In vitro cytotoxicity of low-dose-rate radioimmunotherapy by the alpha-emitting radioimmunoconjugate Thorium-227-DOTA-rituximab.
OBJECTIVE
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
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.
Dahle
Jostein
J
Department of Radiation Biology, Norwegian Radium Hospital, Montebello, Oslo, Norway. jostein.dahle@rr-research.no
Krogh
Cecilie
C
Melhus
Katrine B
KB
Borrebaek
Jørgen
J
Larsen
Roy H
RH
Kvinnsland
Yngve
Y
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects*; D048429:Cell Size; D003470:Culture Media; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D016393:Lymphoma, B-Cell / Q000532:radiotherapy*; D009942:Organometallic Compounds / Q000627:therapeutic use*; D016499:Radioimmunotherapy / Q000379:methods*; D011879:Radiotherapy Dosage; D012062:Relative Biological Effectiveness; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D003470:Culture Media; D018796:Immunoconjugates; D009942:Organometallic Compounds; C544340:thorium-227-DOTA-rituximab; D000069283:Rituximab