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.