25 years after the first approval of cisplatin in the clinic against a number of cancer diseases, cisplatin and related compounds continue to be among the most efficient anticancer drugs used so far. ...Efforts are focused to develop novel platinum- and non-platinum-based antitumor drugs to improve clinical effectiveness, to reduce general toxicity and to broaden the spectrum of activity. In the field of non-platinum compounds exhibiting anticancer properties, ruthenium complexes are very promising, showing activity on tumors which developed resistance to cisplatin or in which cisplatin is inactive. Furthermore, general toxicity was found to be very low. The first ruthenium compound NAMI-A entered phase I clinical trials in 1999 as an antimetastatic drug, whereas the ruthenium complex KP1019 will enter phase I clinical trials in 2003 as an anticancer drug which is among others very active against colon carcinomas and their metastases. Remarkable progress is also seen in developing tumor inhibiting gallium compounds. One of them, KP46, will also enter phase I clinical trials in 2003. This article reviews briefly the achievements in the field of anticancer metal complexes focusing the discussion onto the impact of the group of Bioinorganic Chemistry at the Department of Inorganic Chemistry at the University of Vienna. The development of pH sensitive platinum prodrugs, platinum-based drug targeting strategies with low-molecular-weight carriers, kinetically inert platinum(IV) complexes, as well as tumor inhibiting non-platinum anticancer drugs based on ruthenium and gallium is covered in the following sections.
BOLD-100 (formerly IT-139, KP1339), a well-established chemotherapeutic agent, is currently being investigated in clinical trials for the treatment of gastric, pancreatic, colorectal, and bile duct ...cancer. Despite numerous studies, the exact mode of action is still the subject of discussions. Radiolabeled BOLD-100 could be a powerful tool to clarify pharmacokinetic pathways of the compound and to predict therapy responses in patients using nuclear molecular imaging prior to the therapy. In this study, the radiosyntheses of carrier-added (c.a.)
97/103
RuBOLD-100 were performed with the two ruthenium isotopes ruthenium-103 (
103
Ru; β
−
, γ) and ruthenium-97 (
97
Ru; EC, γ), of which in particular the latter isotope is suitable for imaging by single-photon emission computed tomography (SPECT). To identify the best tumor-to-background ratio for diagnostic imaging, biodistribution studies were performed with two different injected doses of c.a.
103
RuBOLD-100 (3 and 30 mg kg
−1
) in Balb/c mice bearing CT26 allografts over a time period of 72 h. Additionally,
ex vivo
autoradiography of the tumors (24 h p.i.) was conducted. Our results indicate that the higher injected dose (30 mg kg
−1
) leads to more unspecific accumulation of the compound in non-targeted tissue, which is likely due to an overload of the albumin transport system. It was also shown that lower amounts of injected c.a.
103
RuBOLD-100 resulted in a relatively higher tumor uptake and, therefore, a better tumor-to-background ratio, which are encouraging results for future imaging studies using c.a.
97
RuBOLD-100.
Radiolabeling of the chemotherapeutic agent BOLD-100 with ruthenium-103 enables animal experiments with lower amounts of injected drug. This leads to a relatively higher tumor uptake and promising tumor-to-background ratio for future imaging studies.
Highlights • New triapine-resistant cell line was generated by drug selection. • Triapine-resistant cells are cross-resistant against several ABCB1 substrates. • Triapine induces ABCB1 via PKC (in ...chronic as well as short-term treatment). • In-depth analyses showed that triapine is only a weak ABCB1 and no ABCC1 substrate.
Supramolecular Pt(ii) quadrangular boxes bind native and G-quadruplex DNA motifs in a size-dependent fashion. Three Pt molecular squares of distinct size show biological activity against cancer cells ...and heavily influence the expression of genes known to form G-quadruplexes in their promoter regions. The smallest Pt-box displays less activity but more selectivity for a quadruplex formed in the c-Kit gene.
