C169
Treatment of disseminated melanoma with 211At-methylene blue
Eva Link
London, UK
Random metastatic dissemination of melanoma at a very early stage of the disease development calls for a systemic, highly selective and relatively non-toxic treatment that could be used both as an adjuvant therapy immediately after surgery of a primary tumour thicker than 1 mm and to ameliorate growth of larger lesions regardless of their localisation.
Melanin synthesised in melanoma cells presents a unique target to which the treatment can be selectively addressed, provided the pigment is recognised by a suitable drug. (Please note: non-pigmented melanoma that lacks tyrosinase activity, the enzyme responsible for melanin synthesis, is very uncommon.)
By virtue of its exceptionally high affinity to melanin, methylene blue (MTB), a low molecular weight, water-soluble compound that diffuses easily through the cellular membranes, accumulates selectively in melanoma cells. One of its radioderivatives, 211At-MTB (astatine-211 is an α-particle emitter with a short half-life of 7.2 h only and a mean range of radiation of 65 µm, which is an equivalent of a diameter of 3-6 cells), has proved to be particularly effective in treating melanoma and preventing its metastatic spread without damaging normal non-pigmented and pigmented structures when administered systemically to human melanoma-bearing animals. This exceptionally high therapeutic index has been achieved by combining a high and selective uptake of MTB in melanoma cells with the very powerful radiation emitted by the used radionuclide (211At requires only a few disintegrations per cancer cell to kill the cell regardless of its radiosensitivity). At the same time, rapid clearance of 211At-MTB from normal organs and very short range of α-particles emitted by the radioisotope prevent normal tissues from being damaged by the radiation.
Clinical evaluation of the selectivity of the radioiodinated MTB derivatives for melanoma lesions in man, as required prior to clinical trials with 211At-MTB (211At is not suitable for monitoring with gamma cameras or PET) also revealed that the efficacy of the uptake of radiolabelled MTB in melanoma cells is sufficient to employ the compound for detection of early melanoma metastases.
211At-MTB has been approved for the Phase I clinical trial since 1995 with all licences and permissions granted 10 years ago, but the trial still awaits its star. A question remains why?
