title: Effective treatment of advanced colorectal cancer by rapamycin and 5-FU/oxaliplatin monitored by TIMP-1.
abstract: OBJECTIVE
  The mTOR-inhibitor rapamycin has shown antitumor activity in various tumors. Bedside observations have suggested that rapamycin may be effective as a treatment for colorectal carcinomatosis.
  
  
  METHODS
  We established an orthotopic syngenic model by transplanting CT26 peritoneal tumors in Balb/C mice and an orthotopic xenograft model by transplanting SW620 peritoneal tumors in nu/nu mice. Expression levels of tissue inhibitor of matrix-metalloproteinases 1 (TIMP-1) in the tumor and serum was determined by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Rapamycin significantly suppressed growth of syngenic and xenografted peritoneal tumors. The effect was similar with intraperitoneal or oral rapamycin administration. Tumor suppression was further enhanced when rapamycin was combined with 5-fluorouracil and/or oxaliplatin. The combination treatment showed no acute toxicity. TIMP-1 serum levels correlated well (CC = 0.75; P < 0.01) with rapamycin treatment.
  
  
  CONCLUSIONS
  Rapamycin suppressed advanced stage colorectal cancer, even with oral administration. Combining rapamycin with current chemotherapy regimens significantly increased antitumor efficacy without apparent toxicity. The treatment efficacy correlated with serum TIMP-1 levels, suggesting its potential as a surrogate marker in future clinical trials.
authors: Department of Visceral and Transplantation Surgery and Department of Clinical Research, Inselspital, University Hospital Bern and University of Bern, CH-3010, Bern, Switzerland.
authors: Markus
authors: M
authors: Wagner
authors: Vincent
authors: V
authors: Roh
authors: Michael
authors: M
authors: Strehlen
authors: Alexander
authors: A
authors: Laemmle
authors: Deborah
authors: D
authors: Stroka
authors: Bernhard
authors: B
authors: Egger
authors: Markus
authors: M
authors: Trochsler
authors: Kelly K
authors: KK
authors: Hunt
authors: Daniel
authors: D
authors: Candinas
authors: Stephan A
authors: SA
authors: Vorburger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy; D020123:Sirolimus / Q000008:administration & dosage; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D019715:Tissue Inhibitor of Metalloproteinase-1; D000077150:Oxaliplatin; D005472:Fluorouracil; D020123:Sirolimus