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|Title:||DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy|
|Authors:||GRAF Franziska; FAHRER Jörg; MAUS Stephan; MORGENSTERN Alfred; BRUCHERTSEIFER Frank; VENKATACHALAM S.; FOTTNER C.; WEBER M.m.; HUELSENBECK Johannes; SCHRECKENBERGER M; KAINA B; MIEDERER Matthias|
|Citation:||PLOS ONE vol. 9 no. 2 p. e88239 (1-10)|
|Publisher:||PUBLIC LIBRARY SCIENCE|
|Type:||Articles in periodicals and books|
|Abstract:||Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to beta-particle emitter Lutetium-177 labeled somatostatin analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of H2AX-foci formation and its downstream effects. To determine relative biological effectiveness (RBE) between the two isotopes somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks were quantified after immunofluorescence staining of H2AX. Cell cycle was analyzed by flow cytometry. In vivo, uptake of both radiolabeled somatostatin-analogues into subcutaneous AR42J tumors and number of cells displaying H2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities translated from in vitro cytotoxicity. Ac-225-DOTATOC was synthesized with specific activities between 0.2-0.4 MBq/µg and radiochemical purity of > 90%. ED50 values were 30 kBq/ml after 24 h and 14 kBq/ml after 48 h. Lu-177-DOTATOC displayed radiochemical purity of >95% and ED50 values of 10 MBq/ml after 48 h. Number of DNA double strand breaks increased with increasing concentration of Ac 225 DOTATOC and Lu-177-DOTATOC similarly, if a factor of approximately 700 of Lu-177 activities over Ac-225 activities was applied. 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%. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical with 7.5 %ID/g, though overall number of cells with H2AX-foci was higher for tumors treated with 48 kBq Actinium-225-DOTATOC than tumors treated with 30 MBq Lutetium-177-DOTATOC (35% vs. 21%). Tumors with a mean volume of 0.34 ml reached exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC), after 21 days (34 MBq Lu-177-DOTATOC) and after 5 days (control). Thus H2AX-foci displayed the key parameter after irradiation with similar downstream effects for beta and alpha irradiation.|
|JRC Directorate:||Nuclear Safety and Security|
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