Pharmacokinetics in melanoma-bearing mice of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a candidate compound for boron neutron capture therapy

Abstract

Summary Blood pharmacokinetics and tissue distribution of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a boron carrier with postulated melanin-seeking properties for boron neutron capture therapy, were determined in C57/BL mice with subcutaneous pigmented or non-pigmented B16 melanomas. Borocaptate sodium (BSH) was used as a boron compound without melanin-seeking properties in a comparative biodistribution study in the same animal tumour models. Administration of single doses showed that BPTU was retained better in the pigmented B16 tumour than in the non-pigmented variant. BPTU was found in large concentrations in kidney and liver. Brain boron was approximately 10-fold lower than tumour boron. On a molar basis, BPTU demonstrated higher affinity for B16 tumours than BSH. Owing to solubility limits, tumour boron concentrations in this mouse study were too low for effective application of BNCT. However, the high tumour-to-blood and tumour-to-normal tissues ratios indicate that, with appropriate formulation, BPTU could be a promising candidate for clinical BNCT.The primary goal of boron neutron capture therapy (BNCT) at the present time is to achieve more effective treatments for glioma and melanoma than conventional radiotherapy (Allen et al., 1989;Slatkin, 1991). The selective accumulation of "'B-containing compounds in tumours and subsequent irradiation with low-energy (thermal) neutrons form the basis of BNCT. The short track lengths of`'B(n,a)7Li fission products (9 and 5 iLm for a and 7Li respectively) offer partial restriction of the radiation dose to the "'B-containing cells. Additional advantages owing to the high-LET (linear energy transfer) character of the emitted radiation are higher biological efficacies compared with photons or X-rays and less effect of hypoxia or cell cycle distribution on the therapeutic effect. The relatively high resistance of melanomas for photon therapy and the presence of a biochemical rationale for boron targeting explain the efforts made in this area Madoc Jones et al., 1990). The often high rate of melanogenesis in melanoma cells has led to the development of several boron drugs with melanoma-seeking capacity.The L-isomer of boronphenylalanine (BPA) is taken up by melanoma cells both in vitro and in vivo (Ichihashi et al., 1982; Coderre et al., 1987;Allen et al., 1992;Packer et al., 1992). Animal studies on BNCT efficacy and normal tissue tolerance with BPA have also been performed (Coderre et al., 1991; Hiratsuka et al., 1991). Although the uptake of BPA in melanoma cells is well accepted, incorporation of boron into melanin might not occur, resulting in poor retention. Boronated thiouracils that enter the melanogenesis pathway at a different point from BPA have been recently synthesised, aiming at boron incorporation into the melanin for better retention (Tjarks & Gabel, 1991). We have found previously that 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU) and not boronthiouracil (BTU) was retained in vitro in melanotic B16 cells, while BPTU failed to be retained in th...

The Chemistry of Neutron Capture Therapy

“…Roberto and Larsson described the preparation of a decaborane adduct of 5-(dimethylamino)methylthiouracil. − Subsequently, Tjarks and Gabel described the synthesis of carborane-containing cyclic thioureas both as closo and nido derivatives − Their biodistribution in tumor-bearing rodents demonstrated low toxicity as well as significant uptake and selectivity for malignant melanomas. , By comparison with BPA, 5-(dihydroxyboryl)-2-thiouracil (BTU) showed a different boron distributive pattern in the tumor …”

“…[560][561][562] Their biodistribution in tumorbearing rodents demonstrated low toxicity as well as significant uptake and selectivity for malignant melanomas. 560,563 By comparison with BPA, 5-(dihydroxyboryl)-2-thiouracil (BTU) showed a different boron distributive pattern in the tumor. 560 This observation supports the possible desirability of using a cocktail of tumor-seeking boron compounds as a means of achieving a more uniform boron distribution within the tumor.…”

New drugs for BNCT: An experimental approach

“…Between these peaks a remarkable minimum (5.3 +_ 0.2 ppm) at 1.5 h correlated significantly with the boron maximum in the liver at that time. High boron content in the liver and kidney, as well as the entero-hepatic pathway and renal elimination of boron have also been reported after application of other BNCT compounds like BPTU [9,27]. In integral blood, the boron content decreased continously, starting from 10 _+ 1 ppm at 0.5 h. It might be assumed that the drug is bound extracellulary in the integral blood [17].…”