Potential radiopharmaceuticals for the detection of ocular melanoma. Part I. 5-iodo-2-thiouracil derivatives

Langevelde, A. van; Bakker, C. N. M.; Broxterman, H. J.; Korver, J. G. Journée-de; Kaspersen, Frans M.; Oosterhuis, J. A.; Pauwels, E. K. J.

doi:10.1007/bf00252555

Cited by 25 publications

(11 citation statements)

References 11 publications

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“…Various derivatives of thiouracil have also been found to accumulate in melanomas. Thus, 5L1"IJiodo-2-thiouracil and several of its 2-alkyl, 6-alkyl, and 2,6-dialkyl derivatives were observed Olander et al, 1983;Van Langevelde et al, 1983;Bakker et al, 19801 to give high tumour:nontumour tissue ratios in Syrian golden hamsters with Greene melanomas. 5-Iodo-2-thiouracil labeled with both 1311 and lZ3I also exhibits tumour uptake and body distribution that is virtually identical to that of thiouracil [Coderre et al, 19861.…”

Section: Introductionmentioning

confidence: 96%

Synthetic Approaches to a Carboranyl Thiouracil

1989

Pigment Cell Research

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Thiouracil is selectively incorporated into melanotic murine melanomas during melanin synthesis. This selectivity makes thiouracil a likely vehicle for boron in the diagnosis and therapy of melanoma. Several synthetic routes to thiouracils bearing an alkyl decacarboranyl group attached to various positions on the ring have been investigated. The successful syntheses of three new alkynyl thiouracils and the conversion of one of them into a carboranyl thiouracil are described.

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Section: Introductionmentioning

confidence: 96%

Synthetic Approaches to a Carboranyl Thiouracil

1989

Pigment Cell Research

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“…Incorporation of TU was initially demonstrated by autoradiography in embryonic and fetal eyes where melanin synthesis takes place at high rate, but subsequent experiments revealed a selective uptake in melanotic melanoma transplanted to mice as well as in murine melanoma metastases 7c,8 and cultured human melanoma cells . TU tagged with radioiodine for clinical application in melanoma scanning exhibited selective localization in melanoma tissues , and gave promising results in pilot studies on patients with ocular melanoma 11a or disseminated cutaneous melanoma 11b…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Selective Incorporation of the Melanoma Seeker 2-Thiouracil into Growing Melanin

et al. 1996

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The mechanism of selective incorporation of 2-thiouracil (TU), a highly specific melanoma seeker, into growing melanins was investigated both in vitro and in vivo. Methods used included direct analysis of the melanins, by evaluation of the absorption at 350 nm (A350) and chemical degradation coupled with HPLC quantitation of pigment makers, i.e., pyrrole-2,3-dicarboxylic acid (PDCA) and pyrrole-2,3,5-tricarboxylic acid (PTCA), as well as biosynthetic experiments involving tyrosinase-catalyzed oxidation of DOPA, 5,6-dihydroxyindole (DHI), and 5,6-dihydroxyindole-2-carboxylic acid (DHICA). Injection of radiolabeled TU into melanoma-bearing mice resulted in a rapid incorporation of the drug into the tumor pigment, with a substantial decrease in A350 and in PTCA yields. Similar changes in the absorption properties were observed in biosynthetic melanins prepared in the presence of TU, whereas the yields of PTCA and PDCA varied depending on the pigment precursor used. When incubated with DOPA in the presence of tyrosinase, TU profoundly modified the normal course of melanogenesis, favoring formation of a complex mixture of addition products consisting mainly of 6-S-thiouracil-DOPA as well as DHI-TU adducts. The latter were obtained in larger amounts by enzymatic oxidation of DHI in the presence of TU and were identified as the 3- and 2-substituted adducts 1 and 2, the dimer 3, and the trimer 4. Similar reactions carried out on DHICA yielded the 4-substituted adduct 5, the dimer 6, and the trimer 7. A new mechanistic scheme for the incorporation of TU into growing melanin is proposed, which envisages nucleophilic attack of the thioureylene moiety of TU to transient quinonoid intermediates in the melanin pathway, chiefly dopaquinone and 5,6-indolequinones, followed by entrainment of the resulting adducts into the growing pigment via oxidative copolymerization with DHICA and/or DHI.

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“…Thiouracil is selectively retained in melanotic melanoma transplanted to mice (Dencker et al, 1979Fairchild et al, 1982), as well as murine melanoma metastases (Fairchild et al, 1982;Yamada et al, 1988) and cultured human melanoma cells Larsson et al, 1985). Also 5-iodo-2-thiouracil (ITU), labeled with radioiodine for possible clinical use, is similarly localized in melanotic melanoma van Langevelde et al, 1983;Coderre et al, 1986;Yamada et al, 1988). Preliminary clinical pilot studies on patients with ocular melanoma (Franken et al, 1986) or disseminated cutaneous melanoma (Olander et al, 1991) have indicated that radioiodinated ITU might be used for gamma scintigraphy scanning.…”

Section: Introductionmentioning

confidence: 99%

New Thioureas and Related Substances Intended for Melanoma Targeting

Mårs

Larsson

1995

Pigment Cell Research

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Thiouracil and a few related drugs are known to be melanoma-seeking agents owing to specific incorporation into nascent melanin. The melanin-affinic properties are apparently due to binding to intermediates, preferably dopaquinone, produced in the melanin synthetic pathway by tyrosinase-catalysed oxidation of tyrosine. In the present paper, in vitro screening methods have been used for the identification of possible melanoma seekers according to the above principle. The binding of test substance to dopaquinone suppressed dopachrome formation by the withdrawal of dopaquinone from the reaction of the mixture, and the decrease in dopachrome concentration was monitored spectrophotometrically at 475 nm. In order to eliminate false results caused by tyrosinase inhibition, which also will decrease the dopachrome concentration, the oxygen consumption was followed potentiometrically. To avoid the effect of tyrosinase inhibition on dopachrome formation, additional experiments with autoxidation of L-dopa in the presence of test substance were performed. Of the 22 substances (mainly thioureylenes and thioamides) studied, 4,5,6-triamino-2(H)- pyrimidinehtionsulfate, trithiocyanuric acid, 2-thiouracil, 6-methyl-2-thiouracil, and 4- amino-2-mercaptopyrimidine most effectively decreased the dopachrome formation with no or little inhibition of tyrosinase activity. They should therefore be regarded as potential melanoma seekers. In a complementary autoradiographic study on the uptake of the potent tyrosinase inhibitor mercaptobenzothiazole (MBT) in B 16 melanoma transplanted to mice, it was found that strong tyrosinase inhibition seems to decrease incorporation into melanin in vitro. MBT was partially accumulated in restricted areas of the tumor which may be explained by the molar dose injected.

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Potential radiopharmaceuticals for the detection of ocular melanoma. Part I. 5-iodo-2-thiouracil derivatives

Cited by 25 publications

References 11 publications

Synthetic Approaches to a Carboranyl Thiouracil

Synthetic Approaches to a Carboranyl Thiouracil

Mechanism of Selective Incorporation of the Melanoma Seeker 2-Thiouracil into Growing Melanin

New Thioureas and Related Substances Intended for Melanoma Targeting

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