Effective treatment of advanced colorectal cancer by rapamycin and 5-FU/oxaliplatin monitored by TIMP-1.
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.
Wagner
Markus
M
Department of Visceral and Transplantation Surgery and Department of Clinical Research, Inselspital, University Hospital Bern and University of Bern, CH-3010, Bern, Switzerland.
Roh
Vincent
V
Strehlen
Michael
M
Laemmle
Alexander
A
Stroka
Deborah
D
Egger
Bernhard
B
Trochsler
Markus
M
Hunt
Kelly K
KK
Candinas
Daniel
D
Vorburger
Stephan A
SA
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
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D019715:Tissue Inhibitor of Metalloproteinase-1; D000077150:Oxaliplatin; D005472:Fluorouracil; D020123:Sirolimus