Relative biologic effects of low-dose-rate alpha-emitting 227Th-rituximab and beta-emitting 90Y-tiuexetan-ibritumomab versus external beam X-radiation.
OBJECTIVE
To determine the relative biologic effects (RBE) of alpha-particle radiation from 227Th-rituximab and of beta-radiation from 90Y-tiuexetan-ibritumomab (Zevalin) compared with external beam X-radiation in the Raji lymphoma xenograft model.


METHODS
Radioimmunoconjugates were administered intravenously in nude mice with Raji lymphoma xenografts at different levels of activity. Absorbed dose to tumor was estimated by separate biodistribution experiments for 227Th-rituximab and Zevalin. Tumor growth was measured two to three times per week after injection or X-radiation. Treatment-induced increase in growth delay to reach tumor volumes of 500 and 1,000 mm3, respectively, was used as an end point.


RESULTS
The absorbed radiation dose-rate in tumor was slightly more than 0.1 Gy/d for the first week following injection of 227Th-rituximab, and thereafter gradually decreased to 0.03 Gy/d at 21 days after injection. For treatment with Zevalin the maximum dose-rate in tumor was achieved already 6 h after injection (0.2 Gy/d), and thereafter decreased to 0.01 Gy/d after 7 days. The relative biologic effect was between 2.5 and 7.2 for 227Th-rituximab and between 1 and 1.3 for Zevalin.


CONCLUSIONS
Both at low doses and low-dose-rates, the 227Th-rituximab treatment was more effective per absorbed radiation dose unit than the two other treatments. The considerable effect at low doses suggests that the best way to administer low-dose-rates, alpha-emitting radioimmunoconjugates is via multiple injections.
Dahle
Jostein
J
Department of Radiation Biology, The Norwegian Radium Hospital, Montebello, Oslo, Norway. jostein.dahle@rr-research.no
Bruland
Oyvind S
OS
Larsen
Roy H
RH
D000512:Alpha Particles / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D001610:Beta Particles / Q000627:therapeutic use; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006207:Half-Life; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000532:radiotherapy; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000379:methods; D012062:Relative Biological Effectiveness; D000069283:Rituximab; D013910:Thorium / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018796:Immunoconjugates; D015021:Yttrium Radioisotopes; D000069283:Rituximab; C422802:ibritumomab tiuxetan; D013910:Thorium