Cytotoxic mechanisms of inhibitor of RNA synthesis, 1-(3-C-ethynyl- -D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106)

Yokogawa, Tatsushi; Takenaka, Kiyoko; Ogawa, Daisuke; Futagami, Michiko; Matsuda, Akira; Fukushima, Masakazu; Kitade, Yukio; Wataya, Yusuke

doi:10.1093/nass/44.1.193

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“…UCK2 is preferentially expressed in tumor cells compared with normal cells and higher activity of UCK2 has been correlated with TAS-106 sensitivity in tumor cell lines [12,13]. The anti-tumor mechanism of action from preclinical models is believed to involve activation of RNase L and lead to rRNA fragmentation [14,15]. Kazuno et al have reported in a 10-panel human tumor cell lines that TAS-106 treatment decreased 45S rRNA precursor levels [10].…”

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confidence: 99%

Phase II study of TAS‐106 in patients with platinum‐failure recurrent or metastatic head and neck cancer and nasopharyngeal cancer

et al. 2013

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TAS-106, a RNA polymerase inhibitor, was studied in solid tumors with potential clinical benefit and reasonable tolerability. We conducted a multicenter, international phase II trial of TAS-106 in salvage metastatic or recurrent head and neck squamous cell cancer (HNSCC) and nasopharyngeal cancer (NPC) patients. TAS-106 monotherapy was given at 6.5 mg/m2 over 24-h continuous infusion every 3 weeks. Translational studies for blood and tissue were included. Twenty-seven enrolled patients experienced the most common drug-related adverse events of neutropenia, fatigue, non-neutropenic fever, injection site reaction, and skin rash/dermatitis. The greater than or equal to grade 3 adverse events included neutropenia (14.8%), febrile neutropenia (7.4%), pneumonia (7.4%), and peripheral neuropathy (3.7%). The overall response rate was 0% in both subgroups; five HNSCC patients had stable disease (median duration 99 days) and four NPC patients had stable disease (median duration of 92.5 days). Median progression-free survival (PFS) for HNSCC patients was 52 days (95% CI 43.0–99.0 days) and 48 days (95% CI 41.0–83.0 days) for NPC. Median overall survival (OS) for HNSCC patients was 175 days (95% CI 92.0–234.0 days) and 280 days (95% CI 107.0–462.0 days) for NPC. The TAS-106 plasma levels were equivalent between Asian and Caucasian patients. There was no significant correlation of tumor UCK2 protein expression levels to TAS-106 efficacy. TAS-106 was reasonably tolerated in patients with platinum-failure HNSCC and NPC. The administration schedule of 24-h continuous infusion prevented neurologic toxicity, but had myelosuppression as its main toxicity. There was no anti-tumor efficacy seen with TAS-106 monotherapy. Future studies will focus on TAS-106 combinations and mechanisms of drug resistance.

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