RX-3117

RX-3117 is a cytidine analog and a substrate for uridine-cytidine-kinase (UCK) [1].

Cytidine analog is activated by uridine-cytidine-kinase and is incorporated into RNA and DNA and downregulates DNA-methyltransferase-1 [2].

RX-3117 is a cytidine analog and inhibits DNA and RNA synthesis. In sensitive U937 cells, RX-3117 (1 μM) inhibited RNA synthesis by 90% and completely inhibited DNA synthesis. In solid tumor and leukemic cell lines, RX-3117 inhibited cell growth with IC50 values of 0.4-29.6 μM. The uptake of RX-3117 was dependent on human ENT1 (hENT). In SW1573 cells, both uridine and cytidine dose-dependently protected cells against RX-3117. RX-3117 at IC50 concentrations didn’t change the pools of both uridine and cytidine nucleotides. In three tumor cell lines, RX-3117 completely inhibited the expression of DNA-methyltransferase (DNMT). In A2780 and SW1573 cells, RX-3117 was incorporated into both RNA and DNA [1].

In athymic nude mice bearing Colo 205, H460, H69 and CaSki human tumor xenograft models, RX-3117 administrated orally induced tumor growth inhibition (TGI) by 100%, 78%, 62% and 66%, respectively [3].

References:
[1].  Peters GJ, Smid K, Vecchi L, et al. Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360). Invest New Drugs, 2013, 31(6): 1444-1457.
[2].  Peters GJ. Novel developments in the use of antimetabolites. Nucleosides Nucleotides Nucleic Acids, 2014, 33(4-6): 358-374.
[3].  Yang MY, Lee YB, Ahn CH, et al. A novel cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to gemcitabine. Anticancer Res, 2014, 34(12): 6951-6959.

The radiosensitizing effect of fluorocyclopentenyl-cytosine (RX-3117) in ovarian and lung cancer cell lines.[Pubmed:27906620]

Nucleosides Nucleotides Nucleic Acids. 2016 Dec;35(10-12):619-630.

RX-3117 (fluorocyclopentenyl-cytosine) is a novel cytidine analog currently being evaluated in a Phase Ib clinical trial in cancer patients with solid tumors. The radiosensitizing effect of RX-3117 was studied in A2780 ovarian cancer cells and non-small cell lung cancer cell lines and related to cell survival and the effect on cell cycle and cell cycle proteins. RX-3117 has a schedule-dependent radiosensitizing effect, but only at pre-incubation (dose modifying factors: 1.4-1.8), observed at pulse and fractionated irradiation. Radiosensitizion was also seen in a three-dimensional spheroid model. At the low radiosensitizing concentration, RX-3117 in combination with radiation led to an accumulation of cells in S-phase, which was accompanied with an increase of cell cycle proteins such as p-Chk2 and p-cdc25C. In addition, RX-3117 caused DNA damage and increased apoptosis. In conclusion, our in vitro experiments showed a radiosensitizing effect of RX-3117.

A novel cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to gemcitabine.[Pubmed:25503121]

Anticancer Res. 2014 Dec;34(12):6951-9.

RX-3117 (fluorocyclopentenylcytosine) is a cytidine analog and this class of drugs, including gemcitabine, has been widely used for the treatment of various types of cancers. However, there is no oral formulation of gemcitabine and drug resistance to gemcitabine is common. In this study, the efficacy of orally-administered RX-3117 was examined in 9 different human tumor xenograft models (colon, non-small cell lung, small cell lung, pancreatic, renal and cervical), grown subcutaneously in athymic nude mice. In the Colo 205, H460, H69 and CaSki models, gemcitabine treatment resulted in 28%, 30%, 25% and 0% tumor growth inhibition (TGI), respectively, whereas oral treatment with RX-3117 induced 100%, 78%, 62% and 66% TGI, respectively. This indicates that RX-3117 may have the potential to be used for the treatment of tumors that do not respond to gemcitabine. RX-3117 was also evaluated in a single primary low-passage human pancreatic TumorgraftCTG-0298 (TGI 76%), which is relatively resistant to gemcitabine (TGI 38%) and has a favorable RX-3117-activating enzyme profile. These studies demonstrated the therapeutic potential and anticancer efficacy of RX-3117.

