title: Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats.
abstract: S-1, a new oral antitumor agent, is composed of 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur, FT), 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. FT which is a masked compound of 5-fluorouracil (5-FU) acts as an effector, while both CDHP and Oxo which do not have antitumor activity themselves act as modulators. In this study, the antitumor activity and intestinal toxicity of S-1 were investigated using experimental tumor models in rats, and compared with those of other oral fluoropyrimidines, namely 5-FU, FT, FCD (1 M FT/0.4 M CDHP) and UFT (combination of FT and uracil). In rats bearing subcutaneous Yoshida sarcoma, S-1 inhibited tumor growth at the lowest dose (ED50 value: S-1 5, UFT 22, FT 82, FCD 5, and 5-FU 19 mg/kg per day), and induced the least host body weight suppression, leading to the highest therapeutic index (TI) (S-1 4.5, UFT 1.4, FT 1.8, FCD 2.0, and 5-FU 1.4). S-1 also showed a higher therapeutic effect than UFT against AH-130 and Sato lung carcinoma. After administration of S-1 and UFT at equitoxic doses, S-1 showed a higher and more prolonged concentration of 5-FU than UFT both in plasma (AUC0-infinity: S-1 28 nmolh/ml, UFT 15 nmol.h/ml) and in tumor tissue (AUC0-infinity: S-1 95 nmolh/g tissue, UFT 52 nmolh/g tissue), leading to a higher 5-FU level incorporated into the RNA fraction (F-RNA level) in tumor tissue (AUC0-24: S-1 7.0 nmolh/mg RNA, UFT 4.3 nmolh/mg RNA) and 5-8% higher thymidylate synthase (TS) inhibition in tumor tissue at every time-point through 24 h. Compared with other oral fluoropyrimidines after administration of the maximal tolerable dose (MTD), S-1 caused the lowest rates of intestinal toxicities, such as diarrhea and occult blood in feces. S-1 also showed a higher antitumor effect on Yoshida sarcoma implanted intracolonically than UFT at an equitoxic dose (tumor weight: S-1 64 +/- 30 mg, UFT 133 +/- 52 mg; P < 0.05). These results suggest that CDHP, which is a potent inhibitor of 5-FU degradation, increases the antitumor activity of FT, and that Oxo, which is an inhibitor of 5-FU phosphorylation, locally protects the gastrointestinal tract from 5-FU-induced toxicity without decreasing the antitumor activity.
authors.affiliation: Anticancer and Antimicrobials Research Laboratory, Taiho Pharmaceutical Co. Ltd., Tokushima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takechi
authors.forename: K
authors.initials: K
authors.lastname: Nakano
authors.forename: J
authors.initials: J
authors.lastname: Uchida
authors.forename: A
authors.initials: A
authors.lastname: Mita
authors.forename: K
authors.initials: K
authors.lastname: Toko
authors.forename: S
authors.initials: S
authors.lastname: Takeda
authors.forename: N
authors.initials: N
authors.lastname: Unemi
authors.forename: T
authors.initials: T
authors.lastname: Shirasaka
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D007410:Intestinal Diseases / Q000139:chemically induced; D008297:Male; D051381:Rats; D012517:Sarcoma, Yoshida / Q000188:drug therapy; D005641:Tegafur / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D005641:Tegafur