title: Benefits of combined radioimmunotherapy and anti-angiogenic therapy in a liver metastasis model of human colon cancer cells.
abstract: The combined use of anti-angiogenic therapy (AT) and radioimmunotherapy (RIT) may improve the therapeutic outcome in patients with cancer lesions. This hypothesis is based on the ability of AT to suppress tumour endothelial compartments and the direct action of RIT against tumour cells. We previously confirmed this hypothesis in an established subcutaneous xenograft model of colon cancer. The purpose of the current investigation was to determine the benefit of this combination within a liver metastasis model, which mimics treatment of minimal disease in an adjuvant setting. Liver metastases were established in nude mice by intrasplenic inoculation of LS180 colon cancer cells; following such inoculation, metastases of <1 mm in diameter can be observed at 1 week and these lesions can attain a size of several millimetres at 2 weeks. Daily AT with 2-methoxyoestradiol (2-ME), 75 mg/kg, was initiated at 1 week. RIT with 7 MBq of (131)I-A7, an IgG1 anti-colorectal monoclonal antibody, was conducted at 2 weeks. RIT employing an irrelevant IgG1, (131)I-HPMS-1, was implemented for comparison. The weight of liver metastases was measured 4 weeks after cell inoculation. The effect of AT on (131)I-A7 accumulation in metastases was also observed. Toxicity of treatment was monitored by blood cell counts. Monotherapy with 2-ME AT or (131)I-A7 RIT significantly suppressed metastasis growth ( P<0.0001): metastasis weight was 5.96+/-0.87 g in non-treated controls, 2.67+/-1.89 g in cases receiving AT and 0.85+/-0.68 g in those receiving (131)I-A7 RIT. Combination of AT and (131)I-A7 RIT more effectively suppressed the growth to 0.28+/-0.32 g ( P<0.05 vs RIT alone). The effect of (131)I-HPMS-1 RIT, which suppressed metastasis growth to 2.25+/-0.88 g, was significant in comparison with the control ( P<0.0001); however, the combination of AT and (131)I-HPMS-1 RIT (which suppressed growth to 1.41+/-0.68 g) was far less effective than the combination of AT and (131)I-A7 RIT. AT did not decrease (131)I-A7 accumulation in metastases. AT did not affect RIT myelotoxicity. The results of this study demonstrating the combined effects of AT and (131)I-A7 RIT in a small metastasis model indicate that such combination therapy may be suitable for the treatment of minimal disease.
authors.affiliation: Department of Biotracer Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Li
authors.forename: Seigo
authors.initials: S
authors.lastname: Kinuya
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Koshida
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mori
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiba
authors.forename: Naoto
authors.initials: N
authors.lastname: Watanabe
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Shuke
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Michigishi
authors.forename: Norihisa
authors.initials: N
authors.lastname: Tonami
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use; D001822:Body Burden; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy* / Q000556:secondary; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D016499:Radioimmunotherapy / Q000379:methods*; D012016:Reference Values; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D007457:Iodine Radioisotopes