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1.
Clin Exp Metastasis ; 14(2): 115-24, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8605725

ABSTRACT

Four potent, synthetic inhibitors of matrix metalloproteinases (MMPs) were assessed as inhibitors of tumor growth and spontaneous metastasis to the lung. Mat Ly Lu rat prostate tumor, LOX human melanoma and M27 murine Lewis lung tumor were implanted subcutaneously (s.c.) in mice and allowed to grow for 3-12 days. The lungs of the tumor-bearing mice were then removed and implanted s.c. into untreated mice, and the outgrowth of secondary tumors from the implanted lungs measured. The incidence and rate of outgrowth of secondary tumors increased with the length of primary tumor growth, validating these measurements as indices of spontaneous metastasis to the lung. Compounds were tested by s.c. implantation of minipumps which delivered compound throughout the period of primary tumor growth and spontaneous metastasis to the lung at steady-state drug concentrations orders of magnitude greater than the concentrations needed to either inhibit collagenase, gelatinase or stromelysin in vitro. Inhibitor treatment slowed the growth of primary s.c. Mat Ly Lu and LOX tumors by 40-60% but had no significant effect on the growth of primary M27 tumors. Surprisingly, inhibitor treatment had no significant effect on the ability of the lung to generate secondary tumors when reimplanted s.c. in untreated mice. Because of the possible importance of cathepsins B, H and L in tumor growth and metastasis, the irreversible inhibitor E-64 was also infused by s.c. minipump. E-64 had no effect on the growth or spontaneous metastasis of Mat Ly Lu or M27 tumors.


Subject(s)
Antineoplastic Agents/pharmacology , Matrix Metalloproteinase Inhibitors , Metalloendopeptidases/antagonists & inhibitors , Neoplasm Metastasis , Protease Inhibitors/pharmacology , Tumor Cells, Cultured/enzymology , Animals , Cell Division/drug effects , Humans , Lung Neoplasms/secondary , Matrix Metalloproteinase 3 , Mice , Neoplasm Transplantation , Rats , Tumor Cells, Cultured/pathology
2.
J Med Chem ; 37(5): 674-88, 1994 Mar 04.
Article in English | MEDLINE | ID: mdl-8126708

ABSTRACT

Systematic modification of the presumed P1 side chain in a series of (carboxyalkyl)amino-based inhibitors of matrix metalloproteinases enabled identification of the 2-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)ethyl group as a preferred substituent imparting potent inhibition of the enzymes collagenase and gelatinase. It was subsequently found that the P2'-P3' residues in this series could be replaced by small non-peptide residues, while maintaining inhibitory potency. The imide group in this series of compounds can undergo autocatalytic hydrolysis under neutral conditions.


Subject(s)
Dipeptides/chemistry , Extracellular Matrix/enzymology , Indoles/chemistry , Metalloendopeptidases/antagonists & inhibitors , Zinc , Amino Acid Sequence , Chromogenic Compounds/metabolism , Dipeptides/chemical synthesis , Dipeptides/pharmacology , Drug Stability , Fluorescent Dyes , Gelatinases/antagonists & inhibitors , Half-Life , Humans , Hydrogen-Ion Concentration , Indoles/chemical synthesis , Indoles/pharmacology , Isoindoles , Matrix Metalloproteinase 3 , Matrix Metalloproteinase Inhibitors , Molecular Sequence Data , Molecular Structure , Structure-Activity Relationship
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