Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model

Abstract

The therapeutic efficacy of the alpha-particle-emitting radionuclide (223)Ra (t(1/2) = 11.4 days) in the treatment against experimental skeletal metastases in rats was addressed. Biodistribution studies, involving measurement of (223)Ra in bone marrow samples, were performed in rats after i.v. injection. To study the therapeutic effect of (223)Ra, an experimental skeletal metastases model in nude rats was used. Animals that had received 10(6) MT-1 human breast cancer cells were treated with (223)Ra doses in the range of 6-30 kBq after 7 days. The biodistribution experiment demonstrated that (223)Ra was selectively concentrated in bone as compared with soft tissues. The femur content of (223)Ra was 800 +/- 56% of injected dose per gram tissue times gram body weight (b.w.; mean +/- SD) 1 day after the injection and 413 +/- 23% of injected dose per gram tissue times gram b.w. at 14 days. The femur:kidney ratio increased from (5.9 +/- 2.0).10(2) at 1 day to (7.2 +/- 3.0).10(2) at 14 days, whereas the femur:liver ratio increased from (6.2 +/- 0.2).10(2) to (9.1 +/- 6.6).10(2). Femur:spleen ratio increased from (8.1 +/- 0.3).10(2) at 1 day to (6.4 2.2).10(3) at 14 days. The femoral bone:marrow ratio was 6.5 +/- 2.1 after day 1 and larger than 15 at day 14. All of the tumor-bearing control animals had to be sacrificed because of tumor-induced paralysis 20-30 days after injection with tumor cells, whereas the rats treated with > or =10 kBq of (223)Ra had a significantly increased symptom-free survival (P < 0.05). Also 36% (5 of 14) of rats treated with 11 kBq and 40% (2 of 5) of rats treated with 10 kBq were alive beyond the 67-day follow-up period. No signs of bone marrow toxicity or b.w. loss were observed in the groups of treated animals. The significant antitumor effect of (223)Ra at doses that are tolerated by the bone marrow is most likely linked to the intense and highly localized radiation dose from alpha-particles at the bone surfaces. The results of this study indicate that (223)Ra should be additionally studied as a potential bone marrow-sparing treatment of cancers involving the skeleton.