Effects of some ruthenium chelates on MCa mammary carcinoma and on TLX5 lymphoma in mice.

A group of four Ruthenium chelates of the mixed hard/soft N-S donor ligands 2-formylpyridine (4-H/4-phenyl)thiosemicarbazone has been studied in the experimental models of MCa mammary carcinoma and TLX5 lymphoma in the CBA mouse. Although all the four tested complexes, bis-[2-formylpyridine(4- phenyl)thiosemicarbazone]ruthenium(II)chloride]Ru(L1)(L1H)Cl, 1], [2-formylpyridine(4-phenyl)thiosemicarbazone]ruthenium(II)-mu- trichloro chloro(imidazole)ruthenium(III)monomethanolate [Ru2(L1)(imz)Cl4.CH3OH, 9]. [2-formylpyridine(4-phenyl)thiosemicarbazone]dichloroimidazoler uthenium(II) [Ru(L1H)(imz)Cl2,10] and bis[2- formylpyridinethiosemicarbazone]ruthenium(II) perchlorate, dihydrate [Ru(L)(LH)ClO4.2H2O, 16], reduced the formation of lung metastases at the same extent only compound 1 caused parallel inhibition of the growth of the primary tumor. The chemical nature of the tested compounds seems to determine the nature of the antitumor effects and the bis-chelates are found to be endowed with greater cytotoxic properties towards primary tumor than the monochelates. This opens up a very interesting point, whether it is the presence of two chelate rings around the Ruthenium(II)/(III) acceptor centre or the increase in the number of the soft (S) donor centers that generates greater cytotoxic properties in the corresponding ruthenium complexes. As far as the reduction of the metastasis formation is concerned, it appears that among the four Ruthenium chelates tested, it is possible to identify structures capable of controlling the spread of tumor to the lungs in the absence of significant cytotoxicity for tumor cells. This finding appears of importance in that it indicates the possibility of a specific mechanism of interaction with cells of the metastatic tumor. In this context it appears necessary to investigate other congeners of this "family" with more sulfur donor sites and particularly those with better water solubility.

Metal complexes of ruthenium: a potential class of selective anticancer drugs.

Metal complexes of ruthenium were subjected to a number of studies concerning their chemical behaviour and their potential role in medical applications. Particular emphasis was given to the examination of the antineoplastic properties of ruthenium complexes with a number of ligands of biological interest. The possibility of obtaining compounds of potential value in the chemotherapeutic approach to neoplastic disease is supported by observations that ruthenium compounds could interact with tumor cells better than with normal tissues. This interaction can be considered the result of the chemical characteristics of ruthenium ions which can confer much more selectivity than do the actually available and clinically used organic compounds or cis-dichlorodiammine-platinum (II). Thus, ruthenium-based compounds represent the way for introducing a new class of antitumor drugs endowed with a great potential for the management of human tumors.

Antineoplastic effect of mer-trichlorobisdimethylsulphoxideaminorutheniumIII against murine tumors: comparison with cisplatin and with ImH[RuIm2Cl4].

An asymmetric rutheniumIII complex containing dimethylsulphoxide ligands, namely mer-trichlorobisdimethylsulphoxideaminorutheniumIII (BBR2382), has been tested in mice bearing solid metastasizing tumors. The effects of i.p. treatment with BBR2382 on primary tumor growth and on the survival time of hosts carrying s.c. or i.m. tumors have been compared to those of cisplatin and of a rutheniumIII complex with imidazole ligands, ImH[RuIm2Cl4], described as a potent antitumor agent in a number of experimental models of murine neoplasms. In mice bearing Lewis lung carcinoma, BBR2382 results as effective as cisplatin on s.c. primary tumor growth and more potent than cisplatin on the prolongation of host survival time. The combined treatment of mice bearing Lewis lung carcinoma with cisplatin and BBR2382 causes a reduction of s.c. tumors higher than that caused by each single agent; the effects on host survival time are similar to those caused by BBR2382 alone but significantly superior to those caused by cisplatin alone. In CBA mice bearing MCa mammary carcinoma, the effects of BBR2382 are slightly lower than those of cisplatin on i.m. tumors but are equivalent on host survival time. The comparison of the antineoplastic action of BBR2382 with that of ImH[RuIm2Cl4] is always in favor of the former, independently of the parameter chosen and of the tumor system used. Qualitatively, the antitumor action of BBR2382 seems different from that of cisplatin and of ImH[RuIm2Cl4]; it is supposed that this agent, like other "rutheniumIII dimethylsulphoxide" complexes, could have a particular efficacy for tumors localized in the lungs.

Metal complexes of ruthenium: antineoplastic properties and perspectives.

Octahedral ruthenium(III) and ruthenium(II) complexes show antineoplastic properties on a number of experimental tumors. Tetraammine-, pentaammine-, heterocycle-, and dimethylsulfoxide-coordinated ruthenium complexes have shown high affinity for nitrogen donor ligands in vitro and as a result exhibit various degrees of biological activities including antitumor action in vivo. The chemical behavior of ruthenium(III) complexes indicates the possibility of opening a window of selective toxicity, in practice lacking in the chemotherapeutic approach to neoplastic diseases. Ruthenium ions may accumulate in tumor tissues via a mechanism mediated by transferrin transport. Moreover, binding of ruthenium to DNA is several times higher in its reduced ruthenium(II) form and the reduction from ruthenium(III) prodrugs to the more toxic ruthenium(II) compounds is particularly efficient in tumor hypoxic environments. Correspondingly, solid tumors appear to be more susceptible than those of the lymphoproliferative type. In particular, tumors of the colorectal region and lung tumors (primary or metastatic), which are generally associated with a bad prognosis, have given interesting responses in experimental models, indicating these tumors as preferential targets for the development of ruthenium anticancer drugs.