Challenges in predicting the clinical outcome in S-1-based chemotherapy for gastric cancer patients.
S-1 has been considered to be a key drug in the treatment of advanced gastric cancer in Japan as a standard option of chemotherapy. Interindividual variation in the enzymes of the S-1 metabolic pathway can affect the extent of S-1 metabolism and impact the efficacy of S-1-based chemotherapy. In this review, the role of the "candidate" genetic factors affecting the therapeutic efficacy of S-1 is discussed with a special emphasis on polymorphism and gene expressions involved in the S-1 metabolic pathway, including CYP2A6, thymidylate synthase, thymidine phosphorylase, and orotate phosphoribosyltransferase. The predictive values of these candidates might be overcome with drugs combined with S-1. Pharmacogenetic studies based on a "global" approach by DNA microarray are promising to identify gastric cancer patients with both survival benefit and clinical benefit more accurately than those based on the "candidate" approach, especially for S-1 combination therapy. Large and controlled studies are needed to justify changes in the chemotherapeutic strategies, from "one-size fits all" to "tailor-made."
Ichikawa
Wataru
W
Department of Clinical Oncology and Medical Oncology, International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan. wataru@saitama-med.ac.jp
Sasaki
Yasutsuna
Y
D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065637:Cytochrome P-450 CYP2A6; D004338:Drug Combinations; D006801:Humans; D009962:Orotate Phosphoribosyltransferase / Q000235:genetics; D010094:Oxonic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010597:Pharmacogenetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D005641:Tegafur / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013939:Thymidine Phosphorylase / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D013939:Thymidine Phosphorylase