title: Ablation of colorectal xenografts with combined radioimmunotherapy and tumor blood flow-modifying agents.
abstract: Radioimmunotherapy (RIT) does not readily eradicate common solid tumors and therefore requires augmentation by complementary therapies that do not increase normal tissue damage. We have examined the efficacy of RIT combined with 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a drug which induces immunomodulation and cytokine production and preferentially reduces tumor blood flow, using a colorectal xenograft model in nude mice. Although an optimal i.p. dose (27.5 mg/kg) of drug alone induced massive hemorrhagic necrosis of all but a thin peripheral rim of viable tumor cells, survival was unaffected. However, when combined with i.v. 18.5 MBq 131I-labeled anti-carcinoembryonic antigen IgG, DMXAA significantly potentiated the RIT without increased toxicity, with five of six mice showing complete cures. Scheduling was critical because the antibody must be allowed to reach maximum tumor accumulation before initiation of drug-induced blood flow inhibition. Subsequently, the antibody was retained preferentially in the tumor, reaching approximately twice control levels by 5 days after drug delivery. In combined studies, the drug had a narrow therapeutic window, 30 mg/kg being toxic to two of six mice, whereas 20 mg/kg were ineffective. However, the addition of a second vasoactive agent, serotonin, to RIT plus 20 mg/kg DMXAA enhanced therapy without increasing systemic toxicity. Tumor histology and phosphor image plate analysis reflected these results. When given without RIT, the two drugs combined, although not alone, also significantly inhibited tumor growth. Drug-induced tumor necrosis and tumor retention of radioantibody may both contribute to the enhanced RIT produced by this combined complementary therapy.
authors.affiliation: Department of Clinical Oncology, Royal Free Hospital School of Medicine, Rowland Hill Street, London, United Kingdom.
authors.forename: R B
authors.initials: RB
authors.lastname: Pedley
authors.forename: J A
authors.initials: JA
authors.lastname: Boden
authors.forename: R
authors.initials: R
authors.lastname: Boden
authors.forename: G M
authors.initials: GM
authors.lastname: Boxer
authors.forename: A A
authors.initials: AA
authors.lastname: Flynn
authors.forename: P A
authors.initials: PA
authors.lastname: Keep
authors.forename: R H
authors.initials: RH
authors.lastname: Begent
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000378:metabolism / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000628:therapy*; D003131:Combined Modality Therapy; D005419:Flavonoids / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply; D016499:Radioimmunotherapy / Q000379:methods*; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects; D014183:Transplantation, Heterologous; D014966:Xanthenes / Q000008:administration & dosage; D044004:Xanthones
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D002272:Carcinoembryonic Antigen; D005419:Flavonoids; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; D012701:Serotonin; C049328:flavone acetic acid