The development of a [211AT]-astatinated endoradiotherapeutic drug: part IV--late radiation effects.
OBJECTIVE
6-[211At]-astato-MNDP is a high-LET endoradiotherapeutic drug that selectively targets to an oncogenically associated alkaline phosphatase isoenzyme expressed by certain tumors. A detailed histopathological study of the late tissue effects of its endogenous alpha-particle emissions has been carried out in a murine tumor model.


METHODS
Thyroid-blocked male C57BI/10 mice bearing a s.c. transplanted rectal adenocarcinoma were treated with a single i.p. injection of 10-750 kBq 6-[211At]-astato-MNDP. Cured mice (131) were studied. Detailed autopsies and histological examinations were performed on all mice. The study was concluded after 756 days.


RESULTS
Lymphoma, plasmacytoma, and intercurrent infections secondary to chronic pulmonary fibrosis were the most commonly found late manifestations of alpha-radiation exposure. Low grade B-cell non-Hodgkin's lymphoma occurred in 19 (24.7%) of 77 mice, 13-17 months after receiving 3.5-185 kBq 6-[211At]-astato-MNDP. The incidence of lymphoma alone and its latency was similar to that of the control population (23.3%). Treatment doses exceeding 200 kBq 6-[211At]-astato-MNDP, were associated with the development of soft tissue plasmacytoma in 7 (13%) of 54 mice, after 17-22 months. Generalized debilitation and nonspecific infections supervening pulmonary fibrosis significantly contributed to the late morbidity and mortality observed in mice treated with 300-750 kBq 6-[211At]-astato-MNDP. Dosimetry has afforded LD50/360 and LD50/420 estimates of 12-14 and 10-12 Cobalt-Gray equivalent (CGyE), respectively, for chronic lung damage. There was no histological evidence of chronic radiation damage to other critical healthy tissues. Normal thyroid morphology was preserved.


CONCLUSIONS
Dose activities of 6-[211At]-astato-MNDP exceeding 300 kBq, were associated an increased risk of tumor induction and development of varying degrees of chronic pulmonary fibrosis implicated in the onset of terminal intercurrent infections. Within the therapeutic dose range 55-300 kBq 6-[211At]-astato-MNDP, mortality associated with the incidence of significant late radiation damage in critical normal tissues and latent carcinogenesis was less than 15%. Data from this murine model suggest that clinically relevant activities of 6-[211At]-astato-MNDP may be given without unacceptable toxicity.
Brown
I
I
The Research Laboratories, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, UK.
Mitchell
J S
JS
D000818:Animals; D001246:Astatine / Q000009:adverse effects*; D004307:Dose-Response Relationship, Radiation; D004354:Drug Screening Assays, Antitumor; D008168:Lung / Q000528:radiation effects; D008223:Lymphoma / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010954:Plasmacytoma / Q000139:chemically induced; D011833:Radiation Injuries, Experimental / Q000401:mortality / Q000473:pathology*; D019275:Radiopharmaceuticals / Q000009:adverse effects*; D013961:Thyroid Gland / Q000528:radiation effects
D019275:Radiopharmaceuticals; D001246:Astatine