title: Anticancer benefits of early versus late use of rapamycin in a rat model of urothelial carcinoma.
abstract: BACKGROUND
  We previously reported both in vivo and in vitro effects of rapamycin on urothelial carcinoma. Clinically, the use of rapamycin could not completely prevent the recurrence of urothelial carcinoma. Therefore, we designed this study to compare the difference of efficacy between early and late use of rapamycin in a rat model of urothelial carcinoma.
  
  
  METHODS
  The rat model of urothelial carcinoma was induced by adding 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to the drinking water for up to 20 weeks in male Fisher-344 rats. Rapamycin was fed orally from the 1st day, 5th week, 9th week, 13th week, and 17th week. The antitumor effects of different periods of rapamycin treatment were assessed grossly and microscopically.
  
  
  RESULTS
  Papillary tumors of urinary bladder were successfully induced in the BBN group. Simultaneous use of rapamycin and BBN from the 1st day of treatment significantly reduced the tumor growth in urinary bladder: 80% of the rats had no tumor and 20% had low-grade tumors. Adding rapamycin from the 5th week was associated with more tumor growth: 20% of the rats had no tumors, 20% had low-grade tumors, and 60% had high-grade tumors. Moreover, in the groups with rapamycin treatment from the 9th week, 13th week, and 17th week, all rats developed high-grade papillary tumors in urinary bladder, as did the control group that received no rapamycin.
  
  
  CONCLUSIONS
  The study results suggest that the anticancer effect of rapamycin on urothelial carcinoma is stage dependent. Early use of rapamycin provides better anticancer effect, whereas late use of rapamycin fails to inhibit the cancer growth.
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang Ming University, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang Ming University, Taiwan; Department of Pediatrics, Taichung Veterans General Hospital, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Fu
authors.affiliation: Division of Urology, Taichung Veterans General Hospital, Taiwan.
authors.forename: J-R
authors.initials: JR
authors.lastname: Li
authors.affiliation: Division of Nephrology, Taichung Veterans General Hospital, Taiwan; School of Medicine, Chung Shan Medical University, Taiwan.
authors.forename: K-H
authors.initials: KH
authors.lastname: Shu
authors.affiliation: Division of Urology, Taichung Veterans General Hospital, Taiwan.
authors.forename: H-C
authors.initials: HC
authors.lastname: Ho
authors.affiliation: Department of Medicine, Yumin Medical Corporation Yumin Hospital, Taiwan.
authors.forename: Y-N
authors.initials: YN
authors.lastname: Shiu
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang Ming University, Taiwan; Division of Nephrology, Taichung Veterans General Hospital, Taiwan; School of Medicine, Chung Shan Medical University, Taiwan; Graduate Institute of Clinical Medical Science, School of Medicine, China Medical University, Taiwan; Institute of Biomedical Science, National Chung Hsing University, Taiwan; Department of Life Science, Tunghai University, Taiwan. Electronic address: wmj530@gmail.com.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002085:Butylhydroxybutylnitrosamine; D002291:Carcinoma, Papillary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004334:Drug Administration Schedule; D008297:Male; D060787:Neoplasm Grading; D009374:Neoplasms, Experimental; D011916:Rats, Inbred F344; D020123:Sirolimus / Q000008:administration & dosage*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D019459:Urothelium / Q000187:drug effects* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D002085:Butylhydroxybutylnitrosamine; D020123:Sirolimus