prinomastat and Neoplasm-Metastasis

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Design; Humans; Hydroxamic Acids; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Metastasis; Organic Chemicals; Phenylalanine; Thiophenes

Prostate cancer is the leading form of cancer in men. Prostate tumors often contain neuroendocrine differentiation, which correlates with androgen-independent progression and poor prognosis. Matrix metalloproteinases (MMP), a family of enzymes that remodel the microenvironment, are associated with tumorigenesis and metastasis. To evaluate MMPs during metastatic prostatic neuroendocrine cancer development, we used transgenic mice expressing SV40 large T antigen in their prostatic neuroendocrine cells, under the control of transcriptional regulatory elements from the mouse cryptdin-2 gene (CR2-TAg). These mice have a stereotypical pattern of tumorigenesis and metastasis. MMP-2, MMP-7, and MMP-9 activities increased concurrently with the transition to invasive metastatic carcinoma, but they were expressed in different prostatic cell types: stromal, luminal epithelium, and macrophages, respectively. CR2-TAg mice treated with AG3340/Prinomastat, an MMP inhibitor that blocks activity of MMP-2, MMP-9, MMP-13, and MMP-14, had reduced tumor burden. CR2-TAg animals were crossed to mice homozygous for null alleles of MMP-2, MMP-7, or MMP-9 genes. At 24 weeks CR2-TAg; MMP-2(-/-) mice showed reduced tumor burden, prolonged survival, decreased lung metastasis, and decreased blood vessel density, whereas deficiencies in MMP-7 or MMP-9 did not influence tumor growth or survival. Mice deficient for MMP-7 had reduced endothelial area coverage and decreased vessel size, and mice lacking MMP-9 had increased numbers of invasive foci and increased perivascular invasion, as well as decreased tumor blood vessel size. Together, these results suggest distinct contributions by MMPs to the progression of aggressive prostate tumor and to helping tumors cleverly find alternative routes to malignant progression.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Growth Processes; Disease Progression; Enzyme Inhibitors; Lung Neoplasms; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 7; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Transgenic; Neoplasm Metastasis; Neovascularization, Pathologic; Neuroendocrine Tumors; Organic Chemicals; Prostatic Neoplasms; Stromal Cells

Cellular prion protein (PrPc) is a glycosylphosphatidylinositol (GPI) -anchored membrane protein that is highly conserved in mammalian species. PrPc has the characteristics of adhesive molecules and is thought to play a role in cell adhesion and membrane signaling. Here we investigated the possible role of PrPc in the process of invasiveness and metastasis in gastric cancers. PrPc was found to be highly expressed in metastatic gastric cancers compared to nonmetastatic ones by immunohistochemical staining. PrPc significantly promoted the adhesive, invasive, and in vivo metastatic abilities of gastric cancer cell lines SGC7901 and MKN45. PrPc also increased promoter activity and the expression of MMP11 by activating phosphorylated ErK1/2 in gastric cancer cells. MEK inhibitor PD98059 and MMP11 antibody (Ab) significantly inhibited in vitro invasive and in vivo metastatic abilities induced by PrPc. N-terminal fragment (amino acid 24-90) was suggested to be an indispensable region for signal transduction and invasion-promoting function of PrPc. Taken together, the present work revealed a novel function of PrPc that the existence of N-terminal region of PrPc could promote the invasive and metastatic abilities of gastric cancer cells at least partially through activation of MEK/ERK pathway and consequent transactivation of MMP11.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinases; CD8-Positive T-Lymphocytes; Cell Adhesion; Enzyme Inhibitors; Flavonoids; Humans; Hyaluronan Receptors; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Organic Chemicals; Prions; Stomach Neoplasms; Tumor Cells, Cultured

The synthesis and structure-activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16-F10 metastasis model and display very good pharmacokinetic parameters.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Caco-2 Cells; Cyclopentanes; Humans; In Vitro Techniques; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Melanoma, Experimental; Mice; Microsomes, Liver; Models, Molecular; Molecular Conformation; Neoplasm Metastasis; Permeability; Phthalimides; Protease Inhibitors; Stereoisomerism; Structure-Activity Relationship; Triazines

We studied the synthetic matrix metalloproteinase inhibitor (MMPI) prinomastat (AG3340) in a well-established NCI-H460 orthotopic lung cancer model that exhibits highly predictable regional and systemic metastatic patterns. Both primary and metastatic tumors express the matrix metalloproteinases (MMP-2), MT1-MMP (MMP-14) and tissue inhibitor of metalloproteinases (TIMP-2). The anti-tumor activity of prinomastat was investigated both as a single agent and in combination therapy with carboplatin. Treatment with both carboplatin (at two dose levels) and prinomastat commenced when the primary lung cancer was approximately 200-300 mg in size and without gross or microscopic evidence of metastases. As single agents, prinomastat significantly reduced the incidence of kidney metastasis, but had no effect on metastatic frequency to other organs. As single agents neither drug enhanced length of survival over control animals, although microvessel counts in prinomastat-treated tumors were lower than in tumors from control animals (P<0.01). In combination prinomastat and the lower dose of carboplatin significantly enhanced survival over control animals, and over animals treated with carboplatin alone (P<0.05). Tolerance to this combination was assessed with body weight and serum biochemistries. At the higher carboplatin dose, toxicity became evident both as a single agent and in combination with prinomastat. Our results suggest that the administration of prinomastat in combination with standard cytotoxic chemotherapy during early stages of tumor growth and metastasis may prolong survival in non-small cell lung cancer (NSCLC) patients.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blotting, Northern; Carboplatin; Cell Line, Tumor; Humans; Immunohistochemistry; Lung; Lung Neoplasms; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Metastasis; Neoplasm Transplantation; Neovascularization, Pathologic; Organic Chemicals; Random Allocation; Rats; Rats, Nude; RNA, Messenger; Survival Rate; Tissue Inhibitor of Metalloproteinases; Treatment Outcome; Xenograft Model Antitumor Assays

Modulations of alpha and aryl substitutions on 3-aryloxy propionic acid hydroxamates led to novel and potent inhibitors of MMP-2,3,9 and 13, and selectivity versus MMP-1.

Topics: Animals; Antineoplastic Agents; Antirheumatic Agents; Biological Availability; Cartilage; Combinatorial Chemistry Techniques; Drug Stability; Humans; Matrix Metalloproteinase Inhibitors; Mice; Microsomes, Liver; Neoplasm Metastasis; Neoplasms, Experimental; Propionates; Proteoglycans; Structure-Activity Relationship; Substrate Specificity; Tumor Cells, Cultured

Topics: Animals; Antineoplastic Agents; Diagnostic Imaging; Extracellular Matrix Proteins; Fluorescence; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Organic Chemicals; Serine Endopeptidases