Phase 1 study of sulfasalazine and cisplatin for patients with CD44v-positive gastric cancer refractory to cisplatin (EPOC1407)

Kohei Shitara, Toshihiko Doi, Osamu Nagano, Miki Fukutani, Hiromi Hasegawa, Shogo Nomura, Akihiro Sato, Takeshi Kuwata, Kai Asai, Yasuaki Einaga, Kenji Tsuchihashi, Kentaro Suina, Yusuke Maeda, Hideyuki Saya, Atsushi Ohtsu

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

A previous dose-escalation study of sulfasalazine (SSZ), an inhibitor of cystine-glutamate exchange transporter xc (–), in the variant form of CD44 (CD44v)-positive cancer stem cells (CSCs) suggested that administration of SSZ induces the reduction of CD44v-positive cells and intracellular reduced glutathione (GSH) levels in patients with advanced gastric cancer (AGC). Here we report a study to evaluate SSZ in combination with cisplatin in patients with CD44v-expressing AGC refractory to cisplatin. SSZ was given by oral administration four times daily with 2 weeks on and 1 week off. Cisplatin at 60 mg/m2 was administered every 3 weeks. Of the 15 patients who underwent prescreening of CD44v expression, 8 patients were positive, and 7 patients were treated with the dose level of SSZ at 6 g/day. One patient experienced dose-limiting toxicity (DLT) as grade 3 anorexia. Although no other patients experienced DLT, 4 patients required dose interruption or reduction of SSZ; thus, we terminated further dose escalation. No patient achieved objective response, but 1 patient completed six cycles with stable disease for more than 4 months as well as reduction of intratumoral GSH level. The combination of SSZ plus cisplatin was manageable, although dose modification was frequently required during a short observational period.

Original languageEnglish
Pages (from-to)1004-1009
Number of pages6
JournalGastric Cancer
Volume20
Issue number6
DOIs
Publication statusPublished - 2017 Nov 1

Keywords

  • CD44v-positive
  • Cancer stem cell
  • Gastric cancer
  • Sulfasalazine
  • xCT

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology
  • Cancer Research

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    Shitara, K., Doi, T., Nagano, O., Fukutani, M., Hasegawa, H., Nomura, S., Sato, A., Kuwata, T., Asai, K., Einaga, Y., Tsuchihashi, K., Suina, K., Maeda, Y., Saya, H., & Ohtsu, A. (2017). Phase 1 study of sulfasalazine and cisplatin for patients with CD44v-positive gastric cancer refractory to cisplatin (EPOC1407). Gastric Cancer, 20(6), 1004-1009. https://doi.org/10.1007/s10120-017-0720-y