Targeted radionuclide therapy, known as molecular radiotherapy is a novel therapeutic module in cancer medicine. β-radiating radionuclides have definite impact on target cells via interference in cell cycle and particular signalings that can lead to tumor regression with minimal off-target effects on the surrounding tissues. Radionuclides play a remarkable role not only in apoptosis induction and cell cycle arrest, but also in the amelioration of other characteristics of cancer cells. Recently, application of novel β-radiating radionuclides in cancer therapy has been emerged as a promising therapeutic modality. Several investigations are ongoing to understand the underlying molecular mechanisms of β-radiating elements in cancer medicine. Based on the radiation dose, exposure time and type of the β-radiating element, different results could be achieved in cancer cells. It has been shown that β-radiating radioisotopes block cancer cell proliferation by inducing apoptosis and cell cycle arrest. However, physical characteristics of the β-radiating element (half-life, tissue penetration range, and maximum energy) and treatment protocol determine whether tumor cells undergo cell cycle arrest, apoptosis or both and to which extent. In this review, we highlighted novel therapeutic effects of β-radiating radionuclides on cancer cells, particularly apoptosis induction and cell cycle arrest.

186 Re-1-hydroxyethylidene-1,1-diphosphonate (HEDP) is an attractive radiopharmaceutical for the treatment of bone pain arising from skeletal metastatic lesions. Currently, 186 Re-HEDP is most commonly used in European countries. The aim of this study was to investigate the palliative efficacy and adverse effects of 186 Re-HEDP in patients with different types of cancers and skeletal bone pain. Methods: Nineteen (8 male, 11 female) patients with various cancers (breast, prostate, renal cell carcinoma, colon, and neuroendocrine tumors) and painful bone metastases were included in the study. A dose of 1,480-3,330 MBq (40-90 mCi) of 186 Re-HEDP was administered intravenously. The patients' level of pain relief was assessed by the Visual Analog Scale for 8 wk after treatment and by a weekly blood cell count to evaluate for hematologic toxicity. Results: The overall response rate was 89.5%, and the mean pain score assessed by the Visual Analog Scale was reduced from 9.1 to 5.3 after 1 wk (P 5 0.003). No adverse effects were reported by patients during intravenous administration or for up to 24 h after administration. A flare reaction was seen in 63.2% of patients, mainly during days 1-3, and lasted for 2-4 d. There was no significant correlation between the response to therapy and the flare reactions (P . 0.05). The nadir of platelet reduction occurred at the fourth or fifth week and led to platelet infusion in only 4 patients with a low baseline platelet count and diffuse skeletal metastases. Bone marrow suppression occurred in patients receiving higher doses, but no clinical problems were seen except in 2 patients who required packed cell transfusion similar to their prior transfusions. Conclusion: 186 Re-HEDP is an effective radiopharmaceutical for the palliative treatment of metastatic bone pain and has minimal adverse effects.Key Words: rhenium 186(tin) etidronate; pain palliation; bone metastasis Nucl Med Technol 2013; 41:192-196 DOI: 10.2967/jnmt.113.124297 The skeleton is the most common site of metastatic disease, and tumors arising from the breast, prostate, lung, thyroid, and kidney commonly spread to bone. The frequency of bone metastases has been estimated at 65%-75% in patients with breast and prostate cancer (1,2) and about 30%-40% in those with lung cancer (3). Bone pain, as the main symptom of skeletal metastases and the most common type of cancer-related pain, obviously has a negative impact on quality of life (4). Currently, the factors contributing to cancer pain are not completely understood (5,6), and metastatic bone pain might be poorly localized for external radiation therapy (7). Various modalities have been introduced for the treatment of bone metastases, including analgesics, hormone therapy, cytotoxic drugs, biphosphonates, and surgery; however, they are not effective in all patients with painful refractory skeletal metastases. An alternative approach is systemic administration of radiopharmaceuticals, which is a valuable and effective method for relieving bone pain in patients with ...

