Anticancer molecular mechanism of 3'-ethynylcytidine (ECyd)

Wataya, Yusuke; Futagami, Michiko; Naito, Tomoharu; Uchikubo, Yusuke; Yokogawa, Tatsushi; Takenaka, Kiyoko; Kim, Hyesook; Matsuda, Akira; Fukushima, Masakazu; Kitade, Yukio

doi:10.1093/nass/1.1.233

Cited by 3 publications

(1 citation statement)

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“…6) is a ribonucleoside analogue phosphorylated intracellularly by the uridine-cytidine kinase, and exhibiting its cytotoxic activity through RNA polymerase inhibition [27]. The first available preclinical data on this compound, now developed by GlaxoSmithKline in the clinic, showed greater than 89% inhibition of human stomach xenografts [28].…”

Section: Ethynylcytidinementioning

confidence: 99%

Recent Developments to Improve the Efficacy of Cytotoxic Nucleoside Analogues

Jordheim¹,

Galmarini²,

Dumontet³

2006

PRA

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Cytotoxic nucleoside analogues are clinically important anticancer drugs. The newer member of this family, gemcitabine, has shown great activity in solid tumors and thus enlarged the spectra of malignancies treated by this family of molecules. However, the clinical use of nucleoside analogues is limited by important side-effects and primary or acquired drug resistance, and there is an unmet medical need for the development of new molecules and technologies allowing a suitable treatment of cancer patients with these agents. In this article we will review literature data and patents concerning (i) the recent development of some novel nucleoside analogues, (ii) oral formulations for cytotoxic nucleoside analogues, (iii) strategies to circumvent acquired resistance to nucleoside analogues, and (iv) gene therapy strategies used to increase cytotoxicity of nucleoside analogues.

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Section: Ethynylcytidinementioning

confidence: 99%

Recent Developments to Improve the Efficacy of Cytotoxic Nucleoside Analogues

Jordheim¹,

Galmarini²,

Dumontet³

2006

PRA

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Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360)

et al. 2013

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A novel cytidine analog fluorocyclopentenylcytosine (RX-3117; TV-1360) was characterized for its cytotoxicity in a 59-cell line panel and further characterized for cytotoxicity, metabolism and mechanism of action in 15 additional cancer cell lines, including gemcitabine-resistant variants. In both panels sensitivity varied 75-fold (IC50: 0.4- > 30 μM RX-3117). RX-3117 showed a different sensitivity profile compared to cyclopentenyl-cytosine (CPEC) and azacytidine, substrates for uridine-cytidine-kinase (UCK). Dipyridamole, an inhibitor of the equilibrative-nucleoside-transporter protected against RX-3117. Uridine and cytidine protected against RX-3117, but deoxycytidine (substrate for deoxycytidine-kinase [dCK]) not, although it protected against gemcitabine, demonstrating that RX-3117 is a substrate for UCK and not for dCK. UCK activity was abundant in all cell lines, including the gemcitabine-resistant variants. RX-3117 was a very poor substrate for cytidine deaminase (66,000-fold less than gemcitabine). RX-3117 was rapidly metabolised to its nucleotides predominantly the triphosphate, which was highest in the most sensitive cells (U937, A2780) and lowest in the least sensitive (CCRF-CEM). RX-3117 did not significantly affect cytidine and uridine nucleotide pools. Incorporation of RX-3117 into RNA and DNA was higher in sensitive A2780 and low in insensitive SW1573 cells. In sensitive U937 cells 1 μM RX-3117 resulted in 90% inhibition of RNA synthesis but 100 μM RX-3117 was required in A2780 and CCRF-CEM cells. RX-3117 at IC50 values did not affect the integrity of RNA. DNA synthesis was completely inhibited in sensitive U937 cells at 1 μM, but in other cells even higher concentrations only resulted in a partial inhibition. At IC50 values RX-3117 downregulated the expression of DNA methyltransferase. In conclusion, RX-3117 showed a completely different sensitivity profile compared to gemcitabine and CPEC, its uptake is transporter dependent and is activated by UCK. RX-3117 is incorporated into RNA and DNA, did not affect RNA integrity, depleted DNA methyltransferase and inhibited RNA and DNA synthesis. Nucleotide formation is related with sensitivity.

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