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A novel class of dianionic Ru(III) dimers of formula Na2[[trans-RuCl4(Me2SO)]2(mu-L)], with L = pyrazine (pyz, 1), pyrimidine (pym, 2), 4,4'-bipyridine (bipy, 3), and 1,2-bis(4-pyridine) ethane (etbipy, 4), was developed by us with the specific aim of assessing their antitumor properties. The dimers are in fact structurally related to the antimetastatic mononuclear compound (ImH) [trans-RuCl4(Me2SO)(Im)] (NAMI-A, Im = imidazole). Preliminary results concerning the antineoplastic activity of 1-4 against the murine MCa carcinoma model, a tumor which spontaneously metastasizes in the lungs, are reported. Similarly to what is normally observed with NAMI-A, the treatment with the dimeric complexes was scarcely effective against the growth of the primary tumor. However, dimers 1, 2, and 4 reduced very effectively the number and, in particular, the weight of lung metastases (to about 5% with respect to controls); in particular, Na2[[trans-RuCl4(Me2SO)]2(mu-etbipy)] (4) was as effective as NAMI-A in reducing the spontaneous metastases at a dosage which, in terms of moles of ruthenium, is about 3.5 times lower compared to that normally used for NAMI-A. Furthermore, in vitro tests showed that dimers 1-4 are capable of forming interstrand cross-links with linearized plasmidic DNA in a time-dependent manner. All the dimeric species are more active in inducing cross-links compared to NAMI-A, and the dimer bridged by the etbipy ligand (4) is the most effective among those tested.

Rotational stress specifically increases the formation of spontaneous lung metastasis in mice bearing Lewis lung carcinoma, without significantly modifying the growth of primary tumor. The increase in metastasis number and volume caused by rotational stress varies in magnitude with a highly significant circannual rhythm; the acrophase approximately coincides with summer solstice. Rotational stress causes a significant reduction in the number of CD3+ and CD4+ T-lymphocyte subsets in summer, whereas in winter the number of CD3+ subset is significantly increased; the CD4+ CD8+ ratio and the number of NK 1.1 antigen positive cells are not significantly modified by rotational stress in both periods considered. The increase in metastasis formation by rotational stress thus appears to negatively correlate with the number of splenic CD3+ and CD4+ T-lymphocyte subsets. This seasonal behavior occurs in spite of the control of light cycle, temperature and humidity in the animal housing, suggesting the existence in the host of an endogenous oscillator with a circannual period. These data indicate the opportunity to consider endogenous rhythms within the host, as well as seasonal factors, in studies on stress and neuro-immunomodulation in experimental oncology.

Following pioneering observations on the mouse Ehrlich ascites carcinoma, the result of cooperation between the Institutes of Chemistry and Pharmacology of the University of Trieste, more recent studies have characterized some aspects of the antimetastatic properties of coordination metal complexes other than platinum compounds. The compounds examined, rhodium(I) and iridium(I) derivatives of the type [Mchel(LL)] +/o (chel= pyridinalimine (NNR), acetylacetonate; LL= 1,5-hexadiene, 1,5-cyclooctadiene, norbornadiene), both with a square-planar structure, and an octahedral ruthenium(II) derivative RuCl 2 (dimethylsulfoxide) 4 were tested using the solid metastasizing tumor of the mouse, Lewis lung carcinoma. The conclusions which can be drawn from the resulting data concern the role of the metal, of the leaving group and of the non-leaving group as well. It was found that the organometallic complexes of Rh(I) are more active than those of Ir(I); within the Rh(I) derivatives of the type [Rh(I)COD(NNR)] + Cl − (RCH 3 , C 2 H 5 , iC 3 H 7 ), the higher the hydrosolubility, the higher is the antitumor and particularly the antimetastatic effect; as far as the diolefinic ligands are concerned, the higher the chelating effect the higher are the antimetastatic properties of the resulting compound. Separate conclusions can be made for the Ru(II) derivative. Comparison of its antimetastatic effects with those of cis -dichlorodiammineplatinum(II) (cisplatin) using three solid mouse tumors, clearly shows a better therapeutic index for the former, suggesting that within this class of compounds it is conceivable to obtain derivatives with an antineoplastic activity comparable to or even higher than that of cisplatin.

Antitumour drugs may modify the malignant properties of tumour cells and the heterogeneity of tumour cell populations, altering at the same time also the degree of tumour control by host's immune responses . The treatment with 5-(3,3- dimethyl-l-triazeno)imidazole-4-carboxamide (DTIC) or with p-(3,3-dimethyl-l- triazeno)benzoic acid potassium salt (DM-COOK) of mice bearing