Dual Action of NAMI-A in inhibition of solid tumor metastasis: selective targeting of metastatic cells and binding to collagen.
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.
Sava
Gianni
G
Foundation Callerio-Onlus, Trieste, Italy. gsava@fcmail.univ.trieste.it
Zorzet
Sonia
S
Turrin
Claudia
C
Vita
Francesca
F
Soranzo
MariaRosa
M
Zabucchi
Giuliano
G
Cocchietto
Moreno
M
Bergamo
Alberta
A
DiGiovine
Stefano
S
Pezzoni
Gabriella
G
Sartor
Luigi
L
Garbisa
Spiridione
S
D000230:Adenocarcinoma / Q000517:prevention & control / Q000556:secondary; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000517:prevention & control* / Q000556:secondary; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D003094:Collagen; D024141:Collagen Type IV / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007668:Kidney / Q000648:ultrastructure; D007797:Laminin; D008168:Lung / Q000648:ultrastructure; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control*; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control* / Q000556:secondary; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009942:Organometallic Compounds / Q000378:metabolism* / Q000494:pharmacology*; D011509:Proteoglycans; D012428:Ruthenium / Q000378:metabolism; D017975:Ruthenium Compounds; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D024141:Collagen Type IV; D004338:Drug Combinations; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D009942:Organometallic Compounds; D011509:Proteoglycans; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); C059485:matrigel; D012428:Ruthenium; D003094:Collagen; D004121:Dimethyl Sulfoxide