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In vitro cytotoxicity of low-dose-rate radioimmunotherapy by the alpha-emitting radioimmunoconjugate Thorium-227-DOTA-rituximab.

AbstractPURPOSE:
To determine whether the low-dose-rate alpha-particle-emitting radioimmunoconjugate (227)Th-1,4,7,10-p-isothiocyanato-benzyl-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-rituximab can be used to inactivate lymphoma cells growing as single cells and small colonies.
METHODS AND MATERIALS:
CD20-positive lymphoma cell lines were treated with (227)Th-DOTA-rituximab for 1-5 weeks. To simulate the in vivo situation with continuous but decreasing supply of radioimmunoconjugates from the blood pool, the cells were not washed after incubation with (227)Th-DOTA-rituximab, but half of the medium was replaced with fresh medium, and cell concentration and cell-bound activity were determined every other day after start of incubation. A microdosimetric model was established to estimate the average number of hits in the nucleus for different localizations of activity.
RESULTS:
There was a specific targeted effect on cell growth of the (227)Th-DOTA-rituximab treatment. Although the cells were not washed after incubation with (227)Th-DOTA-rituximab, the average contribution of activity in the medium to the mean dose was only 6%, whereas the average contribution from activity on the cells' own surface was 78%. The mean dose rates after incubation with 800 Bq/mL (227)Th-DOTA-rituximab varied from 0.01 to 0.03 cGy/min. The average delay in growing from 10(5) to 10(7) cells/mL was 15 days when the cells were treated with a mean absorbed radiation dose of 2 Gy alpha-particle radiation from (227)Th-DOTA-rituximab, whereas it was 11 days when the cells were irradiated with 6 Gy of X-radiation. The relative biologic effect of the treatment was estimated to be 2.9-3.4.
CONCLUSIONS:
The low-dose-rate radioimmunoconjugate (227)Th-DOTA-rituximab is suitable for inactivation of single lymphoma cells and small colonies of lymphoma cells.
AuthorsJostein Dahle, Cecilie Krogh, Katrine B Melhus, Jørgen Borrebaek, Roy H Larsen, Yngve Kvinnsland
JournalInternational journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 75 Issue 3 Pg. 886-95 (Nov 01 2009) ISSN: 1879-355X [Electronic] United States
PMID19679402 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Culture Media
  • Immunoconjugates
  • Organometallic Compounds
  • thorium-227-DOTA-rituximab
  • Rituximab
Topics
  • Antibodies, Monoclonal (therapeutic use)
  • Antibodies, Monoclonal, Murine-Derived
  • Cell Count
  • Cell Line, Tumor
  • Cell Proliferation (radiation effects)
  • Cell Size
  • Culture Media
  • Drug Screening Assays, Antitumor
  • Humans
  • Immunoconjugates (therapeutic use)
  • Lymphoma, B-Cell (radiotherapy)
  • Organometallic Compounds (therapeutic use)
  • Radioimmunotherapy (methods)
  • Radiotherapy Dosage
  • Relative Biological Effectiveness
  • Rituximab

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