Effective treatment of advanced colorectal cancer by rapamycin and 5-FU/oxaliplatin monitored by TIMP-1.

Abstract

AIM:

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: Markus Wagner, Vincent Roh, Michael Strehlen, Alexander Laemmle, Deborah Stroka, Bernhard Egger, Markus Trochsler, Kelly K Hunt, Daniel Candinas, Stephan A Vorburger
• Journal: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract (J Gastrointest Surg) Vol. 13 Issue 10 Pg. 1781-90 (Oct 2009) ISSN: 1873-4626 [Electronic] United States
• PMID: 19565301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Tissue Inhibitor of Metalloproteinase-1
• Oxaliplatin
• Fluorouracil
• Sirolimus

Topics

• Animals
• Antineoplastic Agents (administration & dosage)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Fluorouracil (administration & dosage)
• Humans
• Mice
• Organoplatinum Compounds (administration & dosage)
• Oxaliplatin
• Peritoneal Neoplasms (drug therapy)
• Sirolimus (administration & dosage)
• Tissue Inhibitor of Metalloproteinase-1 (metabolism)
• Treatment Outcome
• Xenograft Model Antitumor Assays