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|Title:||Combined 213Bi-DTPA- F3 and paclitaxel treatment of peritoneal spread of human ovarian carcinoma in a mouse model enhances therapeutic efficacy due to enhanced induction of apoptosis and G2/M phase cell-cycle arrest|
|Authors:||SEIDL C.; VALLON M.; BLECHERT B.; GILBERTZ K.-P.; AICHLER M; FEUCHTINGER A; GÄRTNER Florian; BRUCHERTSEIFER Frank; MORGENSTERN Alfred; ESSLER M.|
|Citation:||EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING vol. 39 no. S2 p. 155|
|Type:||Articles in periodicals and books|
|Abstract:||Aim: High cytotoxicity of α-emitters is due to a high linear energy transfer resulting in induction of lethal DNA double-strand breaks. Therefore, targeted therapy with alpha-particle emitting radionuclides is a promising option in treatment of peritoneal carcinomatosis. Stable conjugates of the vascular tumor-homing peptide F3 with the α-emitter 213Bi specifically target nucleolin on the surface of proliferating tumor cells. In proliferating cells, nucleolin cycles between the cell surface and the nucleus. The aim of our study was to determine efficacy of combined 213Bi-DTPA-F3 and paclitaxel treatment compared to treatment with either 213Bi-DTPA-F3 or paclitaxel both in vitro and in vivo. Materials and methods: Effects on OVCAR3 ovarian carcinoma cells of treatment with 213Bi-DTPA-F3 and paclitaxel, alone or in combination, respectively, were assayed in terms of cell viability (alamarBlue assay), cell survival (clonogenic assay), cell-cycle arrest and the mode of cell death (flow cytometric analyses). For analysis of therapeutic efficacy SCID mice were injected intraperitoneally with OVCAR3 cells (1x107). Starting at day 10 after tumor cell inoculation animals were treated intraperitoneally six times at intervals of two or three days with PBS (control; n=12), paclitaxel (120 μg; n=6), 213Bi-DTPA-F3 (1.85 MBq; n=6) or combinded paclitaxel and 213Bi-DTPA-F3 (120 μg, 1.85 MBq; n=6). Therapeutic efficacy of the different treatment regimens was monitored non-invasively by bioluminescence imaging and registration of overall survival in combination with histopathologic analyses. Results: Treatment of OVCAR-3 cells in vitro with combined 213Bi-DTPA-F3 and paclitaxel was superior to treatment with either 213Bi-DTPA-F3 or paclitaxel in terms of reduction of cell viability, reduction of cell survival, induction of apoptosis and arrest of cells in G2/M phase. Accordingly, treatment of i.p. xenograft OVCAR-3 tumors was most efficient using combined 213Bi-DTPA-F3 (1.85 MBq) and paclitaxel (120 μg) as demonstrated by non-invasive bioluminescence imaging at different time points after tumor cell inoculation and histophatologic investigation of tumor spread on mesentery of the small and large intestine. Moreover, mean survival of xenograft mice that received combined 213Bi-DTPA-F3 and paclitaxel therapy (119 ± 13 days) was significantly superior to mice treated with either 213Bi-DTPA-F3 (84 ± 1 days) or paclitaxel (42 ± 9 days) or to controls treated with PBS (37 ± 6 days). Conclusion: Combined treatment with 213Bi-DTPA-F3 and paclitaxel significantly increased mean survival of mice with peritoneal carcinomatosis of ovarian origin compared to treatment with either 213Bi-DTPA-F3 or paclitaxel thus favouring future therapeutic application of a combined treatment regimen.|
|JRC Directorate:||Nuclear Safety and Security|
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