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4. Efficacy of 5-FU combined to Na[trans-RuCl4(DMSO)(Im)], a novel selective antimetastatic agent, on the survival time of mice with P388 leukemia, P388/DDP subline and MCa mammary carcinoma

Author

Coluccia, M., Sava, Gianni, Salerno, G., Bergamo, A., Pacor, Sabrina, Mestroni, G., Alessio, Enzo, Coluccia, M., Sava, Gianni, Salerno, G., Bergamo, A., Pacor, Sabrina, Mestroni, G., Alessio, Enzo, Coluccia, M, Sava, G, Salerno, G, Bergamo, A, Pacor, S, Mestroni, G, and Alessio, E

Subjects
Research Article
Abstract

The combinational treatment between the selective antimetastatic agent, sodium-trans-rutheniumtetrachloridedimethylsulfoxideimidazole, Na[trans-RuCl(4)(DMSO)Im], and the cytotoxic drug 5-fluorouracil (5-FU) on primary tumor growth and on the survival time of experimental tumors results in an effect significantly greater than that of each single agent used alone either with the solid metastasizing MCa mammary carcinoma of the CBA mouse or with the lymphocytic leukemia P388 and its platinum resistant P388/DDP subline. Thus the inorganic compound Na[trans-RuCl(4)(DMSO)Im], known for its potent and selective antimetastatic effects, positively interacts with the antitumor action of an organic anticancer agent such as 5-FU on both a solid metastasizing tumor and a tumor of lymphoproliferative type. In particular, the effects of the combinational treatment on the survival time of tumor bearing mice seem to be related to the selective antimetastatic activity of the ruthenium complex that joins the potent cytotoxicity of 5-FU for the tumor. Moreover, these data show that Na[trans-RuCl(4)(DMSO)Im] is almost as effective on the subline of P388 made resistant to cisplatin as it was on the parental line.

Published
1995

5. Fate of the antimetastatic ruthenium complex ImH[trans-RuCl4(DMSO)Im] after acute i.v. treatment in mice

Author

Cocchietto M, Salerno G, Alessio E, Mestroni G, Gianni Sava, Cocchietto, M., Salerno, G., Alessio, Enzo, Mestroni, G., and Sava, Gianni

Subjects
NAMI-A, Animal studies, Pharmacokinetics, Antineoplastic Agents, Body Fluid Compartments, Models, Biological, Mice, Animal studie, Area Under Curve, Injections, Intravenous, Mice, Inbred CBA, Organometallic Compounds, Animals, Ruthenium Compounds, Dimethyl Sulfoxide, Kidney Diseases, Tissue Distribution, Neoplasm Metastasis
Abstract

The content of ruthenium in blood and different organs of healthy CBA mice was determined by AAS after single i.v. treatment of 200 mg kg-1 of NAMI-A, a new antimetastatic ruthenium compound. Ruthenium concentration in blood falls 5 min after i.v. treatment. In the kidney, ruthenium concentration is markedly higher than in any other analysed tissue. No ruthenium was detected in brains. Pharmacokinetic parameters for a mono- or a bi-compartment model are identifiable: t1/2 is 10.45 h vs 12.02 (t1/2 alpha 0.023 h + t1/2 beta 12 h) with Cltot of 1.60 ml*h-1 vs 1.59); Vd is 24.15 vs 27.48 ml and (model dependent) AUC is 689 vs 694 mg*L-1*h. AUC(0--infinity) calculated by noncompartmental method (linear trapezoidal rule) is 719.77 mg*L-1*h. NAMI-A is rapidly cleared from the blood compartment immediately after i.v. administration. Apparently, there is no differential accumulation of ruthenium in the lungs which might account for a selective antimetastatic effect caused by a cytotoxic concentration in this site, nor in any other specific organ examined.

Published
2000

6. Rhodium(III) analogues of antitumour-active ruthenium(III) compounds: the crystal structure of [ImH][trans-RhCl4(Im)2] (Im= imidazole)

Author

Mestroni, G., Alessio, Enzo, Sessanta, O., Santi, A., Geremia, S., Bergamo, Alberta, Sava, Gianni, Boccarelli, A., Schettino, A., Coluccia, M., Mestroni, G., Alessio, Enzo, Sessanta, O., Santi, A., Geremia, S., Bergamo, Alberta, Sava, Gianni, Boccarelli, A., Schettino, A., and Coluccia, M.

Subjects
Experimental, Sulphoxide ruthenium complexes, Lymphoma, Antineoplastic, Sulphoxide ruthenium complexe
Published
1998

15. Mechanism of tumor inhibition by the metal complex trans-RuCl2(dimethylsulphoxide)4

Author

SAVA, GIANNI, PACOR, SABRINA, ALESSIO, ENZO, Bregant F., Ceschia V., Luxich E., Mestroni G., Sava, Gianni, Pacor, Sabrina, Bregant, F., Ceschia, V., Luxich, E., Alessio, Enzo, and Mestroni, G.

