CONVERSION OF HIGHLY MALIGNANT COLON-CANCER FROM AN AGGRESSIVE TO A CONTROLLED DISEASE BY ORAL-ADMINISTRATION OF A METALLOPROTEINASE INHIBITOR

In this study, we describe the activity of CT1746, an orally-active sy nthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and ma trilysin, in a nude mouse model that better mimics the clinical develo pment of human colon cancer, The model is constructed by surgical orth otopic implantation (SOI) of histologically-intact tissue of the metas tatic human colon tumor cell line Co-3. Animals were gavaged with CT17 46 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 da ys, In this model CT1746 significantly prolonged the median survival t ime of the tumor-bearing animals from 51 to 78 days, Significant effic acy of CT1746 was observed on primary tumor growth (32% reduction in m ean tumor area at day 36), total spread and metastasis (6/20 treated a nimals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups), Efficacy of CT1746 c ould also be seen on reducing tumor spread and metastasis to individua l organ sites such as the abdominal wall, cecum and lymph nodes compar ed to vehicle and untreated controls, We conclude that chronic adminis tration of a peptidomimetic MMP inhibitor via the oral route is feasib le and results in inhibition of solid tumor growth, spread and metasta sis with increase in survival in this model of human cancer, thus conv erting aggressive cancer to a more controlled indolent disease.