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Uptake and Therapeutic Effectiveness of ¹²⁵I- and ²¹¹At-Methylene Blue for Pigmented Melanoma in an Animal Model System¹

Department of Chemical Pathology, Academic Unit, University College and Middlesex School of Medicine, Cleveland Street, London W1P 6DB [E. M. L.] and The Research Laboratories, Radiotherapeutic Centre, Cambridge University School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ [I. B., R. N. C., J. S. M.], United Kingdom

The investigations concerning a targeted radiotherapy for pigmented melanoma with a radiolabeled phenothiazine derivative, 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB)], were continued using melanotic and amelanotic sublines of B16 melanoma. Two radionuclides, ¹²⁵I and ²¹¹At, emitting Auger electrons and particles, respectively, replaced ³⁵S previously studied since their biological effectiveness is significantly higher. In vitro autoradiography revealed a selective accumulation of methylene blue labeled with either of the radioisotopes in pigmented melanoma cells but its absence in nonpigmented cells. Treatments with [¹²⁵I]MTB and [²¹¹At]MTB were performed both in vitro and in vivo, with their effectiveness determined by lung clonogenic assay. [¹²⁵I]MTB proved to be relatively ineffective when incorporated into melanosomes distributed in the cytoplasm, i.e., too far away from the genome. Conspicuous therapeutic effects were achieved with [²¹¹At]MTB for pigmented melanoma only. ²¹¹At itself did not affect either of the investigated sublines of B16 melanoma confirming once again the high affinity of methylene blue to melanin. Calculations of cumulative radiation doses from [²¹¹At]MTB deposited in melanotic melanoma tumors and pigmented normal organs which would be at a particular risk led to the conclusion that [²¹¹At]MTB could be used for a highly selective and very efficient targeted radiotherapy of pigmented melanomas without damaging normal tissues.

¹ Financial support from the Association for International Cancer Research and, more recently, from the Cancer Research Campaign is gratefully acknowledged.

² To whom requests for reprints should be addressed, at Department of Chemical Pathology, Academic Unit, University College and Middlesex School of Medicine, Cleveland Street, London W1P 6DB, United Kingdom.

³ Deceased February 22, 1987.

Received 2/ 1/89. Revised 4/24/89. Accepted 5/ 3/89.