Pharmacological control of lung metastases of solid tumours by a novel ruthenium complex.
Imidazolium trans-imidazoledimethylsulphoxidetetrachlororuthenate ImH[trans-RuCl4(DMSO)Im] (NAMI-A), a ruthenium compound that replaces Na+ with ImH+ in the molecule of Na[trans-RuCl4(DMSO)Im] (NAMI), was studied for the anti-metastasis effects in models of solid metastasizing tumours of the mouse. NAMI-A, given i.p. at 35 mg/kg/day for six consecutive days, a dose equimolar to that of NAMI, to mice bearing Lewis lung carcinoma and MCa mammary carcinoma, markedly reduces lung metastasis weight by 80-90%, with an effect equal or even superior to that of NAMI, depending on the experimental system adopted. Correspondingly, NAMI-A increases the content of connective tissue in the tumour matrix, around blood vessels, and in the tumour capsule, augments the percentage of tumour cells in G2/M phase and reduces the amount of CD45+ cells infiltrating the tumour parenchyma. The effects of the same doses on spleen lymphocytes correspond to an increase of CD8+ subset without any change of the distribution of cells in G0/G1, S and G2/M phases. The study shows that NAMI-A behaves similarly to NAMI on the several parameters examined in comparison experiments and therefore we suggest to credit NAMI-A with all the biological actions already described for NAMI during the last 3 years. The replacement of Na+ with ImH+ therefore, besides the better chemical stability of the molecule, confers to [trans-RuCl4(DMSO)Im]- a closer similarity with a true drug to be used in humans, and suggests this molecule for future studies of preclinical toxicology and phase I and II clinical trials.
Sava
G
G
Callerio Foundation, Institutes of Biological Research, University of Trieste, Italy. gsava@fc.univ.trieste.it
Capozzi
I
I
Clerici
K
K
Gagliardi
G
G
Alessio
E
E
Mestroni
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000494:pharmacology*; D012428:Ruthenium / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C075498:dimethylsulfoxideimidazoletetrachlororuthenate(III); D012428:Ruthenium; D004121:Dimethyl Sulfoxide