title: Low-dose docetaxel enhances the sensitivity of S-1 in a xenograft model of human castration resistant prostate cancer.
abstract: S-1 is a recently developed dihydropyrimidine dehydrogenase inhibitor fluoropyrimidine and has demonstrated high maximum plasma 5-Fluorouracil (5-FU) levels with mild toxicity, and an oral formulation has resulted in an improvement in patient quality of life. The aims of the present study were to determine the efficacy of S-1 or S-1 combined with docetaxel (DOC) using castration resistant prostate cancer (CRPC) cells and to explore their clinical potential for treating CRPC patients. LNCaP cells, androgen dependent prostate cancer (ADPC) cells and C4-2 cells, which are a CRPC subline of LNCaP cells, were used. Specimens obtained from ADPC and CRPC patients were also evaluated. The CRPC specimens and C4-2 cells exhibited significantly lower thymidylate synthase (TS) expression, a target of 5-FU, than the ADPC specimens and LNCaP cells. In vitro, C4-2 cells exhibited higher sensitivity to 5-FU than LNCaP cells. In C4-2 xenograft model, S-1 monotherapy suppressed tumor growth and low-dose DOC enhanced the anti-tumor effect of S-1. In vitro, low-dose DOC, which did not induce G2/M arrest, increased p53 and p21 and resulted in down-regulation of TS in C4-2 cells, and down-regulation of TS is considered to be responsible for the synergistic effect of S-1 in vivo. The present findings indicate that CRPC patients with androgen ablation may be good candidates for 5-FU based chemotherapy, and these regimens have attractive therapeutic potential for clinical practice, and they may have a significant impact on therapeutic options.
authors.affiliation: Department of Urology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Akira
authors.initials: A
authors.lastname: Miyajima
authors.forename: Takeo
authors.initials: T
authors.lastname: Kosaka
authors.forename: Yota
authors.initials: Y
authors.lastname: Yasumizu
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Maeda
authors.forename: Suguru
authors.initials: S
authors.lastname: Shirotake
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ide
authors.forename: Eiji
authors.initials: E
authors.lastname: Kikuchi
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
mesh_terms: D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004338:Drug Combinations; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010094:Oxonic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000601:surgery; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D005641:Tegafur / Q000008:administration & dosage / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000096:biosynthesis / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D004338:Drug Combinations; D019394:Ki-67 Antigen; D043823:Taxoids; C079198:S 1 (combination); D005641:Tegafur; D000077143:Docetaxel; D010094:Oxonic Acid; D013940:Thymidylate Synthase; D005472:Fluorouracil