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The reaction of platinum(II) [Pt(II)] or palladium(II) [Pd(II)] with 2-acetyl pyridine 4N-ethyl thiosemicarbazone, HAc4Et (1) results in the complexes [Pt(Ac4Et)(2)] (2) and [Pd(Ac4Et)(2)] (3). In a panel of human tumor cell lines of different origins (breast, colon, and ovary cancers), and containing also cisplatin-refractory/resistant cell lines, the in vitro growth inhibitory effect of 1-3 was compared to that of cisplatin by using the sulforodamine B assay. After a 96-hour continuous treatment, both the thiosemicarbazone HAc4Et and the metal compounds [Pt(Ac4Et)(2)] and [Pd(Ac4Et)(2)] exhibit very remarkable growth inhibitory activities with mean IC(50) values of 0.9 nM (0.22-2.47 nM), 0.7 nM (0.15-2 nM) and 0.5 nM (0.17-1.02 nM), respectively. In contrast, cisplatin shows a markedly lower growth inhibitory potency, the mean IC(50) in the panel being 2.8 muM (0.2-8 muM). In addition to their major cell growth inhibitory potency, complexes 1-3 are characterized by a growth inhibitory profile different from that of cisplatin, being active towards cisplatin-refractory tumor cell lines. These findings, along with the ability of completely overcoming acquired cisplatin resistance from either multifocal or reduced uptake origin, confirm the antitumor potential of HAc4Et and support the hypothesis that both [Pt(Ac4Et)(2)] and [Pd(Ac4Et)(2)] complexes can be characterized by cellular pharmacological properties distinctly different from those of cisplatin.

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NAMI-A is a ruthenium-based compound with selective anti-metastasis activity in experimental models of solid tumours. We studied whether this activity was dependent on anti-angiogenic ability of NAMI-A. We thus investigated its in vitro effects on endothelial cell functions necessary for angiogenesis to develop, as well as its in vivo effects in the chick embryo chorioallantoic membrane model. Endothelial cell proliferation, chemotaxis, and secretion of the matrix-degrading enzyme metalloproteinase-2 were inhibited by NAMI-A in a dose-dependent manner, and without morphologic signs of cell apoptosis or necrosis. Lastly, NAMI-A displayed a dose-dependent in vivo anti-angiogenic activity in the chorioallantoic membrane model. These data suggest that the anti-angiogenic activity of NAMI-A can contribute to its anti-metastatic efficacy in mice bearing malignant solid tumours.

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To investigate the modifications of antitumor activity and DNA binding mode of transplatin after replacement of one nonleaving group NH(3) by an iminoether group, trans-[PtCl(2)(Z-HN=C(OMe)Me)(NH(3)] and trans-[PtCl(2)(E-HN=C(OMe)Me)(NH(3)] complexes (differing in the Z or E configuration of iminoether, and abbreviated mixed Z and mixed E, respectively), have been synthesized. In a panel of human tumor cell lines, both mixed Z and mixed E show a cytotoxic potency higher than that of transplatin, the mean IC(50) values being 103, 37, and 215 microM, respectively. In vivo mixed Z is more active and less toxic than mixed E in murine P388 leukemia and retains its efficacy against SK-OV-3 human cancer cell xenograft in nude mice. In the reaction with naked DNA, mixed Z forms monofunctional adducts that do not evolve into intrastrand cross-links but close slowly into interstrand cross-links between complementary guanine and cytosine residues. The monofunctional mixed Z adducts are removed by thiourea and glutathione. The interstrand cross-links behave as hinge joints, increasing the flexibility of DNA double helix. The mixed Z, transplatin, and cisplatin interstrand cross-links, as well as mixed Z monofunctional adducts are not specifically recognized by HMG1 protein, which was confirmed to be able to specifically recognize cisplatin d(GpG) intrastrand cross-links. These data demonstrate that the DNA interaction properties of the antitumor-active mixed Z are very similar to those of transplatin, thus suggesting that clinical inactivity of transplatin could not depend upon its peculiar DNA binding mode.

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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.

