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|Title:||In vitro evaluation of alpha-particle emitter Ac-225 for somatostatin receptor radiotherapy|
|Authors:||GRAF Franziska; MORGENSTERN Alfred; BRUCHERTSEIFER Frank; VENKATACHALAM S.; FOTTNER C.; WEBER M.m.; KAINA B; SCHRECKENBERGER M; MIEDERER Matthias|
|Citation:||NUKLEARMEDIZIN-NUCLEAR MEDICINE vol. 51 no. 2 p. A113-A114|
|Publisher:||SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN|
|Type:||Articles in periodicals and books|
|Abstract:||Ziel/ Aim Alpha-particle emitters display high linear energy transfer combined with short range and are promising for treatment of tumor micrometastases. Indeed, efficiency and high specificity of tumor-specific antibodies labeled with alpha emitting nuclides were described in vitro and in vivo. Radiolabeled somatostatin analogues with high affinity to somatostatin receptor overexpressing tumors are an attractive option for peptide-receptor radionuclide therapy of metastasized neuroendocrine tumors. In this study, we investigated cellular effects of alpha-particle emitter Ac-225 labeled somatostatin analogue DOTATOC in vitro. Cellular studies were performed in p53 dependent and somatostatin receptor expressing rat pancreatic acinar carcinoma AR42J cells. Methodik/ Methods Ac-225-DOTATOC was synthesized with a specific activity of 0,4 MBq/µg and radiochemical purity of > 90% as assessed via ITLC. For investigation of alpha radiation induced cytotoxicity AR42J cells were incubated with Ac-225-DOTATOC (0.005 to 250 kBq/ml) for 24 and 48 h, respectively. Viability of cells was analyzed using the MTT colorimetric assay. DNA double strand breaks were quantified by microscopy after immunofluorescence staining of H2AX. Furthermore, cell cycle studies and induction of apoptosis was analyzed after incubation with Ac-225-DOTATOC by flow cytometry. Ergebnisse/ Results Cellular studies showed a reduced viability of AR42J cells after incubation with Ac-225-DOTATOC. ED50 values were calculated to 30 kBq/ml after 24 h and respectively 10 kBq/ml after 48 h. The number of DNA double strand breaks, localized by H2AX staining, increased with increasing concentration of Ac 225 DOTATOC after 24 and 48 h. Already 24 h after incubation with 2.5, 5, and 10 kBq/ml Ac 225 DOTATOC cell cycle studies showed an increment of the percentage of tumor cells in G2/M phase up to 60%. Further, increasing amount of polyploid cells could be detected after 48 and 72 h. After 72 h also subG1 peak was detectable. Preliminary data indicated induction of apoptosis after 72 h by Annexin-V staining. Schlussfolgerungen/ Conclusions Our data demonstrate a G2/M cell cycle arrest and induction of apoptosis in AR42J tumor cells due to efficient induction of DNA double strand breaks after Ac-225 alpha-particle radiation. The results are a promising prerequisite for further evaluation of Ac-225-DOTATOC in vitro and in vivo for peptide-receptor radionuclide therapy.|
|JRC Institute:||Nuclear Safety and Security|
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