Dual Action of NAMI-A in inhibition of solid tumor metastasis: selective targeting of metastatic cells and binding to collagen.

Abstract

NAMI-A is a ruthenium complex endowed with a selective effect on lung metastases of solid metastasizing tumors. The aim of this study is to provide evidence that NAMI-A's effect is based on the selective sensitivity of the metastasis cell, as compared with other tumor cells, and to show that lungs represent a privileged site for the antimetastatic effects. The transplantation of Lewis lung carcinoma cells, harvested from the primary tumor of mice treated with 35 mg/kg/day NAMI-A for six consecutive days, a dose active on metastases, shows no change in primary tumor take and growth but a significant reduction in formation of spontaneous lung metastases. Transmission electron microscopy examination of lungs and kidney shows NAMI-A to selectively bind collagen of the lung extracellular matrix and also type IV collagen of the basement membrane of kidney glomeruli. The half lifetime of NAMI-A elimination from the lungs is longer than for liver, kidney, and primary tumor. NAMI-A bound to collagen is active on tumor cells as shown in vitro by an invasion test, using a modified Boyden chamber and Matrigel, and it inhibits the matrix metallo-proteinases MMP-2 and MMP-9 at micromolar concentrations, as shown in vitro by a zimography test. These data show NAMI-A to significantly affect tumor cells with metastatic ability. Binding to collagen allows NAMI-A to exert its selective activity on metastatic cells during dissemination and particularly in the lungs. These data also stress the wide spectrum of daily doses and treatment schedules at which NAMI-A is active against metastases.

• Authors: Gianni Sava, Sonia Zorzet, Claudia Turrin, Francesca Vita, MariaRosa Soranzo, Giuliano Zabucchi, Moreno Cocchietto, Alberta Bergamo, Stefano DiGiovine, Gabriella Pezzoni, Luigi Sartor, Spiridione Garbisa
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 5 Pg. 1898-905 (May 2003) ISSN: 1078-0432 [Print] United States
• PMID: 12738748 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Collagen Type IV
• Drug Combinations
• Laminin
• Matrix Metalloproteinase Inhibitors
• Organometallic Compounds
• Proteoglycans
• Ruthenium Compounds
• imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III)
• matrigel
• Ruthenium
• Collagen
• Dimethyl Sulfoxide

Topics

• Adenocarcinoma (prevention & control, secondary)
• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Lewis Lung (prevention & control, secondary)
• Cell Adhesion
• Cell Division (drug effects)
• Collagen
• Collagen Type IV (metabolism)
• Dimethyl Sulfoxide (analogs & derivatives, metabolism, pharmacology)
• Drug Combinations
• Female
• Humans
• Kidney (ultrastructure)
• Laminin
• Lung (ultrastructure)
• Lung Neoplasms (pathology, prevention & control)
• Mammary Neoplasms, Experimental (prevention & control, secondary)
• Matrix Metalloproteinase Inhibitors
• Mice
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Neoplasm Invasiveness (prevention & control)
• Organometallic Compounds (metabolism, pharmacology)
• Proteoglycans
• Ruthenium (metabolism)
• Ruthenium Compounds
• Tumor Cells, Cultured