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²¹¹At-Methylene Blue for Targeted Radiotherapy of Human Melanoma Xenografts: Treatment of Micrometastases¹

Department of Chemical Pathology, Academic Unit, University College and Middlesex School of Medicine, Cleveland Street, London W1P 6DB [E. M. L.], and Department of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT [R. N. C.], United Kingdom

Treatment of micrometastases of HX34 human melanoma grown as xenografts in nude mice represents an advanced stage of preclinical investigations concerning targeted radiotherapy of this neoplasm using 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB) labeled with astatine-211 (²¹¹At) (-particle emitter). The therapeutic effectiveness of ²¹¹At-MTB administered i.v. was determined by a lung colony assay combined with a search for metastases to organs other than the lungs. A single dose of ²¹¹At-MTB lowered the HX34 cell surviving fraction in lungs to below 10% almost independently of the time interval between cell inoculation and radioisotope injection and of ²¹¹At-MTB radioactivity within its investigated range. Radiation dose and the time of its administration did, however, influence the size of lung colonies. In contrast, the efficacy of ²¹¹At-MTB treatment as assessed by both surviving fraction and colony size was significantly dependent on a number of HX34 cells inoculated initially into mice. These results are explained by a short range of -particles emitted by ²¹¹At and a mechanism of growth of lung colonies from tumor cells circulating with blood and blocking lung capillaries. Metastases in organs other than lungs and characteristic of control animals were not found in mice treated with ²¹¹At-MTB. The high therapeutic efficacy achieved proved that ²¹¹At-MTB is a very efficient scavenger of single melanoma cells distributed through blood and micrometastases with sizes below the limit of clinical detection.

¹ Financial support from the Cancer Research Campaign is gratefully acknowledged.

² To whom requests for reprints should be addressed.

Received 9/19/89. Revised 1/18/90.