Thymidine Phosphorylase Inhibitors: Recent Developments and Potential Therapeutic Applications

Abstract

Thymidine Phosphorylase (TPase) catalyses the reversible phosphorolysis of pyrimidine 2'-deoxynucleosides to 2-deoxyribose-1-phosphate and their respective pyrimidine bases, including the phosphorolysis of nucleoside analogues with important antiviral or anticancer properties. Moreover, TPase, identified also as the angiogenic platelet-derived endothelial cell growth factor (PD-ECGF), stimulates endothelial cell migration in vitro and angiogenesis in vivo and plays an important role in tumour progression and metastasis. Here we have summarized the most recent approaches in the search for novel TPase inhibitors together with the potential therapeutic applications of such inhibitors.

A polymorphism in the TYMP gene is associated with the outcome of HLA‐identical sibling allogeneic stem cell transplantation

“…As found by the univariate (Table IIa) and multivariate (Table IVa) analyses, the only factor associated with the risk of relapse was disease stage at transplantationpatients transplanted in the advanced stage having a nearly two-fold higher risk of relapse than the rest (HR5 1.8, 95%CI 5 1.2-2.8; P 5 0.010). At 3 years after transplantation, the cumulative incidence of relapse in patients with advanced disease was 35% (95%CI, 27-45) as compared to 18% (95%CI, [14][15][16][17][18][19][20][21][22][23][24][25] in those with early stage disease.…”

“…Results of the univariate and multivariate regression analyses of factors associated with each specific cause of mortality are displayed in Tables IIc and IVc, respectively. With regard to relapse-related mortality (RRM), the only factor significantly associated with this condition in the multivariate analysis was disease stage at the time of transplantation (P < 0.001). The cumulative incidence of RRM at 3 years was 33% (95%CI, 26-43) for patients with advanced disease at transplant, and 16% (95%CI, [11][12][13][14][15][16][17][18][19][20][21][22] for those with early stage disease. research article…”

“…The cumulative incidence of GVHDRM at 3 years was 9% (95%CI, 6-13) in patients who received myeloablative conditioning, and 23% (95%CI, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] in those who received reduced-intensity regimens.…”

“…Specifically, TYMP catalyzes the reversible phosphorolysis of thymidine, thereby regulating the amount of nucleosides within the cells [19] in order to maintain a balanced deoxyribonucleoside triphosphate pool for DNA replication and repair [20][21][22][23]. The TYMP gene has a non-synonymous single nucleotide polymorphism (SNP) located in codon 465 of the coding sequence, in which a change of nucleotides (G to A) leads to an Ala-toThr substitution (rs112723255).…”

Identification of aspartic acid-203 in human thymidine phosphorylase as an important residue for both catalysis and non-competitive inhibition by the small molecule “crystallization chaperone” 5′-O-tritylinosine (KIN59)

“…During the last decade, several novel classes of TP inhibitors have been developed [12]. For more than 30 years, the reference TP inhibitors were 6-aminouracil derivatives including 6-aminothymine (6AT) and 6-amino-5-bromouracil (6A5BU) [13].…”