Murine hematopoietic ablation by alpha-particle-emitting radiopharmaceuticals - a potential preparative regimen for bone-marrow transplantation.

Overview

Although short-lived alpha-particle-emitting radiopharmaceuticals are currently under evaluation for biologically targeted radiotherapy, very little is known about the dose-response kinetics of the hematosuppression produced by low level or transient exposure to these compounds while in the circulation. We have used hematopoietic progenitor cell colony-forming-unit assays to establish the dose-response curve for Bi-212 alpha particle radiation delivered in vitro, and have compared it to the dose-response curves for equivalent doses of Y-90 beta and Cs-137 gamma radiation. We then evaluated the dose-response effects for these radiopharmaceuticals after in vivo injection in mice. Both in vitro and in vivo, the Bi-212 was extremely hematosuppressive (50% inhibitory dose 20-30 cGy in culture) but this myelosuppression was transient at low or intermediate doses. Serum froin mice recovering from Bi-212-induced hematosuppression produced significant stimulation of naive syngeneic marrow progenitor cells, supporting the existence of a physiologic feedback mechanism that involves a poorly defined humoral factor released after radiation injury. Short-lived alpha emitters may be well suited to the development of tumor-seeking radiopharmaceuticals that can be used in the preparation of patients for autologous and allogeneic marrow transplantation.