TAS-106: Preclinical, Clinical and Beyond

Abstract

5-Fluorouracil, other fluorinated pyrimidines and their derivatives are frequently used in chemotherapy to treat different types of cancer. These agents are classified as metabolic antagonists that target the DNA synthesis phase of the cell cycle. Therefore, these agents are more effective in rapidly growing tumors than in more indolent cancers. In order to develop new drugs that interfere with both DNA and RNA synthesis, the metabolism of pyrimidines was investigated, and new compounds were developed by the molecular design method, which analyzes the biochemical properties of the compounds. The nucleoside 3′-C-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis by blocking RNA polymerases I, II, and III, which occur throughout the cell cycle except for the M phase. This review article discusses the antitumor activity of TAS-106 as a single agent or in combination therapy with the focus on preclinical and clinical findings.

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

“…Cyclopentenylcytosine (CEPC) is a cytidine analog with a modification in the sugar and was evaluated for efficacy in several tumors, including neuroblastoma, but failed because of neurotoxicity [7]. Another cytidine analog with a modification in the side chain of the base is ethynylcytidine (ETC; TAS-106) which had a unique mechanism of action, acting predominantly on RNA polymerase I, II and III [8,9]. This drug failed because of uncontrollable neutropenia, neurotoxicity and lack of efficacy.…”

Induction of apoptosis in cervical cancer cells by the duplex drug 5-FdU–ECyd, coupling 2′-deoxy-5-fluorouridine and 3′-C-ethinylcytidine

“…The nucleoside analogue 3′-C-ethinylcytidine (ECyd) is a new anticancer drug being tested in clinical trials that inhibits growth of a wide variety of cancers in vitro, including gastric, colon, lung, breast, pancreatic, bladder, and pharyngeal carcinoma cell lines, as well as osteosarcomas, leiofibrosarcomas, and melanomas. ECyd shows promising antitumor efficacy in vivo in several human solid cancer xenografts in nude mice [8]. However, the interim efficacy of ECyd monotherapy in phase II trials demonstrates a lack of sufficient clinical benefit and therefore more effective combination schedules and strategies with other cytostatic drugs are needed [8].…”

“…ECyd shows promising antitumor efficacy in vivo in several human solid cancer xenografts in nude mice [8]. However, the interim efficacy of ECyd monotherapy in phase II trials demonstrates a lack of sufficient clinical benefit and therefore more effective combination schedules and strategies with other cytostatic drugs are needed [8].…”

Transcription and Translation Inhibitors in Cancer Treatment

“…TAS-106 (ECyd), 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl) cytosine(3 ′ -Cethynylcytidine; Figure 2), is a cytidine analog and a non-selective competitive inhibitor of all three RNA polymerases, thereby inhibiting RNA synthesis (Abdelrahim et al, 2013). It is a potent inhibitor of more than 40 kinds of cultured cancer cells and also human solid tumors xenografted into mice (Shimamoto et al, 2002;Abdelrahim et al, 2013). TAS-106 has been tested in multiple phase I and phase II clinical trials.…”