Subjects
Experimental tumours, Antitumour drugs, trans-Ruthenium dimethylsulfoxide, mechanism of action, Antitumour drug
Published
1990

24. Na[trans-RuCl4(DMSO)(Im)]*2DMSO - antimetastatic ruthenium agent

Author

Sava, Gianni, Pacor, Sabrina, Alessio, Enzo, Mestroni, G., Gagliardi, R., Cocchietto, M., Coluccia, M., Sava, Gianni, Pacor, Sabrina, Alessio, Enzo, G., Mestroni, R., Gagliardi, M., Cocchietto, and M., Coluccia

Subjects
ruthenium, anticancer metal compounds
Published
1993

26. Interaction of RuCl2(DMSO)4 isomers with DNA

Author

Loseto, F., Alessio, Enzo, Mestroni, G., Lacidogna, G., Nassi, A., Giordano, D., Coluccia, M., F., Loseto, Alessio, Enzo, G., Mestroni, G., Lacidogna, A., Nassi, D., Giordano, and M., Coluccia

Subjects
anticancer metal compounds, ruthenium, DNA, anticancer metal compound
Published
1991

30. Synthesis and characterization of new halogen -tetramethylene sulfoxide-ruthenium(II) and ruthenium(III) complexes; crystal structure of cis-dichlorotetrakis(tetramethylene sulfoxide) ruthenium(II) and hydrogen trans-bis(tetramethylene sulfoxide)tetrachlororuthenate(III)

Author

Alessio, Enzo, Milani, Barbara, Mestroni, G., Calligaris, M., Faleschini, P., Attia, W. M., Alessio, Enzo, Milani, Barbara, G., Mestroni, M., Calligari, P., Faleschini, and W. M., Attia

Subjects
linkage isomers, ruthenium, dimethylsulfoxide
Published
1990

31. Influence of the binding of reduced NAMI-A to human serum albumin on the pharmacokinetics and biological activity.

Author

Novohradský, V., Bergamo, A., Cocchietto, M., Zajac, J., Brabec, V., Mestroni, G., and Sava, G.

Subjects
RUTHENIUM, METASTASIS, CHEMICAL kinetics, DRUG metabolism, SERUM albumin
Abstract

NAMI-A is a ruthenium-based drug endowed with the unique property of selectively targeting solid tumour metastases. Although two clinical studies had already been completed, limited information exists on the behavior of NAMI-A after injection into the bloodstream. PK data in humans informs us of a rather low free drug concentration, of a relatively high half-life time of elimination and of a linear relationship between the administered dose and the corresponding AUC for up to toxic doses. In the present study, we examined the chemical kinetics of albumin binding with or without the presence of reducing agents, and we evaluated how these chemical aspects might influence the in vivo PK and the in vitro ability of NAMI-A to inhibit cell migration, which is a bona fide, rapid and easy way to suggest anti-metastatic properties. The experimental data support the binding of NAMI-A to serum albumin. The reaction is facilitated when the drug is in its reduced form and, in agreement with already reported data, the adduct formed with albumin maintains the biological activity of the ruthenium drug. The formation of the adduct is favored by low ratios of NAMI-A : HSA and by the reduction of the drug with ascorbic acid. The difference in in vivo PK and the faster binding to albumin of the reduced NAMI-A seem to suggest that the drug is not rapidly reduced immediately upon injection, even at low doses. Most probably, cell and protein binding prevail over the reduction of the drug. This observation supports the thesis that the reduction of the drug before injection must be considered relevant for the pharmacological activity of NAMI-A against tumour metastases. [ABSTRACT FROM AUTHOR]

Published
2015
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32. Effects of two pyridinalalkyliminerhodium(I) complexes in mice bearing MCa mammary carcinoma.

Author

Sava, Gianni, Zorzet, Sonia, Pacor, Sabrina, Mestroni, Giovanni, Zassinovich, Grazia, Sava, G, Zorzet, S, Pacor, S, Mestroni, G, and Zassinovich, G

Abstract

The examination of the differential effects of two square-planar rhodium(I) complexes on primary tumor growth and on the formation of spontaneous and artificially (i.v. tumor injection) induced lung metastases of MCa mammary carcinoma suggests different mechanisms of action, depending on the chemical characteristics of the compound used. Of the two complexes used, cyclooctadiene(2-pyridinalmethylimine)Rh(I) chloride and cyclooctadiene(2-pyridinalisopropylimine)Rh(I) chloride, the former compound confirmed the antineoplastic action previously shown in the Lewis lung carcinoma model. The activity of this derivative on lung metastasis formation seems to be unrelated to a cytotoxic action for tumor cells localized in the lungs. More likely, it appears that modifications occurring at the primary tumor level, probably different from a tumor-cell-directed lethality, are responsible for the reduction of spontaneous lung metastasis formation observed in treated animals. The hyperplasia of the spleen induced in treated animals seems to suggest that this compound is endowed with properties typical for biological response modifiers. [ABSTRACT FROM AUTHOR]

Published
1989
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38. Inhibitory effects of some organometallic complexes of rhodium(I) and iridium(I) on carrageenin paw edema in rats

Author

Gianni Sava, Piccini P, Mestroni G, Zassinovich G, Bontempi A, Sava, Gianni, Piccini, P., Mestroni, G., Zassinovich, G., and Bontempi, A.

