Explore the vast range of titles available.

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. TAS‐106 was reasonably tolerated in patients with platinum‐failure HNSCC and NPC with the 24‐h continuous infusion administration schedule; however, there was no anti‐tumor efficacy seen with TAS‐106 monotherapy. Future studies will focus on TAS‐106 combinations and mechanisms of drug resistance.

TAS–106 [l–(3–C‐ethynyl‐β‐d‐ribo‐pentofuranosyl)cytosine] is a new anticancer ribo‐nucleoside with promising antitumor activity. We have previously presented evidence suggesting that the TAS–106 sensitivity of cells is correlated with intracellular accumulation of the triphosphate of TAS–106, which may be affected both by cellular membrane transport mechanisms and uridine‐cytidine kinase (UCK) activity. Since the presence of a UCK family consisting of two members, UCK1 and UCK2, has recently been reported in human cells, we investigated the relation between expression of UCK1 and UCK2 at both the mRNA and protein levels and UCK activity (TAS–106 phosphorylation activity) in a panel of 10 human cancer cell lines. Measurement of UCK activity in these cell lines revealed that it was well correlated with the cells' sensitivity to TAS–106. In addition, the mRNA or protein expression level of UCK2 was closely correlated with UCK activity in these cell lines, but neither the level of expression of UCK1 mRNA nor that of protein was correlated with enzyme activity. We therefore compared the protein expression level of UCK2 in several human tumor tissues and the corresponding normal tissues. Expression of UCK2 protein was barely detectable in 4 of the 5 human tumor tissues, but tended to be high in the pancreatic tumor tissue. It could not be detected at all in any of the normal tissues. Thus, expression of UCK2 appeared to be correlated with cellular sensitivity to TAS–106, and it may contribute to the tumor‐selective cytotoxicity of TAS–106.

We examined the effects of dosage schedule on antitumor activity in vitro and in vivo to determine the optimal administration schedule for a new nucleoside antimetabolite l‐(3‐C‐ethynyl‐β‐D‐ribo‐pentofuranosyl)cytosine (ECyd, TAS‐106). The cytotoxicity of TAS‐106 in vitro against human tumors was evaluated at three drug exposure periods. TAS‐106 exhibited fairly potent cytotoxicity even with 4 h exposure, and nearly equivalent and sufficiently potent cytotoxicity with 24 and 72 h exposures. These results suggest that long‐term exposure to TAS‐106 will not be required to achieve maximal cytotoxicity. The antitumor activity of TAS‐106 in vivo was compared in nude rat models bearing human tumors on three administration schedules, once weekly, 3 tunes weekly, and 5 tunes weekly for 2 or 4 consecutive weeks. TAS‐106 showed strong antitumor activity without serious toxicity on all three schedules, but the antitumor activity showed no obvious schedule‐dependency in these models. When tumor‐bearing nude rats were given a single i.v. dose of [3H]TAS‐106, tumor tissue radioactivity tended to remain high for longer periods of time as compared to the radioactivity in various normal tissues. Furthermore, when the metabolism of TAS‐106 in the tumor was examined, it was found that TAS‐106 nucleotides (including the active metabolite, the triphosphate of TAS‐106) were retained at high concentrations for prolonged periods. These pharmacodynamic features of TAS‐106 may explain the strong antitumor activity without serious toxicity, observed on intermittent administration schedules, in nude rat models with human tumors. We therefore consider TAS‐106 to be a promising compound which merits further investigation in patients with solid tumors.

We have established variants of DLD‐1 human colon carcinoma and HT‐1080 human fibrosarcoma cells resistant to the new anticancer ribo‐nucleosides, 1‐(3‐C‐ethynyl‐β‐D‐ribo‐pentofuranosyl)‐cytosine (ECyd, TAS‐106) and 1‐(3‐C‐ethynyl‐p‐D‐ribo‐pentofuranosyl)uracil (EUrd). Both variants were shown to have decreased (3‐ to 24‐fold decrease) uridine‐cytidine kinase (UCK) activity, and exhibited cross‐resistance to EUrd and TAS‐106. Based on the IC50 values determined by chemosensitivity testing, a 41‐ to 1102‐fold resistance to TAS‐106 was observed in the resistant cells. TAS‐106 concentration‐dependently inhibited RNA synthesis, while its effect on DNA synthesis was negligible. The degree of resistance (14‐ to 3628‐fold resistance) calculated from the inhibition of RNA synthesis tended to be close to the degree of chemoresistance of tested cells to TAS‐106. The experiments on the intracellular metabolism of TAS‐106 in the parental cells revealed a rapid phosphorylation to its nucleotides, particularly the triphosphate (ECTP), its major active metabolite. The amount of TAS‐106 transported into the resistant cells was markedly reduced and the intracellular level of ECTP was decreased from 1/19 to below the limit of detection; however, the unmetabolized TAS‐106 as a percentage of the total metabolite level was high as compared with the parental cells. The ratio of the intracellular level of ECTP between parental and resistant cells tended to approximate to the degree of resistance calculated from the inhibitory effect on RNA synthesis. These results indicate that the TAS‐106 sensitivity of cells is correlated with the intracellular accumulation of ECTP, which may be affected by both the cellular membrane transport mechanism and UCK activity.