Down-regulation of tumour gelatinase/inhibitor balance and preservation of tumour endothelium by an anti-metastatic ruthenium complex.
The anti-metastatic ruthenium complex Na[trans-RuCl4(DMSO)Im] was given i.p. at 22 and 44 mg/kg/day, on days 8-13 after tumour implantation, to mice carrying s.c. implants of MCa mammary carcinoma. The aim of the study was to compare the effects on lung metastasis formation with those on primary tumour cells. This investigation was based on flow cytometry analysis after propidium iodide and acridine orange staining, histology of tumour parenchyma and RT-PCR analysis for the type-IV collagenases MMP-9 and MMP-2 and their respective inhibitors TIMP-1 and TIMP-2 mRNAs. Na[trans-RuCl4(DMSO)Im] is not cytotoxic for tumour cells but has the capacity of interacting with nucleic acids, giving a general reduction of nucleic acid content as shown by a marked reduction of acridine orange staining and a tendency to a reduction of DNA polyploidy with marked reduction of 8n and 4n cell populations. Na[trans-RuCl4(DMSO)Im] also influences a proteolytic system which has the potential of degrading the basement membrane and has been related to metastatic aggressiveness: it markedly reduces, in a dose-dependent manner, MMP-2/TIMP-2 balance, but not that of MMP-9/TIMP-1. The different enzyme/inhibitor mRNA levels between untreated and treated tumours seem to be unaffected by tumour-infiltrating lymphocytes and are paralleled by the maintenance of connective tissue around blood vessels in the tumour mass. Correspondingly, lung metastasis formation is markedly reduced, to less than 10% of that seen in controls.
Department of Biomedical Sciences, University of Trieste, Italy.
G
G
Sava
I
I
Capozzi
A
A
Bergamo
R
R
Gagliardi
M
M
Cocchietto
L
L
Masiero
M
M
Onisto
E
E
Alessio
G
G
Mestroni
S
S
Garbisa
D000165:Acridine Orange; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D004396:Coloring Agents; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004727:Endothelium / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology* / Q000517:prevention & control; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D011419:Propidium; D011480:Protease Inhibitors / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012194:RNA-Directed DNA Polymerase; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases
D000970:Antineoplastic Agents; D004396:Coloring Agents; D006023:Glycoproteins; D009942:Organometallic Compounds; D011480:Protease Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; C075498:dimethylsulfoxideimidazoletetrachlororuthenate(III); D011419:Propidium; D012194:RNA-Directed DNA Polymerase; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000165:Acridine Orange; D004121:Dimethyl Sulfoxide