Effective Treatment of Advanced Colorectal Cancer by Rapamycin and 5-FU/Oxaliplatin Monitored by TIMP-1
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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.
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.
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.
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.
KeywordsmTOR inhibitor Rapamycin 5-FU Oxaliplatin TIMP-1 Colorectal cancer
We would like to thank Cynthia Fuhrer (University of Bern) for her help with immunohistochemistry.
This work was supported by the 3R Research Foundation Switzerland (no 94/04); Swiss National Foundation (SNF 3100A0-104023); Oncosuisse (OCS 01431-08-2003) (SAV).
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