prinomastat and Carcinoma--Lewis-Lung

Inhibitors of VEGF signaling can block angiogenesis and reduce tumor vascularity, but little is known about the reversibility of these changes after treatment ends. In the present study, regrowth of blood vessels in spontaneous RIP-Tag2 tumors and implanted Lewis lung carcinomas in mice was assessed after inhibition of VEGF receptor signaling by AG-013736 or AG-028262 for 7 days. Both agents caused loss of 50%-60% of tumor vasculature. Empty sleeves of basement membrane were left behind. Pericytes also survived but had less alpha-SMA immunoreactivity. One day after drug withdrawal, endothelial sprouts grew into empty sleeves of basement membrane. Vessel patency and connection to the bloodstream followed close behind. By 7 days, tumors were fully revascularized, and the pericyte phenotype returned to baseline. Importantly, the regrown vasculature regressed as much during a second treatment as it did in the first. Inhibition of MMPs or targeting of type IV collagen cryptic sites by antibody HUIV26 did not eliminate the sleeves or slow revascularization. These results suggest that empty sleeves of basement membrane and accompanying pericytes provide a scaffold for rapid revascularization of tumors after removal of anti-VEGF therapy and highlight their importance as potential targets in cancer therapy.

Topics: Actins; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Axitinib; Basement Membrane; Blood Vessels; Carcinoma, Lewis Lung; Collagen Type IV; Endothelium, Vascular; Imidazoles; Indazoles; Insulinoma; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms; Neovascularization, Pathologic; Organic Chemicals; Pericytes; Platelet Endothelial Cell Adhesion Molecule-1; Receptor, Platelet-Derived Growth Factor beta; Receptors, Vascular Endothelial Growth Factor; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Matrix metalloproteinases are a family of zinc-containing proteases that degrade extracellular matrix and basement membranes. These enzymes are thought to play a role in processes essential for tumor growth, invasion, and metastasis. Here we report pharmacokinetic and anti-tumor efficacy studies with a series of structurally related inhibitors of these enzymes that were synthesized at Agouron Pharmaceuticals using protein structure based drug design. The compounds studied were AG3287, AG3293, AG3294, AG3296, AG3319, and AG3340. Rat oral bioavailability ranged from 15 to 68%. Despite similar profiles of enzyme inhibition across the family of enzymes, and similar pharmacokinetics following i.p. administration to mice, efficacy against the Lewis lung carcinoma murine model varied from tumor growth enhancement, to significant reductions in the size of primary tumors and the number of lung metastases. AG3340 was the most efficacious compound against the Lewis lung carcinoma model, resulting in the complete cessation of primary tumor growth throughout the experiment in 4/6 mice treated with daily i.p. injections at a dose of 50 mg/kg. This treatment inhibited the formation of lung metastases greater than 5 mm in diameter by 90%.

Topics: Animals; Antineoplastic Agents; Biological Availability; Carcinoma, Lewis Lung; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Half-Life; Melanoma, Experimental; Metalloendopeptidases; Mice; Organic Chemicals; Rats; Solubility; Structure-Activity Relationship