title: Postchemotherapy and tumor-selective targeting with the La-specific DAB4 monoclonal antibody relates to apoptotic cell clearance.
abstract: Early identification of tumor responses to treatment is crucial for devising more effective and safer cancer treatments. No widely applicable, noninvasive method currently exists for specifically detecting tumor cell death after cytotoxic treatment and thus for predicting treatment outcomes.
  
  
  METHODS
  We have further characterized the targeting of the murine monoclonal antibody DAB4 specifically to dead tumor cells in vitro, in vivo, and in clinical samples. We found that sustained DAB4 binding to treated cells was closely associated with markers of intrinsic apoptosis and DNA double-strand break formation. In a competition binding assay, DAB4 bound EL4 murine thymic lymphoma cells in preference to the normal counterpart of murine thymocytes. Defective in vivo clearance of apoptotic cells augmented in vivo accumulation of DAB4 in tumors particularly after chemotherapy but was unchanged in normal tissues. Tumor targeting of DAB4 was selective for syngeneic murine tumors and for human tumor xenografts of prostate cancer (PC-3) and pancreatic cancer (Panc-1) before and more so after chemotherapy. Furthermore, DAB4 was shown to bind to dead primary acute lymphoblastic leukemic blasts cultured with cytotoxic drugs and dead epithelial cancer cells isolated from peripheral blood of small cell lung carcinoma patients given chemotherapy.
  
  
  CONCLUSIONS
  Collectively, these results further demonstrate the selectivity of DAB4 for chemotherapy-induced dead tumor cells. This postchemotherapy selectivity is related to a relative increase in the availability of DAB4-binding targets in tumor tissue rather than in normal tissues. The in vitro findings were translated in vivo to human xenograft models and to ex vivo analyses of clinical samples, providing further evidence of the potential of DAB4 as a marker of tumor cell death after DNA-damaging cytotoxic treatment that could be harnessed as a predictive marker of treatment responses.
authors.affiliation: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Fares
authors.initials: F
authors.lastname: Al-Ejeh
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Staudacher
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Smyth
authors.forename: Jocelyn M
authors.initials: JM
authors.lastname: Darby
authors.forename: Delphine
authors.initials: D
authors.lastname: Denoyer
authors.forename: Chris
authors.initials: C
authors.lastname: Tsopelas
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001324:Autoantigens / Q000737:chemistry*; D001667:Binding, Competitive; D049109:Cell Proliferation; D053903:DNA Breaks, Double-Stranded; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding; D011877:Radionuclide Imaging; D012261:Ribonucleoproteins / Q000737:chemistry*; D060168:Thymocytes / Q000378:metabolism; D013953:Thymus Neoplasms / Q000188:drug therapy / Q000378:metabolism; D016896:Treatment Outcome; D000097585:SS-B Antigen
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001324:Autoantigens; D012261:Ribonucleoproteins; D000097585:SS-B Antigen
keywords: APOMAB; DAB4; La; apoptosis; chemotherapy; therapy response