Accumulation of 125I-labelled thiouracil and propylthiouracil in murine melanotic melanomas

Abstract

We have shown that thioamides are incorporated as false precursors into melanin during its synthesis. To be clinically useful in the diagnosis or therapy of melanotic melanomas, they would have to be tagged with an appropriate isotope or possibly a cytotoxic moiety. 125I-Thiouracil (125I-TU) is here shown to be accumulated in the melanin of melanotic melanomas transplanted into mice in a similar way as is 14C-thiouracil (14C-TU). 125I-TU gives tumour/liver and tumour/muscle ratios up to 22 and 778 respectively, at 4 days after administration. 125I-TU is accumulated by melanoma cells in vitro more effectively than 14C-TU (125I-TU/14C-TU, 2.7), while the in vivo accumulation into melanomas is slightly lower for 125I-TU as compared to 14C-TU (125I-TU/14C-TU, 0.35). This appears to be due to a partial deiodination (less than 14% of the dose within 4 days) and probably a more rapid excretion of 125I-TU or its metabolite(s). The accumulation of radioactivity in the thyroid can essentially be eliminated by pretreatment with potassium iodide and/or thyroxine. 125I-Propylthiouracil is also accumulated in melanotic melanoma cells in vivo and in vitro, but at a lower level than in 125I-TU and 14C-TU. Images Fig.

Accumulation of Chlorpromazine and Thiouracil by Human Melanoma Cells in Culture

“…In view of reports that inhibition of melanin synthesis suppressed the growth of rodent melanomas (Demopoulous, 1973;Pawelek, 1976;Prabhakaram et ai, 1969), it was of interest that PTU strongly inhibited tyrosinase activity in MM418 cells without being excessively toxic. The lack of additional toxicity by the ^"^C compounds, in particular by ^'C-TU in MM418 cells, is not considered a significant problem at the present stage of investigation because of the possibility of using higher specific activities of ^"^C-TU or of using '25i-labelled material (Broxterman et al, 1983;Dencker et al, 1982;Larsson et al, 1982).…”

The Chemistry of Neutron Capture Therapy

“…Also, BTU had greater tumor persistence than did BPA . Substantial synthetic work by Wilson has focused on the synthesis of closo -carboranylthiouracils. − Biodistribution studies in melanoma-bearing mice, especially with liposomal formulations of these derivatives, showed selective tumor uptake . More recently, Gabel and his collaborators have synthesized nido -carboranyl and B 12 H 11 -substituted methimazoles. ,, No biological data for these compounds have been published as yet.…”

Interaction Between Chemicals and Melanin

“…The incorporation of thiouracil into melanin is apparently due to covalent binding to dopaquinone, formed during the melanin synthetic pathway, and the thiouracil-dopaquinone adduct is gradually inglobated within the melanin polymer during its formation (F'alumbo et al, 1990). The thioureylenes are selectively incorporated into melanotic melanoma (Dencker et al, 1979;Larsson et al, 1982) and much interest has been focused on the clinical potential of using thiouracil derivatives, e.g., 5iodo-2-thiomcil (Fig. 31, as selective tumour seekers for the diagnosis by radio-scanning or treatment of malignant melanoma (for review, see Larsson, 1991).…”