title: Optimizing the sequence of combination therapy with radiolabeled antibodies and fractionated external beam.
abstract: The purpose of this study was to determine the optimum sequence for combined modality therapy with radiolabeled antibodies and fractionated external beam radiation.
  
  
  METHODS
  The uptake and distribution of a nontherapeutic activity of 125I-labeled tumor-associated A33 monoclonal antibody was determined in SW1222 human colon carcinoma xenografts in nude mice for 4 study groups: group 1, radiolabeled antibody alone; group 2, radiolabeled antibody administered (day 0) immediately before the first of 5 daily fractions of 2-Gy, 320-kilovolt peak x-rays; group 3, radiolabeled antibody administered after the fifth radiation fraction (day 5); and group 4, radiolabeled antibody administered 5 d after irradiation (day 10). Tumors were excised 5 d after antibody administration. Tumors were frozen and sectioned for histology and phosphor plate autoradiography. The percentage of A33 antigen-expressing cells was estimated by immunohistochemical staining.
  
  
  RESULTS
  The average tumor uptake values relative to control group 1 were 1.47 (group 2), 0.78 (group 3), and 0.21 (group 4), which illustrates that tumor uptake is increased by almost 50% when the antibody is present in the blood at the start of irradiation. Five days into a fractionated irradiation protocol, antibody uptake was reduced, falling more significantly on day 10. Phosphor plate autoradiographs showed decreased uptake uniformity for groups 3 and 4. Immunohistochemical data showed a reduction in A33 antigen-positive cells from 85%, 64%, 50%, to 41% for groups 1-4, respectively.
  
  
  CONCLUSIONS
  Maximum radiolabeled antibody tumor uptake was achieved when the antibody was administered just before radiation therapy. This might be explained by a transient increase in capillary leakage to macromolecules, followed by a reduction at later times, possibly the result of capillary damage and occlusion.
authors.affiliation: Department of Medical Physics and Nuclear Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ruan
authors.forename: J A
authors.initials: JA
authors.lastname: O'Donoghue
authors.forename: S M
authors.initials: SM
authors.lastname: Larson
authors.forename: R D
authors.initials: RD
authors.lastname: Finn
authors.forename: A
authors.initials: A
authors.lastname: Jungbluth
authors.forename: S
authors.initials: S
authors.lastname: Welt
authors.forename: J L
authors.initials: JL
authors.lastname: Humm
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000032:analysis; D001345:Autoradiography; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D019583:Dose Fractionation, Radiation; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy; D011879:Radiotherapy Dosage; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens