[211At]methylene blue for targeted radiotherapy of human melanoma xenografts: dose fractionation in the treatment of cutaneous tumours.
3,7-(dimethylamino) phenazathionium chloride [methylene blue (MTB)] labelled with alpha-particle emitter astatine-211 (211At) selectively accumulates in melanoma cells due to an exceptionally high affinity of MTB to melanin, and proves to be a very effective agent in targeting radiotherapy for pigmented human melanoma grown in mice. This study aimed at a selection of the most advantageous [211At]MTB dose fractionation leading to irreversible regression of the treated lesions. Nude mice bearing subcutaneous human melanoma xenografts of either highly pigmented HX118 or poorly pigmented HX34 human melanoma were treated with [211At]MTB administered intravenously. The treatment was performed using three different schedules of [211At]MTB fractionation: a single large dose, five fractions delivered sequentially every 48 h and two to five fractions given with a mean frequency of one per week. The effectiveness of [211At]MTB treatment was assessed by determination of the growth rate of cutaneous tumours and length of time between tumour implantation and killing of moribund mice. [211At]MTB applied with a mean frequency of one fraction per week appeared to be the most efficient treatment for highly pigmented HX118 melanomas. Its effectiveness was dependent on [211At]MTB activity used per fraction and the size of the cutaneous tumours at the beginning of the treatment. A total dose of [211At]MTB seemed of less importance. An irreversible regression of the lesions was achieved. Poorly pigmented cutaneous melanoma xenografts were affected most significantly by [211At]MTB applied as five fractions given every 48 h. The treatment caused a temporary inhibition of tumour growth after which the lesions regained the control growth rate. These and previous results suggest that [211At]MTB could successfully control the growth of already formed lesions of pigmented melanoma, as well as prevent metastatic spread of the tumour, provided an appropriate fractionation régime of the radiolabelled compound is employed.
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E M
EM
Department of Molecular Pathology, University College, London, U.K.
Carpenter
R N
RN
Hansen
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G
D000818:Animals; D001246:Astatine / Q000627:therapeutic use*; D004337:Drug Carriers; D005260:Female; D006801:Humans; D008545:Melanoma / Q000473:pathology / Q000532:radiotherapy*; D008751:Methylene Blue; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010858:Pigmentation; D012878:Skin Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D013997:Time Factors; D014183:Transplantation, Heterologous
D004337:Drug Carriers; D008751:Methylene Blue; D001246:Astatine