Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor. 906 95

Melanoma incidence is increasing worldwide, and metastatic melanoma is almost completely resistant to every known therapy. New approaches to treating melanoma are urgently needed, and a greater understanding of the biology of melanoma invasion and metastasis will aid in their creation. A high proportion of invasive melanomas have a constitutively active Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascade; however, the downstream effectors of ERK signaling that contribute to melanoma invasion and metastasis are unknown. ERK signaling drives the production of the interstitial collagenase matrix metalloproteinase-1 (MMP-1), which is expressed specifically by invasive melanomas. Using short hairpin RNAs (shRNA) to knock down MMP-1 expression in a human melanoma cell line, we investigated the role of MMP-1 in melanoma metastasis in a xenograft model. Knockdown of MMP-1 had no effect on primary tumor growth, but reduction of MMP-1 expression significantly decreased the ability of the melanoma to metastasize from the orthotopic site in the dermis to the lung. Mechanistically, tumor cells expressing MMP-1 shRNAs had diminished collagenase activity, which is required for tumor cell invasion. Additionally, attenuation of MMP-1 expression reduced angiogenesis. These results show, for the first time, that targeted inhibition of MMP-1, a single effector of the Raf/MEK/ERK signaling cascade, prevents the progression of melanoma from a primary to metastatic tumor and, as such, may represent a useful therapeutic tool in controlling this disease.
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PMID:RNA interference inhibition of matrix metalloproteinase-1 prevents melanoma metastasis by reducing tumor collagenase activity and angiogenesis. 1800 30