The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2.[Pubmed:27612203]

PLoS One. 2016 Sep 9;11(9):e0162901.

Fluorocyclopentenylcytosine (RX-3117) is an orally available cytidine analog, currently in Phase I clinical trial. RX-3117 has promising antitumor activity in various human tumor xenografts including gemcitabine resistant tumors. RX-3117 is activated by uridine-cytidine kinase (UCK). Since UCK exists in two forms, UCK1 and UCK2, we investigated which form is responsible for RX-3117 phosphorylation. For that purpose we transfected A549 and SW1573 cell lines with UCK-siRNAs. Transfection of UCK1-siRNA efficiently downregulated UCK1-mRNA, but not UCK2-mRNA expression, and did not affect sensitivity to RX-3117. However, transfection of UCK2-siRNA completely downregulated UCK2-mRNA and protein and protected both A549 and SW1573 against RX-3117. UCK enzyme activity in two panels of tumor cell lines and xenograft cells correlated only with UCK2-mRNA expression (r = 0.803 and 0.915, respectively), but not with UCK1-mRNA. Moreover, accumulation of RX-3117 nucleotides correlated with UCK2 expression. In conclusion, RX-3117 is activated by UCK2 which may be used to select patients potentially sensitive to RX-3117.

Sensitive liquid chromatography mass spectrometry (LC-MS) assay reveals novel insights on DNA methylation and incorporation of gemcitabine, its metabolite difluorodeoxyuridine, deoxyuridine, and RX-3117 into DNA.[Pubmed:27906622]

Nucleosides Nucleotides Nucleic Acids. 2016 Dec;35(10-12):652-662.

Antimetabolites are incorporated into DNA and RNA, affecting their function. Liquid-chromatography-mass-spectrometry (LC-MS-MS) permits the sensitive, selective analysis of normal nucleosides. The method was adapted to measure the incorporation of deoxyuridine, gemcitabine (difluorodeoxycytidine), its metabolite difluorodeoxyuridine (dFdU), and the novel compound fluorocyclopentenylcytosine (RX3117). DNA was degraded to its deoxynucleotides for quantification by LC-MS-MS, gradient chromatography on a Phenomenex prodigy-3-ODS with positive ionization. The range of deoxyuridine DNA-mis-incorporation varied nine-fold in 27 cell lines (leukemia, colon, ovarian, lung cancer). At low-folate conditions a 2.1-fold increase in deoxyuridine was observed. Global methylation (given as % 5-methyl-deoxycytidine) was comparable between the cell lines (4.6-6.5%). Exposure of A2780 cells to 1 muM gemcitabine (4 hours) resulted in 3.6 pmol gemcitabine/mug DNA, but in AG6000 cells (deoxycytidine-kinase-deficient) no incorporation was found. However, when A2780, AG6000, or CCRF-CEM cells were exposed to 100 muM dFdU we found it as gemcitabine, 20.5, 19.6, and 0.51 pmol gemcitabine/mug DNA, respectively. Preincubation of CCRF-CEM cells with cyclopentenyl-cytosine (a CTP-synthetase inhibitor) increased dFdU incorporation four-fold. Apparently dFdU is activated independently of deoxycytidine-kinase and possibly converted in-situ to dFdCMP. RX3117 was incorporated into both DNA and RNA (0.0037 and 0.00515 pmol/mug, respectively). In summary, a sensitive method to quantify the incorporation of gemcitabine, deoxyuridine, and RX-3117 was developed, which revealed that dFdU was incorporated into DNA as the parent compound gemcitabine.

RX-3117(TV-1360; Fluorocyclopentenylcytosine) is novel a cytidine analog; shows anticancer activity in several cancer cell lines, including gemcitabine-resistant variants.

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