title: Enhanced efficacy of combined 213Bi-DTPA-F3 and paclitaxel therapy of peritoneal carcinomatosis is mediated by enhanced induction of apoptosis and G2/M phase arrest.
abstract: OBJECTIVE
  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 (213)Bi specifically target tumour cells. The aim of our study was to determine efficacy of combined (213)Bi-diethylenetriaminepentaacetic acid (DTPA)-F3 and paclitaxel treatment compared to treatment with either (213)Bi-DTPA-F3 or paclitaxel both in vitro and in vivo.
  
  
  METHODS
  Cytotoxicity of treatment with (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.
  
  
  RESULTS
  Treatment of OVCAR-3 cells in vitro with combined (213)Bi-DTPA-F3 and paclitaxel resulted in enhanced cytotoxicity, induction of apoptosis and G2/M phase arrest compared to treatment with either (213)Bi-DTPA-F3 or paclitaxel. Accordingly, i.p. xenograft OVCAR-3 tumours showed the best response following repeated (six times) combined therapy with (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 (213)Bi-DTPA-F3 and paclitaxel was significantly superior to mice treated with either (213)Bi-DTPA-F3 or paclitaxel alone.
  
  
  CONCLUSIONS
  Combined treatment with (213)Bi-DTPA-F3 and paclitaxel significantly increased mean survival of mice with peritoneal carcinomatosis of ovarian origin, thus favouring future therapeutic application.
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Vallon
authors.forename: Christof
authors.initials: C
authors.lastname: Seidl
authors.forename: Birgit
authors.initials: B
authors.lastname: Blechert
authors.forename: Zhoulei
authors.initials: Z
authors.lastname: Li
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Gilbertz
authors.forename: Anja
authors.initials: A
authors.lastname: Baumgart
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.forename: Annette
authors.initials: A
authors.lastname: Feuchtinger
authors.forename: Florian C
authors.initials: FC
authors.lastname: Gaertner
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: Axel K
authors.initials: AK
authors.lastname: Walch
authors.forename: Reingard
authors.initials: R
authors.lastname: Senekowitsch-Schmidtke
authors.forename: Markus
authors.initials: M
authors.lastname: Essler
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D057809:HEK293 Cells; D024242:HMGN2 Protein / Q000737:chemistry; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*; D010534:Peritoneal Neoplasms / Q000628:therapy*; D017434:Protein Structure, Tertiary; D019275:Radiopharmaceuticals / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: C580872:(213)Bi-DTPA-F3; D000972:Antineoplastic Agents, Phytogenic; D024242:HMGN2 Protein; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D017239:Paclitaxel