Alpha- versus beta-particle radiopeptide therapy in a human prostate cancer model (213Bi-DOTA-PESIN and 213Bi-AMBA versus 177Lu-DOTA-PESIN).

Recurrent prostate cancer presents a challenge to conventional treatment, particularly so to address micrometastatic and small-volume disease. Use of α-radionuclide therapy is considered as a highly effective treatment in such applications due to the shorter range and exquisite cytotoxicity of α-particles as compared with ß-particles. (213)Bi is considered an α-emitter with high clinical potential, due to its short half-life (45.6 minutes) being well matched for use in peptide-receptor radionuclide α-therapy; however, there is limited knowledge available within this context of use. In this study, two novel (213)Bi-labeled peptides, DOTA-PEG(4)-bombesin (DOTA-PESIN) and DO3A-CH(2)CO-8-aminooctanoyl-Q-W-A-V-G-H-L-M-NH(2) (AMBA), were compared with (177)Lu (ß-emitter)-labeled DOTA-PESIN in a human androgen-independent prostate carcinoma xenograft model (PC-3 tumor). Animals were injected with (177)Lu-DOTA-PESIN, (213)Bi-DOTA-PESIN, or (213)Bi-AMBA to determine the maximum tolerated dose (MTD), biodistribution, and dosimetry of each agent; controls were left untreated or were given nonradioactive (175)Lu-DOTA-PESIN. The MTD of (213)Bi-DOTA-PESIN and (213)Bi-AMBA was 25 MBq (0.68 mCi) whereas (177)Lu-DOTA-PESIN showed an MTD of 112 MBq (3 mCi). At these dose levels, (213)Bi-DOTA-PESIN and (213)Bi-AMBA were significantly more effective than (177)Lu-DOTA-PESIN. At the same time, (177)Lu-DOTA-PESIN showed minimal, (213)Bi-DOTA-PESIN slight, and (213)Bi-AMBA marked kidney damage 20 to 30 weeks posttreatment. These preclinical data indicate that α-therapy with (213)Bi-DOTA-PESIN or (213)Bi-AMBA is more efficacious than ß-therapy. Furthermore, (213)Bi-DOTA-PESIN has a better safety profile than (213)Bi-AMBA, and represents a possible new approach for use in peptide-receptor radionuclide α-therapy treating recurrent prostate cancer.

Detection of reticulated platelets in whole blood of rats using flow cytometry.

As opposed to erythropoiesis, which is regularly assessed in the peripheral blood of animals by reticulocyte count, thrombopoiesis is rarely assessed in assays that detect immature platelets in the peripheral blood. An assessment of recent thrombopoiesis is feasible with the analysis of reticulated platelets in the peripheral blood via flow cytometry, but rarely performed. The aim of this study was to establish an assay for the detection of reticulated platelets in whole blood of rats via flow cytometry, using a two-color staining method with a platelet-specific antibody (CD61-PE) and thiazole orange to detect RNA-containing platelets. Platelets were detected in K3EDTA-anticoagulated, paraformaldehyde-fixed samples, using a CD61-PE antibody as well as a gate specific for the light scatter properties of platelets. The intra-assay coefficient of variation varied between 3.6% and 8.3% (n=6 animals). The stability of the assay was determined by storing blood prior to staining, storing stained samples for up to 2h at room temperature, and by diluting the blood prior to analysis with autologous plasma to create samples with artificial anemia and thrombocytopenia. Only samples stored at room temperature prior to analysis showed a significantly lower percentage of reticulated platelets. Percentage of reticulated platelets in the reference population (n=41 rats) was 10.0+/-1.3% reticulated platelets (mean+/-SD; min=6.2%; max=12.5%). These data show that the detection of reticulated platelets in whole blood of rats using a platelet-specific antibody is feasible. This test presents a minimal-invasive method to assess thrombopoiesis in rats that can be used for example in preclinical toxicological studies.