The aim of developing new tumor-inhibiting ruthenium complexes, in particular compounds which act against tumors that have been chemoresistant up to now, has led us to the synthesis of different classes of ruthenium complexes. These were selected for further evaluation on the basis of increase in survival time in the P388 tumor model and water-solubility. The water-soluble ruthenium complexes coordinated with heterocycle ligands in trans-position, HB(RuB 2 CI 4 ), and the corresponding pentachloro derivatives, (HBMRuBCI s )' were identified as being the most active ones. Their chemical properties were investigated by means of x-ray analyses, M6ssbauer spectra, NMR spectra, and other methods. Their galenic formulation was relatively easy to establish owing to their solubility in water or in physiological saline. Stability of the complexes turned out to be sufficient for infusion therapy. Antitumor activity of such compounds was confirmed not only in the P388 tumor model but also in the Walker 256 carcinosarcoma, the Stockholm Ascitic tumor, the subcutaneously growing B 16 melanoma, the intramusculary growing sarcoma 180 and the AMMN-induced colorectal tumors of the rat.In particular, the two compounds ImH(Rulm 2 Ci 4 ) and IndH(RuInd 2 CI 4 ), 1m = Imidazole, Ind = Indazole, turned out to be highly active against these tumor models, with the emphasis on activity against AMMN-induced colorectal tumors. This is a strong indication of future clinical activity against such adenotumors. The toxicological target organs turned out to be the kidneys and the liver. In addition, erythropenia and an increase in both creatinine and liver enzymes were observed. Nevertheless, in chronic application at therapeutic doses, toxicity is well tolerated. On account of these promising properties, the two compounds were selected for further toxicological studies, which are the prerequisites for the beginning of clinical studies.

Plakophilins 1 and 3 (PKP1/3) are members of the arm repeat family of catenin proteins and serve as structural components of desmosomes, which are important for cell-cell-adhesion. In addition, PKP1/3 occur as soluble proteins outside desmosomes, yet their role in the cytoplasm is not known. We found that cytoplasmic PKP1/3 coprecipitated with the RNA-binding proteins FXR1, G3BP, PABPC1, and UPF1, and these PKP1/3 complexes also comprised desmoplakin and PKP2 mRNAs. Moreover, we showed that the interaction of PKP1/3 with G3BP, PABPC1, and UPF1 but not with FXR1 was RNase sensitive. To address the cytoplasmic function of PKP1/3, we performed gain-and-loss-of-function studies. Both PKP1 and PKP3 knockdown cell lines showed reduced protein and mRNA levels for desmoplakin and PKP2. Whereas global rates of translation were unaffected, desmoplakin and PKP2 mRNA were destabilized. Furthermore, binding of PKP1/3 to FXR1 was RNA independent, and both PKP3 and FXR1 stabilized PKP2 mRNA. Our results demonstrate that cytoplasmic PKP1/3 are components of mRNA ribonucleoprotein particles and act as posttranscriptional regulators of gene expression.