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J Nucl Med. 2008; 49 (Supplement 1):332P
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Oncology-Basic Science: Therapy, Metrics & Intervention

Therapy, Metrics & Intervention Posters

Uptake and biodistribution of the histone deacetylase inhibitor SAHA in tumor bearing animals

Uwe Haberkorn1, Barbro Beijer1, Annette Altmann1, Juri Gelovani3, Ludwig Strauss2, Antonia Dimitrakopoulou-Strauss2, Michael Eisenhut2 and Walter Mier1

1 Nuclear Medicine, University of Heidelberg, Heidelberg, Germany; 2 DKFZ, Heidelberg, Germany; 3 MD Anderson Cancer Center, Houston, Texas

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Objectives: Histone deacetylase (HDAC) inhibitors trigger differentiation, decrease cell proliferation and induce apoptosis in tumors. In order to assess a preferential tumor accumulation of suberoylanilide hydroxamic acid (SAHA) we studied the uptake of the drug in 3 tumor cell lines.

Methods: After labelling of SAHA with iodide a MTT assay was done to assess the effects of iodination on therapeutic efficacy in different tumor cell lines (thyroid carcinoma, hepatoma, colon carcinoma). Therefafter, uptake, competition and efflux studies were done using I-125 labeled SAHA. Finally, a biodistribution study was performed in tumor bearing mice.

Results: Iodinated SAHA analogs showed equal toxicity as compared to unmodified SAHA. The uptake of I-125-SAHA was time dependent with a plateau at 1 h and was inhibited by the presence of unlabeled SAHA with IC50 values around 800 nM. Furthermore, a rapid efflux was observed with a 60% decrease of intracellular activity after 10 min. The biodistribution study showed high accumulation in liver and kidney and a moderate accumulation in the tumor. Also a rapid washout was seen with 2.9%ID/g and 0.13%ID/g in the tumor at 1 h and 4h after tracer administration, respectively. The tumor to organ ratios were highest for brain 3 and 9 for 1 h and 4 h) and muscle (1.6 and 2.3 for 1 h and 4 h).

Conclusions: Iodinated SAHA showed rapid efflux and no preferential tumor accumulation. For therapeutic activity tumor selective uptake may be not a necessary condition. Rather low amounts of the drug seem to be sufficient to change the balance between acetylated and non-acetylated histones in a manner that leads to differentiation, inhibition of proliferation and apoptosis.





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Right arrow Articles by Mier, W.