Recurrence in hepatocellular carcinoma (HCC) after conventional treatments is a crucial challenge. Despite the promising progress in advanced targeted therapies, HCC is the fourth leading cause of cancer death worldwide. Radionuclide therapy can potentially be a practical targeted approach to address this concern. Rhenium-188 (188Re) is a β-emitting radionuclide used in the clinic to induce apoptosis and inhibit cell proliferation. Although adherent cell cultures are efficient and reliable, appropriate cell-cell and cell-extracellular matrix (ECM) contact is still lacking. Thus, we herein aimed to assess 188Re as a potential therapeutic component for HCC in 2D and 3D models. The death rate in treated Huh7 and HepG2 lines was significantly higher than in untreated control groups using viability assay. After treatment with 188ReO4, Annexin/PI data indicated considerable apoptosis induction in HepG2 cells after 48 h but not Huh7 cells. Quantitative RT-PCR and western blotting data also showed increased apoptosis in response to 188ReO4 treatment. In Huh7 cells, exposure to an effective dose of 188ReO4 led to cell cycle arrest in the G2 phase. Moreover, colony formation assay confirmed post-exposure growth suppression in Huh7 and HepG2 cells. Then, the immunostaining displayed proliferation inhibition in the 188ReO4-treated cells on 3D scaffolds of liver ECM. The PI3-AKT signaling pathway was activated in 3D culture but not in 2D culture. In nude mice, Huh7 cells treated with an effective dose of 188ReO4 lost their tumor formation ability compared to the control group. These findings suggest that 188ReO4 can be a potential new therapeutic agent against HCC through induction of apoptosis and cell cycle arrest and inhibition of tumor formation. This approach can be effectively combined with antibodies and peptides for more selective and personalized therapy.

Background Recurrence in hepatocellular carcinoma (HCC) after conventional treatments is a big challenge. Despite the promising progress in advanced targeted therapies, HCC is the fourth leading cause of cancer death worldwide. Radionuclide therapy could be an effective targeted approach to address this concern. Rhenium-188 (188Re) is a β-emitting radionuclide that can be used in clinic for apoptosis induction and inhibit cell proliferation. Although adherent cell cultures are efficient and reliable, the lack of appropriate cell-cell and cell-ECM contact exists. It has been demonstrated that three-dimensional organotypic human cancer models are suitable alternatives. Methods Conventional adherent culture and 3D constructs of Huh7 or HepG2 hepatoma cell lines cultured on liver extracellular matrix (ECM) were treated by different doses of 188 Rhenium Perrhenate (188ReO4). To evaluate cell viability, live/dead assay carried out. The flow-cytometric assay, qRT-PCR, western bolting, colony formation assay, and immunofluorescence (IF) studies were performed to investigate the therapeutic effect of 188ReO4. Subsequently, the tumor formation ability of 188ReO4-treated Huh7 cells was evaluated in animal model. Results According to viability assay and live/dead staining, the number of dead cells in Huh7 and HepG2 lines were significantly increased compared to untreated control groups. Data obtained from Annexin/PI showed that Huh7 and HepG2 cells showed typical apoptotic changes after treatment with 188ReO4. Quantitative RT-PCR and western blotting data also supported that 188ReO4 treatment can induce apoptosis. Furthermore, cell cycle arrest observed in G2 phase after exposure to effective dose of 188ReO4 in Huh7 cells. Colony formation assay confirmed growth suppression in Huh7 and HepG2 cells post exposure. The IF also displayed proliferation inhibition in the 188ReO4 treated cells on 3D scaffolds of liver extracellular matrix (LEM). In 2D culture, PI3-AKT signaling pathway remained unchanged whereas, in the 3D condition it was activated. Treated Huh7 cells with effective dose of 188ReO4 lose their tumor formation ability in nude mice compare to the control group. Conclusion The results supported that 188ReO4 could induce apoptosis and cell cycle arrest and inhibit tumor formation capacity in HCC cells.