Enhanced efficacy of combined ^sup 213^Bi-DTPA-F3 and paclitaxel therapy of peritoneal carcinomatosis is mediated by enhanced induction of apoptosis and G2/M phase arrest

• Published in: European journal of nuclear medicine and molecular imaging 2012-12, Vol.39 (12), p.1886
• Main Authors: Vallon, Mario, Seidl, Christof, Blechert, Birgit, Li, Zhoulei, Gilbertz, Klaus-peter, Baumgart, Anja, Aichler, Michaela, Feuchtinger, Annette, Gaertner, Florian C, Bruchertseifer, Frank, Morgenstern, Alfred, Walch, Axel K, Senekowitsch-schmidtke, Reingard, Essler, Markus
• Format: Article
• Language: English
• Subjects: Apoptosis; Cancer; Cell cycle; Chemotherapy; Nuclear medicine; Peptides; Radiation therapy
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-012-2203-z

Targeted therapy with α-particle emitting radionuclides is a promising new option in cancer therapy. Stable conjugates of the vascular tumour-homing peptide F3 with the α-emitter ^sup 213^Bi specifically target tumour cells. The aim of our study was to determine efficacy of combined ^sup 213^Bi-diethylenetriaminepentaacetic acid (DTPA)-F3 and paclitaxel treatment compared to treatment with either ^sup 213^Bi-DTPA-F3 or paclitaxel both in vitro and in vivo. Cytotoxicity of treatment with ^sup 213^Bi-DTPA-F3 and paclitaxel, alone or in combination, was assayed towards OVCAR-3 cells using the alamarBlue assay, the clonogenic assay and flow cytometric analyses of the mode of cell death and cell cycle arrest. Therapeutic efficacy of the different treatment options was assayed after repeated treatment of mice bearing intraperitoneal OVCAR-3 xenograft tumours. Therapy monitoring was performed by bioluminescence imaging and histopathologic analysis. Treatment of OVCAR-3 cells in vitro with combined ^sup 213^Bi-DTPA-F3 and paclitaxel resulted in enhanced cytotoxicity, induction of apoptosis and G2/M phase arrest compared to treatment with either ^sup 213^Bi-DTPA-F3 or paclitaxel. Accordingly, i.p. xenograft OVCAR-3 tumours showed the best response following repeated (six times) combined therapy with ^sup 213^Bi-DTPA-F3 (1.85 MBq) and paclitaxel (120 μg) as demonstrated by bioluminescence imaging and histopathologic investigation of tumour spread on the mesentery of the small and large intestine. Moreover, mean survival of xenograft mice that received combined therapy with ^sup 213^Bi-DTPA-F3 and paclitaxel was significantly superior to mice treated with either ^sup 213^Bi-DTPA-F3 or paclitaxel alone. Combined treatment with ^sup 213^Bi-DTPA-F3 and paclitaxel significantly increased mean survival of mice with peritoneal carcinomatosis of ovarian origin, thus favouring future therapeutic application.[PUBLICATION ABSTRACT]