A crucial role of uridine/cytidine kinase 2 in antitumor activity of 3'-ethynyl nucleosides.

The antitumor 3'-ethynyl nucleosides, 1-(3-C-ethynyl-beta-D-ribopentofuranosyl)cytosine (ECyd) and 1-(3-C-ethynyl-beta-D-ribopentofuranosyl)uridine (EUrd), are potent inhibitors of RNA polymerases and show excellent antitumor activity against various human solid tumors in xenograft models. ECyd is being investigated in phase I clinical trials as a novel anticancer drug possessing a unique antitumor action. ECyd and EUrd require the activity of uridine/cytidine kinase (UCK) to produce the corresponding active metabolite. The UCK family consists of two members, UCK1 and UCK2, and both UCKs are expressed in many tumor cells. It was unclear, however, whether UCK1 or UCK2 is responsible for the phosphorylation of the 3'-ethynyl nucleosides. We therefore established cell lines that are highly resistant to the 3'-ethynyl nucleosides from human fibrosarcoma HT-1080 and gastric carcinoma NUGC-3. All the resistant cell lines showed a high cross-resistance to ECyd and EUrd. As a result of cDNA sequence analysis, we found that UCK2 mRNA expressed in EUrd-resistant HT-1080 cells has a 98-base pair deletion of exon 5, whereas EUrd-resistant NUGC-3 cells were harboring the point mutation at nucleotide position 484 (C to T) within exon 4 of UCK2 mRNA. This mutation was confirmed by genome sequence analysis of the UCK2 gene. Moreover, the expression of UCK2 protein was decreased in these resistant cells. In contrast, no mutation in the mRNA or differences in protein expression levels of UCK1 were shown in the EUrd-resistant HT-1080 and NUGC-3 cells. These results suggest that UCK2 is responsible for the phosphorylation and activation of the antitumor 3'-ethynyl nucleosides.     

Poor responses to tyrosine kinase inhibitors in a child with precursor B‐cell acute lymphoblastic leukemia with SNX2‐ABL1 chimeric transcript

In addition to BCR, various rare fusion partners for the ABL1 gene have been reported in leukemia. We have identified the fusion gene SNX2‐ABL1 in a pediatric case of acute lymphoblastic leukemia (ALL), which has only once previously been reported in an adult patient. Cytogenetic analysis detected this fusion gene arising from a t(5;9)(q22;q34) translocation. ALL cells carrying a SNX2‐ABL1 fusion exhibited a BCR‐ABL1+ ALL‐like gene expression profile. The patient poorly responded to dasatinib but partially responded to imatinib. Treatment using tyrosine kinase inhibitors requires further investigation to optimize the genotype‐based treatment stratification for patients with SNX2‐ABL1 fusion.     

The melatonin metabolite N1‐acetyl‐5‐methoxykynuramine facilitates long‐term object memory in young and aging mice

Melatonin (MEL) has been reported to enhance cognitive processes, making it a potential treatment for cognitive decline. However, the role of MEL’s metabolites, N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine (AFMK) and N1‐acetyl‐5‐methoxykynuramine (AMK), in these effects are unknown. The current study directly investigated the acute effects of systemic MEL, AFMK, and AMK on novel object recognition. We also analyzed MEL, AFMK, and AMK levels in hippocampus and temporal lobe containing the perirhinal cortex following systemic MEL and AMK treatment. AMK administered post‐training had a more potent effect on object memory than MEL and AFMK. AMK was also able to rescue age‐associated declines in memory impairments when object memory was tested up to 4 days following training. Results from administering AMK at varying times around the training trial and the metabolism time course in brain tissue suggest that AMK’s memory‐enhancing effects reflect memory consolidation. Furthermore, inhibiting the MEL‐to‐AMK metabolic pathway disrupted object memory at 24 hours post‐training, suggesting that endogenous AMK might play an important role in long‐term memory formation. This is the first study to report that AMK facilitates long‐term object memory performance in mice, and that MEL crosses the blood‐brain barrier and is immediately converted to AMK in brain tissue. Overall, these results support AMK as a potential therapeutic agent to improve or prevent memory decline.