title: Targeted α-therapy using 227Th-APOMAB and cross-fire antitumour effects: preliminary in-vivo evaluation.
abstract: Resistance to conventional cancer treatments is a major problem associated with solid tumours. Tumour hypoxia is associated with a poor prognosis and with poor treatment outcomes; therefore, there is a need for treatments that can kill hypoxic tumour cells. One potential option is targeted α-radioimmunotherapy, as α-particles can directly kill hypoxic tumour cells. The murine monoclonal antibody DAB4 (APOMAB), which binds dead tumour cells after DNA-damaging treatment, was conjugated and radiolabelled with the α-particle-emitting radionuclide thorium-227 (Th). Mice bearing Lewis lung tumours were administered Th-DAB4 alone or after chemotherapy and the tissue biodistribution of the radioimmunoconjugate was examined, as was the effect of these treatments on tumour growth and survival. Th-DAB4 accumulated in the tumour particularly after chemotherapy, whereas the distribution in healthy tissues did not change. Th-DAB4 as a monotherapy increased survival, with more pronounced responses observed when given after chemotherapy. We have shown that targeted α-therapy of necrotic tumour cells with Th-DAB4 had significant and surprising antitumour activity as it would occur only through a cross-fire effect.
authors.affiliation: aTranslational Oncology Laboratory, Centre for Cancer Biology, SA Pathology bSchool of Medicine cSchool of Chemistry and Physics, University of Adelaide dDepartment of Medical Physics eCancer Clinical Trials Unit, Royal Adelaide Hospital fEnvironment Protection Authority SA, Adelaide, Australia.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Staudacher
authors.forename: Eva
authors.initials: E
authors.lastname: Bezak
authors.forename: Artem
authors.initials: A
authors.lastname: Borysenko
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D051379:Mice; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000627:therapeutic use*; D013910:Thorium / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D011868:Radioisotopes; D013910:Thorium; C530969:apomab