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

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Summary

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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Acknowledgments

This study was supported by Rexahn Pharmaceuticals. RX-3117 is licensed to TEVA Pharmaceuticals. Employees (the co-authors) of both companies participated in the design of the studies, discussed data and commented on the manuscript, and approved final submission.

Conflict of interest

OO, AO, EB are employees of TEVA Pharmaceuticals, YBL, C-HA, DJK are employees of Rexahn, Pharmaceuticals. GJP got a grant from Rexahn Pharmaceuticals.

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Authors and Affiliations

  1. Department of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands

    Godefridus J. Peters, Kees Smid, Leonardo Vecchi, Ietje Kathmann, Dzjemma Sarkisjan, Richard J. Honeywell & Nienke Losekoot

  2. Teva Pharmaceutical Industries Ltd., Innovative Global Branded Products, P.O.BOX 8077, Hatrufa St. Poleg Industrial Zone, Netanya, 42504, Israel

    Osnat Ohne, Aric Orbach & Eran Blaugrund

  3. College of Pharmacy, Ewha Woman’s University, Seoul, Korea

    Lak Shin Jeong

  4. Rexahn Pharmaceuticals, Inc., Rockville, MD, USA

    Young Bok Lee, Chang-Ho Ahn & Deog Joong Kim

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Correspondence to Godefridus J. Peters.

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Peters, G.J., Smid, K., Vecchi, L. et al. Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360). Invest New Drugs 31, 1444–1457 (2013). https://doi.org/10.1007/s10637-013-0025-x

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