Takashi Nasu

Orotate phosphoribosyltransferase localizes to the Golgi complex and its expression levels affect the sensitivity to anti-cancer drug 5-fluorouracil

Orotate phosphoribosyltransferase (OPRT) is engaged in de novo pyrimidine synthesis. It catalyzes oronitine to uridine monophosphate (UMP), which is used for RNA synthesis. De novo pyrimidine synthesis has long been known to play an important role in providing DNA/RNA precursors for rapid proliferative activity of cancer cells. Furthermore, chemotherapeutic drug 5-fluorouracil (5-FU) is taken up into cancer cells and is converted to 5-fluoro-UMP (FUMP) by OPRT or to 5-fluoro-dUMP (FdUMP) through intermediary molecules by thymidine phosphorylase. These 5-FU metabolites are misincorporated into DNA/RNA, thereby producing dysfunction of these information processing. However, it remains unclear how the subcellular localization of OPRT and how its variable expression levels affect the response to 5-FU at the cellular level. In this study, immunocytochemical analysis reveals that OPRT localizes to the Golgi complex. Results also show that not only overexpression but also downregulation of OPRT render cells susceptible to 5-FU exposure, but it has no effect on DNA damaging agent doxorubicin. This study provides clues to elucidate the cellular response to 5-FU chemotherapy in relation to the OPRT expression level.

Clinical Investigation of Surgical Closure of Tracheoesophageal Shunt

The purpose of this study was to elucidate the appropriate time for closing a tracheoesophageal shunt for a safe and non-invasive surgical procedure, after acquiring another type of vocal rehabilitation. A tracheoesophageal shunt is globally considered to be the most useful tool for excellent vocal rehabilitation; nevertheless, it must be closed for several reasons. In some cases, surgical closure of a tracheoesophageal shunt is difficult due to poor histological conditions around the shunt. We herein propose a new strategy of vocal rehabilitation to utilize a tracheoesophageal shunt effectively. Materials and methods: Between 1995 and 2014, 46 patients underwent voice prosthesis insertion surgery. Nine (eight laryngeal cancer patients, one thyroid cancer patient) of these patients underwent surgical closure of a tracheoesophageal shunt. We investigated their cancer treatments, reasons for closing the tracheoesophageal shunt, period of voice prosthesis insertion, operative method, number of operations, and outcome. Results: The reasons for closing the tracheoesophageal shunt were aspiration pneumonia and acquisition of esophageal voice in 4 patients each. Regarding the period of voice prosthesis speech, 6 patients had used it for approximately 3 years and 3 patients for more than 7 years. Approximately all 3-year users underwent a non-invasive surgical procedure, such as triple-layered suture, and their operation succeeded the first time. Conversely, the more than 7-year users required an invasive surgical procedure, such as a pedicle flap, and had to undergo more than one operation. Conclusion: In the present study, tracheoesophageal shunt closure could be performed within 3 years via a safe and non-invasive surgical procedure. We recommend that the operation for a tracheoesophageal shunt be undertaken at a relatively early stage after total laryngectomy. Such patients should acquire esophageal voice within 3 years and undergo surgical closure of the tracheoesophageal shunt as soon as possible.