Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor |
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Authors: | Zili An Xiaoen Wang Neville Willmott Surinder K Chander Simon Tickle Andrew J P Docherty Andrew Mountain Andrew T Millican Richard Morphy John R Porter R Ola Epemolu Tetsuro Kubota A R Moossa Robert M Hoffman |
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Institution: | (1) AntiCancer Inc., 7917 Ostrow St, San Diego, CA, USA;(2) Celltech Therapeutics Ltd, 216 Bath Road, Slough Berkshire, UK;(3) Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku Tokyo, Japan;(4) Department of Surgery, School of Medicine, University of California, San Diego, 402 Dickinson Street, San Diego, CA, USA |
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Abstract: | In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease. |
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Keywords: | CT1746 matrix metalloproteinase inhibitors MMPs tumor growth |
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