Subjects
Male, Rats, Inbred Strains, Metal based complexe, Carrageenan, Rubidium, Iridium, Rats, Rhodium, Metal based complexes, Carragenin oedema, Organometallic Compounds, Animals, Edema
Abstract

A group of 4 organometallic complexes of Rhodium (I) and 1 Iridium(I) was tested for the evaluation of their anti-inflammatory activity on carrageenin paw edema in rats. All the compounds used inhibited the development of paw edema by more than 50% at different dose-levels. The activity of the pyridinalmethylimine derivative [Rh(COD)PMI]+ Cl- had better results than that of [Rh(NBD)PMI]+ Cl- and even more than the dimeric complexes tested. The higher activity of [Ir(COD)Cl]2 as compared with [Rh(COD)Cl]2 suggests that it would be of interest to examine further Iridium(I) complexes, among which [Ir(COD)PMI]+ Cl- could be a good candidate.

Published
1987

40. Antitumor effects of rhodium(I), iridium(I) and ruthenium(II) complexes in comparison with cis-dichloro-diamminoplatinum(II) in mice bearing Lewis lung carcinoma

Author

Sava, Gianni, Giraldi, Tullio, Mestroni, G., Zassinovich, G., Sava, Gianni, Giraldi, Tullio, Mestroni, G., and Zassinovich, G.

Subjects
Organometallic Compound, Animals, Antineoplastic Agents, Cisplatin, Iridium, Lethal Dose 50, Lung Neoplasms, Mice, Neoplasm Transplantation, Neoplasms, Experimental, Organometallic Compounds, Rhodium, Ruthenium, Animal, Antineoplastic Agent, Lung Neoplasm, Neoplasm
Abstract

The effects of square planar rhodium, [RhacacCOD]o and iridium, [IracacCOD]o complexes and of octahedral ruthenium, [cis-RuCl2 (DMSO)4]o complex have been examined in comparison with cis-dichlorodiammino platinum(II) (cis-PDD). The toxicity in BDF1 mice varies widely and decreasing LD50-values, ranging from 0.94 mg/kg to 1000 mg/kg, have been obtained for cis-PDD, [RhacacCOD]o, [IracacCOD]o and [cis-RuCl2(DMSO)4]o, respectively. All the tested complexes similarly inhibit the growth of subcutaneous Lewis lung carcinoma and the development of spontaneous as well as of artificial metastases, with the exception of [IracacCOD]o which is inactive on metastases. The antitumor activity of [RhacacCOD]o and [cis-RuCl2(DMSO)4]o appears interesting, since it is of the same magnitude as that of cis-PDD, considering also that they were found to be only marginally nephrotoxic.

Published
1983

42. Chemical, biological and antitumor properties of ruthenium-dimethylsulfoxide complexes

Author

Mestroni, G., Alessio, Enzo, Calligaris, M., Attia, W. M., Quadrifoglio, F., Cauci, S., Sava, Gianni, Zorzet, Sonia, Pacor, Sabrina, MONTI BRAGADIN, C., Tamaro, M., Dolzani, Lucilla, AUTORI VARI, G., Mestroni, Alessio, Enzo, M., Calligari, W. M., Attia, F., Quadrifoglio, S., Cauci, Sava, Gianni, Zorzet, Sonia, Pacor, Sabrina, C., MONTI BRAGADIN, M., Tamaro, and Dolzani, Lucilla

Subjects
metal anticancer compounds, ruthenium, DNA, metal anticancer compound
Published
1989

44. Metal complexes of platinum group: the promising antitumor features of cis-dichlorotetrakis(dimethylsulfoxide)Ru(II) (cis- RuCl2(DMSO)4) and related complexes

Author

Alessio, Enzo, Attia, W., Calligaris, M., Cauci, S., Dolzani, Lucilla, Mestroni, G., MONTI BRAGADIN, C., Nardin, G., Quadrifoglio, F., Sava, Gianni, Tamaro, M., Zorzet, Sonia, AUTORI VARI, Alessio, Enzo, W., Attia, M., Calligari, S., Cauci, Dolzani, Lucilla, G., Mestroni, C., MONTI BRAGADIN, G., Nardin, F., Quadrifoglio, Sava, Gianni, M., Tamaro, and Zorzet, Sonia

Subjects
metal anticancer compounds, ruthenium, metal anticancer compound
Published
1988

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