Radiation doses to non-Hodgkin's lymphoma cells and normal bone marrow exposed in vitro. Comparison of an alpha-emitting radioimmunoconjugate and external gamma-irradiation.
OBJECTIVE
The alpha-emitting radionuclide 211At conjugated to the CD20 targeting chimeric monoclonal antibody rituximab was studied to: (a) Estimate radiation dose components to lymphoma and bone marrow (BM) cells exposed in vitro. (b) Calculate the mean absorbed radiation doses in various normal tissues of mice following intravenous injection.


METHODS
B-lymphoma cells (RAEL) and normal human BM cells were incubated with increasing concentrations of the radioimmunoconjugate. Based on binding kinetics and on measured cellular and nuclear diameters, the radiation doses were calculated using microdosimetric methods.


RESULTS
Targeting of 211At-rituximab to RAEL cells was extensive and stable compared with the binding to BM cells. The absorbed radiation doses from cell-bound activity at an initial activity concentration of 10 kBq ml(-1) were 0.645 and 0.021 Gy to RAEL and BM cells, respectively. In comparison, the contribution from unbound conjugate in the medium during 1h exposure was 0.042 and 0.043 Gy. The D(0) value for RAEL cells was 0.55 Gy, but only 0.34 Gy for BM cells, whereas corresponding D(0) values were 0.72 and 1.21 Gy after a single exposure to external 60Co gamma-rays. Mean absorbed doses of 1.31, 0.48 and 0.36 Gy for blood, lungs and heart were calculated in mice injected with 5.4kBq g(-1) of 211At-rituximab.


CONCLUSIONS
Despite the higher inherent sensitivity of the BM cells to the alpha-irradiation, there was, related to the radioactivity concentrations of 211At-rituximab, several logs greater cell kill in RAEL cells, illustrating the tumour-specific nature of the targeting.
Aurlien
E
E
Department of Medical Oncology and Radiotherapy, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway. ellen.aurlien@klinmed.uio.no
Kvinnsland
Y
Y
Larsen
R H
RH
Bruland
Ø S
ØS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000378:metabolism; D001246:Astatine / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000528:radiation effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000528:radiation effects; D002469:Cell Separation; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry; D005720:Gamma Rays; D006801:Humans; D007554:Isotopes / Q000627:therapeutic use; D007700:Kinetics; D008228:Lymphoma, Non-Hodgkin / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D015233:Models, Statistical; D011485:Protein Binding; D011863:Radioimmunoassay; D011874:Radiometry; D000069283:Rituximab; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D007554:Isotopes; D000069283:Rituximab; D001246:Astatine