Unit Radiation Therapy, German Cancer Research Center, Heidelberg, Germany
³ Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany
⁴ Department of Radiation Protection, German Cancer Research Center, Heidelberg, Germany

The transport of MIBG by the human norepinephrine transporter (hNET) seems to be the critical step in the treatment of MIBG-concentrating tumors. Therefore, we investigated whether the accumulation of MIBG may be induced by retroviral transfection of the hNET gene in Morris hepatoma cells. Methods: A bicistronic retroviral vector for the transfer of the hNET coding sequence and the hygromycin resistance gene was generated. Morris hepatoma cells (MH3924A) were infected with the respective retroviral particles, and hNET-expressing cell lines MHhNEThyg1 to MHhNEThyg9 were obtained through hygromycin selection. The uptake of ³H-norepinephrine or ¹³¹I-MIBG and the efflux of ¹³¹I-MIBG were determined in transfected and wild-type cells. In addition, the ¹³¹I-MIBG distribution was monitored in nude mice and rats bearing wild-type and hNET-expressing hepatomas. Results: hNET-expressing hepatoma cell lines accumulated up to 36 times more norepinephrine than did wild-type cells and 8 times more than did hNET-expressing neuroblastoma cell line SK-N-SH. The addition of nisoxetine, a selective inhibitor of noradrenaline uptake, inhibited norepinephrine uptake. Maximal ¹³¹I-MIBG accumulation was observed 2 h after incubation and was followed by 43% efflux within 4 h after the ¹³¹I-MIBG-containing medium had been removed. In vivo experiments performed with nude mice bearing both hNET-expressing and wild-type tumors showed a 10-fold-higher accumulation of ¹³¹I-MIBG in transfected tumors than in wild-type tumors. The ex vivo calculations revealed doses of 605 and 75 mGy in hNET-expressing and wild-type tumor tissues, respectively. Conclusion: Transduction of the hNET gene enables Morris hepatoma cells to accumulate norepinephrine and MIBG. However, the retention of MIBG is brief; therefore, the absorbed dose of radiation in vivo is not expected to be therapeutically effective.

Key Words: human norepinephrine transporter • gene therapy • MIBG uptake

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