title: Dose-escalation study for the targeting of CD44v+cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205).
abstract: BACKGROUND
  Cancer stem cells (CSCs) have enhanced mechanisms of protection from oxidative stress. A variant form of CD44 (CD44v), a major CSC marker, was shown to interact with xCT, a subunit of cystine-glutamate transporter, which maintains high levels of intracellular reduced glutathione (GSH) which defend the cell against oxidative stress. Sulfasalazine (SSZ) is an inhibitor of xCT and was shown to suppress the survival of CD44v-positive stem-like cancer cells both in vitro and in vivo. To find the dose of SSZ which can safely reduce the population of CD44v-positive cells in tumors, a dose-escalation study in patients with advanced gastric cancer was conducted.
  
  
  METHODS
  SSZ was given four times daily by oral administration with 2 weeks as one cycle. Tumor biopsies were obtained before and after 14 days of administration of SSZ to evaluate expression of CD44v and the intratumoral level of GSH.
  
  
  RESULTS
  Eleven patients were enrolled and received a dosage from 8 to 12 g/day. Safety was confirmed up to a dosage of 12 g/day, which was considered the maximum tolerated dose. Among the eight patients with CD44v-positive cells in their pretreatment biopsy samples, the CD44v-positive cancer cell population appeared to be reduced in the posttreatment biopsy tissues of four patients. Intratumoral GSH levels were also decreased in two patients, suggesting biological effectiveness of SSZ at 8 g/day or greater.
  
  
  CONCLUSIONS
  This is the first study of SSZ as an xCT inhibitor for targeting CSCs. Reduction of the levels of CD44v-positive cells and GSH was observed in some patients, consistent with the mode of action of SSZ in CSCs.
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shitara
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tdoi@east.ncc.go.jp.|Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tdoi@east.ncc.go.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
authors.affiliation: Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Chiyo K
authors.initials: CK
authors.lastname: Imamura
authors.affiliation: Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ozeki
authors.affiliation: Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Yokohama, 223-8522, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsuchihashi
authors.affiliation: Medical Oncology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Medical Oncology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan.
authors.forename: Takako E
authors.initials: TE
authors.lastname: Nakajima
authors.affiliation: Clinical Trial Promotion Department, Chiba Cancer Center, 666-2 Nitonacho, Chuo-ku, Chiba, Chiba, 260-8717, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hironaka
authors.affiliation: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Fukutani
authors.affiliation: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Nomura
authors.affiliation: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Yokohama, 223-8522, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Einaga
authors.affiliation: Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuwata
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. hsaya@a5.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012460:Sulfasalazine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D017382:Reactive Oxygen Species; D012460:Sulfasalazine
keywords: CD44 variant positive; Cancer stem cell; Gastric cancer; Sulfasalazine; xCT