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The platinum complex trans-[PtCl2¿E-HN=C(OMe)Me¿2] was compared to cisplatin for cytotoxicity towards tumour cells, and for cellular pharmacological properties in A2780 and cisplatin-resistant A2780/Cp8 ovarian cancer cells. Trans-[PtCl2¿E-HN=C(OMe)Me¿2] was comparably cytotoxic to cisplatin (mean IC50 after 72 h exposure = 6. 1 microM and 7 microM, respectively) and did not show cross-resistance in A2780/Cp8 cells (resistance factor = 0.9). Cellular accumulation measurements after treatment with equimolar drug concentrations showed that trans-[PtCl2¿E-HN=C(OMe)Me¿2] entered both A2780 and A2780/Cp8 cells much more efficiently than cisplatin, whose accumulation was reduced in A2780/Cp8 cells. Unlike cisplatin, trans-[PtCl2¿E-HN=C(OMe)Me¿2] induced rapidly cell death and cell cycle modifications of treated cells, thus indicating substantially different mechanistic properties.

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The platinum-iminoether complexes trans-[PtCl2[E - HN = C(OEt)Me]2] (1) and trans-[PtCl2[Z - HN = C(OEt)Me[2] (2), differing in the configuration of the iminoether ligands, were investigated for cytotoxicity towards human tumor cell lines, the involvement of DNA as a cytotoxic target, and their DNA binding mode. The cytotoxicity of isomer 1 was comparable to that of cisplatin, whereas isomer 2 was slightly less active. Excision-repair-deficient xeroderma pigmentosum group A cells were four times more sensitive to both isomers than normal cells, thus implicating cellular DNA as the cytotoxic target. Replication mapping experiments showed that both isomers interact preferentially with guanine residues at py-G-py sites. Oligodeoxyribonucleotides containing unique N7-guanine monofunctional adducts of the more cytotoxic isomer 1 were prepared and investigated for chemical reactivity, stability and DNA conformational alterations. The results showed that the ability of thiourea to labilize the monofunctional adducts depends upon the DNA secondary structure, but not upon the sequence context. Monofunctional adducts evolve to bidentate adducts in single-stranded oligonucleotides, but they are stable in double-stranded oligonucleotides and produce conformational distortions selectively located at the 5'-adjacent base pair. This study gives new insight into the mechanism of action of trans platinum-iminoether complexes, enabling for the first time comparison between different ligand isomers.

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In order to widen our knowledge on antitumour trans-[PtCl2(iminoether)2] complexes, we have synthesised two new derivatives, trans-[PtCl2¿E-HN = C(OEt)Me¿2] (1) and trans-[PtCl2¿Z-HN = C(OEt)Me¿2] (2), which differ in the configuration of the iminoether ligands. Isomer 1 showed an in vitro cytotoxicity similar to that of cisplatin in a panel of human tumour cell lines (mean IC50 = 8 and 7.7 microM, respectively), whereas isomer 2 showed a lower activity (IC50 = 14.3 microM). Both 1 and 2 isomers overcame cisplatin resistance of ovarian cancer cell line A2780/Cp8. In agreement with the n-octanol/saline partition ratios, intracellular platinum content (and DNA platination) after a 2-h exposure to equimolar drug concentrations was in the order 1 > 2 >> cisplatin, thus indicating that substitution of imminoethers for ammines determines a major lipophilicity and cellular uptake of the platinum drug. Both 1 and 2 showed a major toxic effect towards an excision repair-defective Drosophila strain, thus indicating cellular DNA as cytotoxic target. Finally, both 1 and 2 were active in vivo against the murine P388 system, but, contrary to the in vitro activity, isomer 2 was slightly more active than 1. On the whole, the results confirm the antitumour activity of trans-[PtCl2(iminoether)2] complexes, and indicate that the configuration of the iminoether ligands may affect the pharmacological properties of this class of complexes.

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The biological activity of cis and trans complexes of formula [PtCl2(HN = C(OMe)Me)2] has been investigated. The iminoether ligands can have either E or Z configuration about the C = N double bond, therefore EE, EZ and ZZ isomers are obtainable. Substitution of iminoether with EE configuration for amine leads to unexpectedly high antitumor activity for the complex with trans geometry which turns out to be more active than the cis congener in the P388 leukaemia system. The same trans-EE complex shows an activity comparable to that of cisplatin in reducing the primary tumour mass and lung metastases in mice bearing Lewis lung carcinoma, thus representing a trans platinum complex active on both limphoproliferative and solid metastasizing murine tumours. Also the cytotoxicity, the inhibition of DNA synthesis and the mutagenic activity, which are greater for the cis- with respect to the trans-isomer in the amine complexes, are instead greater for the trans- than for the cis- isomer in the case of iminoether compounds. Binding to calf thymus DNA is slower for iminoether complexes than it is for amine complexes, however after 24 h reaction time the level of binding is similar for both types of complexes. Trans-EE, like trans-DDP, does not give the DNA conformational alterations (terbium fluorescence) typical of antitumour-active cis- platinum compounds, but, under strictly analogous experimental conditions, shows a greatly reduced DNA interstrand cross-linking ability (heat denaturation/renaturation assay) with respect to either trans-DDP or cis-EE and cis-DDP. The data in hand point to a new trans platinum antitumour complex with a mechanism of action different from that of cis-DDP and classical analogues.

