Increased uptake of [123I]meta-iodobenzylguanidine, [18F]fluorodopamine, and [3H]norepinephrine in mouse pheochromocytoma cells and tumors after treatment with the histone deacetylase inhibitors

Abstract

Purpose [131I]-meta-iodobenzylguanidine ([131I]-MIBG) is the most commonly employed treatment for metastatic pheochromocytoma and paraganglioma; however, its success is limited. Its efficacy depends on the [131I]-MIBG concentration reached within the tumor through its uptake via the norepinephrine transporter and retention in neurosecretory granules. Purpose is to enhance [123I]-MIBG uptake in cells and liver pheochromocytoma tumors. Experimental Design We report the in vitro effects of two histone deacetylase (HDAC) inhibitors, romidepsin and trichostatin A, on increased uptake of [3H]-norepinephrine and [123I]-MIBG in mouse pheochromocytoma (MPC) cells, and the effect of romidepsin on [18F]-fluorodopamine and [123I]-MIBG uptake in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in MPC cells by [123I]-MIBG uptake studies with and without the transporter blocking agent desipramine and the vesicular blocking agent reserpine. Results Both HDAC inhibitors increased [3H]-norepinephrine, [123I]-MIBG, and [18F]-fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in increased uptake of [18F]-fluorodopamine and in pheochromocytoma liver metastases as measured by maximal standardized uptake values on PET imaging (p < 0.001). Analysis of biodistribution after inhibitor treatment confirmed the PET results in that uptake of [123I]-MIBG was significantly increased in liver metastases (p < 0.05). Therefore, HDAC inhibitor treatment increased radioisotope uptake in MPC cells in vitro and in liver metastases in vivo, through increased norepinephrine transporter activity. Conclusion These results suggest that HDAC inhibitors could enhance the therapeutic efficacy of [131I]-MIBG treatment in patients with malignant pheochromocytoma.

Toward tailored medicine (and beyond): the phaeochromocytoma and paraganglioma model

“…Therefore, FDG may play a clinical role in prognosis or before radionuclide therapy, when a dedifferentiation is suspected, identifying patients with a worse prognosis and/or nonresponders to radionuclide therapy. A very interesting perspective is provided by the study by Martiniova et al [16] of mouse PCC cells and tumours, demonstrating the effect of treatment with histone deacetylase inhibitors in increasing the amount of norepinephrine transporters expressed in tumours. In this way it may be possible to enhance MIBG uptake and the therapeutic efficacy of treatments with 131 I-MIBG in patients with advanced PCC and PGL.…”

15 YEARS OF PARAGANGLIOMA: Imaging and imaging-based treatment of pheochromocytoma and paraganglioma

“…However, some tumors are not positive on 123 I-MIBG scintigraphy. Manipulation of NETs using HDAC inhibitors or other drugs need to be further evaluated (Martiniova et al 2011). These approaches, in conjuction with radiosensitizers, might increase the number of patients eligible for radionuclide therapy and enhance antitumoral effect by elevating radiation doses delivered to the tumors.…”

111In-DTPA0-octreotide (Octreoscan), 131I-MIBG and other agents for radionuclide therapy of NETs

“…A combination offering possible clinical benefit may be 131 I-MIBG with histone deacetylase inhibitors (romidepsin and trichostatin A). In vitro studies have shown that these agents upregulate the noradrenaline transporter in Pheo cells; thus they may enhance tumoral uptake of the tracer [64].…”

“…Of the other SSTR analogues, 64 Cu-TETA-octreotide ( 64 Cu-TETA-OC) exhibits similar affinity to Octreoscan. 64 Cu is a simultaneous positron-and β − -emitter.…”

“…64 Cu is a simultaneous positron-and β − -emitter. It has been mainly applied in diagnostic imaging, but possesses some therapeutic potential owing to the β − emission.…”