title: Ruthenium-based NAMI-A type complexes with in vivo selective metastasis reduction and in vitro invasion inhibition unrelated to cell cytotoxicity.
abstract: A series of analogues of NAMI-A, a reference compound active on solid tumor metastases, were synthesized (NAMI-A type complexes). They share the same chemical structure of NAMI-A, and differ from it in the nature of the coordinated nitrogen ligand, such as pyrazole, thiazole and pyrazine, which are less basic than imidazole. This modification confers to the new NAMI-A type complexes a better stability in aqueous solution compared to the parent compound, a very important characteristic for a class of compounds that, with NAMI-A, is currently completing a phase I clinical trial at the Netherlands Cancer Institute of Amsterdam. Cytotoxicity and the effects on cell cycle and invasion were investigated on TS/A, B16-F10 and MCF-7 tumor cell lines, while the inhibition of lung metastases was determined on the mouse experimental tumors Lewis lung carcinoma and MCa mammary carcinoma. The new complexes show a pharmacological activity very similar to that of the parental compound NAMI-A: in vitro they are devoid of meaningful cytotoxicity against tumor cells, and in vivo they inhibit metastasis formation and growth approximately to the same extent as NAMI-A. Thus the new NAMI-A type complexes retain the same potent characteristic of NAMI-A to selectively interact with solid tumor metastases. However, compared to NAMI-A they do not stop cell cycle progression at G2-M level and are more active in preventing the spontaneous invasion of Matrigel by tumor cells exposed for 1 h to 10(-4) M concentration. Globally, these complexes take advantage of the knowledge on NAMI-A and appear particularly interesting for future clinical handling and applications.
authors.affiliation: Fondazione Callerio Onlus, Trieste, Italy.
authors.forename: Alberta
authors.initials: A
authors.lastname: Bergamo
authors.forename: Barbara
authors.initials: B
authors.lastname: Gava
authors.forename: Enzo
authors.initials: E
authors.lastname: Alessio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mestroni
authors.forename: Barbara
authors.initials: B
authors.lastname: Serli
authors.forename: Moreno
authors.initials: M
authors.lastname: Cocchietto
authors.forename: Sonia
authors.initials: S
authors.lastname: Zorzet
authors.forename: Gianni
authors.initials: G
authors.lastname: Sava
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000517:prevention & control* / Q000556:secondary; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control* / Q000556:secondary; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008938:Mitosis / Q000187:drug effects; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009942:Organometallic Compounds / Q000494:pharmacology*; D012428:Ruthenium / Q000378:metabolism; D017975:Ruthenium Compounds; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D012428:Ruthenium; D004121:Dimethyl Sulfoxide