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A platinum(II) complex with the antiviral drug acyclovir was synthesized and its antiviral and anticancer properties were investigated in comparison to those of acyclovir and cisplatin. The platinum-acyclovir complex maintained the antiviral activity of the parent drug acyclovir, though showing a minor efficacy on a molar basis (ID(50) = 7.85 and 1.02 muMu for platinum-acyclovir and cisplatin, respectively). As anticancer agent, the platinum-acyclovir complex was markedly less potent than cisplatin on a mole-equivalent basis, but it was as effective as cisplatin when equitoxic dosages were administered in vivo to P388 leukaemia-bearing mice (%T/C = 209 and 211 for platinum-acyclovir and cisplatin, respectively). The platinum-acyclovir complex was also active against a cisplatin-resistant subline of the P388 leukaemia (%T/C = 140), thus suggesting a different mechanism of action. The DNA interaction properties (sequence specificity and interstrand cross-linking ability) of platinum-acyclovir were also investigated in comparison to those of cisplatin and [Pt(dien)Cl](+), an antitumour-inactive platinum-triamine compound. The results of this study point to a potential new drug endowed, at the same time, with antiviral and anticancer activity and characterized by DNA interaction properties different from those of cisplatin.

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In this paper we report a review of the results obtained in the last few years by our group in the development of ruthenium(III) complexes characterized by the presence of sulfoxide ligands and endowed with antitumor properties. In particular, we will focus on ruthenates of general formula Na[trans-RuCl(4)(R(1)R(2)SO)(L)], where R(1)R(2)SO = dimethylsulfoxide (DMSO) or tetramethylenesulfoxide (TMSO) and L = nitrogen donor ligand. The chemical behavior of these complexes has been studied by means of spectroscopic techniques both in slightly acidic distilled water and in phosphate buffered solution at physiological pH. The influence of biological reductants on the chemical behavior is also described. The antitumor properties have been investigated on a number of experimental tumors. Out of the effects observed, notheworthy appears the capability of the tested ruthenates to control the metastatic dissemination of solid metastasizing tumors. The analysis of the antimetastatic action, made in particular on the MCa mammary carcinoma of CBA mouse, has demonstrated a therapeutic value for these complexes which are able to significantly prolong the survival time of the treated animals. The antimetastatic effect is not attributable to a specific cytotoxicity for metastatic tumor cells although in vitro experiments on pBR322 double stranded DNA has shown that the test ruthenates bind to the macromolecule, causing breaks corresponding to almost all bases, except than thymine, and are able to cause interstrand bonds, depending on the nature of the complex being tested, some of which results active as cisplatin itself.

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Two ruthenium(II) complexes, characterised by the presence of dimethylsulphoxide ligands, were investigated in comparison to cisplatin on mouse P388 leukaemia and on a subline made resistant to cisplatin (P388/DDP). Both cis- and trans-RuCl2(DMSO)4 significantly prolonged the survival time of leukaemic mice, independently of the tumour line used. Unlike cisplatin, the prolongation of life-span of tumour-bearing hosts caused by ruthenium complexes was not supported by a parallel inhibition of the number of tumour cells in the treated hosts, as evidenced by tumour cell count in the peritoneal cavity and by vivo-vivo bioassays of blood samples and of whole brains. Thus, cis- and trans-RuCl2(DMSO)4 appear capable of preventing leukaemic spread into the central nervous system also when the number of tumour cells in the peritoneal cavity and in the blood stream is as high as in untreated controls. When the drug-induced DNA damage was investigated by modifying double stranded DNA and identifying the lesions able to inhibit DNA synthesis in vitro, trans-RuCl2(DMSO)4 and, to a lesser extent, cis-RuCl2(DMSO)4 formed blocking lesions at the same sites of cisplatin; nevertheless, the mechanism of antitumour activity of ruthenium complexes appears to be different from that of cisplatin for the absence of any relationship between cytotoxicity and prevention of leukaemic dissemination into the central nervous system. These data indicate that the activity of cis- and trans-RuCl2(DMSO)4 on the P388 leukaemia is characterised by the lack of cross-resistance with cisplatin and by the alteration of the metastasising behaviour of leukaemic cells which lose their natural capacity to invade the central nervous system.

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