TY - JOUR
T1 - RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment
AU - Balboni, Beatrice
AU - el Hassouni, Btissame
AU - Honeywell, Richard J.
AU - Sarkisjan, Dzjemma
AU - Giovannetti, Elisa
AU - Poore, Julie
AU - Heaton, Callie
AU - Peterson, Christine
AU - Benaim, Ely
AU - Lee, Young B.
AU - Kim, Deog J.
AU - Peters, Godefridus J.
PY - 2019/4/3
Y1 - 2019/4/3
N2 - Introduction: RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells. It has shown clinical activity in refractory bladder cancer and pancreatic cancer. Areas covered: The review provides an overview of the relevant market and describes the mechanism of action, main pharmacokinetic/pharmacodynamic features and clinical development of this investigational small molecule. Expert opinion: RX-3117 is selectively activated by uridine-cytidine kinase 2 (UCK2), which is expressed only in tumors and has a dual mechanism of action: DNA damage and inhibition of DNA methyltransferase 1 (DNMT1). Because of its tumor selective activation, novel mechanism of action, excellent oral bioavailability and candidate biomarkers for patient selection, RX-3117 has the potential to replace gemcitabine in the treatment of a spectrum of cancer types.
AB - Introduction: RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells. It has shown clinical activity in refractory bladder cancer and pancreatic cancer. Areas covered: The review provides an overview of the relevant market and describes the mechanism of action, main pharmacokinetic/pharmacodynamic features and clinical development of this investigational small molecule. Expert opinion: RX-3117 is selectively activated by uridine-cytidine kinase 2 (UCK2), which is expressed only in tumors and has a dual mechanism of action: DNA damage and inhibition of DNA methyltransferase 1 (DNMT1). Because of its tumor selective activation, novel mechanism of action, excellent oral bioavailability and candidate biomarkers for patient selection, RX-3117 has the potential to replace gemcitabine in the treatment of a spectrum of cancer types.
KW - Cytidine analogs
KW - DNA methyltransferase
KW - fluorocyclopentenyl cytosine
KW - uridine-kinase 2
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85063098464&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30879349
U2 - https://doi.org/10.1080/13543784.2019.1583742
DO - https://doi.org/10.1080/13543784.2019.1583742
M3 - Article
C2 - 30879349
SN - 1354-3784
VL - 28
SP - 311
EP - 322
JO - Expert opinion on investigational drugs
JF - Expert opinion on investigational drugs
IS - 4
ER -