Nano-scale secondary ion mass spectrometry (NanoSIMS) enables trace element and isotope analyses with high spatial resolution. This unique capability has recently been exploited in several studies ...analyzing the subcellular distribution of Au and Pt anticancer compounds. However, these studies were restricted to cell culture systems. To explore the applicability to the
in vivo
setting, we developed a combined imaging approach consisting of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), NanoSIMS and transmission electron microscopy (TEM) suitable for multi-scale detection of the platinum distribution in tissues. Applying this approach to kidney and tumor samples upon administration of selected platinum(
iv
) anticancer prodrugs revealed uneven platinum distributions on both the organ and subcellular scales. Spatial platinum accumulation patterns were quantitatively assessed by LA-ICP-MS in histologically heterogeneous organs (
e.g.
, higher platinum accumulation in kidney cortex than in medulla) and used to select regions of interest for subcellular-scale imaging with NanoSIMS. These analyses revealed cytoplasmic sulfur-rich organelles accumulating platinum in both kidney and malignant cells. Those in the tumor were subsequently identified as organelles of lysosomal origin, demonstrating the potential of the combinatorial approach for investigating therapeutically relevant drug concentrations on a submicrometer scale.
A NanoSIMS, LA-ICP-MS and TEM combinatorial approach was applied to analyze the distribution of platinum(
iv
) prodrugs in murine tissue samples.
The ruthenium complex salt indazolium trans-tetrachlorobisindazole-ruthenate(III) (KP1019) and the analogous sodium salt KP1339 are effective tumor-inhibiting drugs in experimental therapy of ...autochthonous colorectal carcinomas in rats. This paper examines the cell biological mechanisms underlying their antineoplastic effects.
Colorectal tumor cell lines were used to analyze uptake of the ruthenium(III) complexes into the cells and the mechanism as well as the efficacy of their cytotoxic effects.
KP1019 and KP1339 are efficiently taken up into the cells: 100 microM ruthenium(III) complex in the growth medium led to the uptake of 120-160 ng ruthenium per 10(6) cells within 30 min. Uptake of KP418 was tenfold lower correlating with its lower cytotoxic efficiency. KP1019 and KP1339 induced apoptosis in SW480 and HT29 cells predominantly by the intrinsic mitochondrial pathway as indicated by loss of mitochondrial membrane potential. Correspondingly sensitivity of the cells paralleled expression of bcl(2) while it was only slightly affected by mutations in Ki-ras.
Our data demonstrate that trans-tetrachlorobisindazole-ruthenate(III) complex salts are promising candidate drugs in the second-line treatment of colorectal cancers resistant to other cytostatic drugs and has been introduced into phase I clinical trials.
Research in the field of bioinorganic chemistry has been stimulated by the worldwide success of the anticancer drug cisplatin. 40 years after the first report about its biological activity, ...carboplatin and oxaliplatin are in routine clinical use today, whereas nedaplatin, lobaplatin, and heptaplatin (SKI2053R) are only approved in Japan, China, and South Korea, respectively. Up to now, about 35 platinum complexes entered clinical trials in order to circumvent the side-effects and the problem of tumor resistance to cisplatin. Additionally, improvement of tumor selectivity as well as the need for a broader spectrum of indications are the motivations for tremendous efforts in the development of novel anticancer platinum-based drugs. New synthetic strategies and innovative analytical approaches provide a basis for a deeper understanding of the pharmacological profile of cisplatin and analogues (biodistribution, clearance, detoxification, sideeffects, tumor specificity, cellular uptake, acquired or intrinsic resistance, platinum-DNA adduct removal by the cellular machinery) and give rise to a rational design of promising anticancer platinum coordination compounds. This article reviews the recent development of preclinical platinum complexes with interesting in vitro and in vivo tumor inhibiting properties. It focuses also on innovative synthetic strategies leading to novel classes of platinum complexes. A small part of the review is dedicated to new analytical approaches which have been supplied to or emerged in this field of research.
The proto-oncogene KIT encodes for a tyrosine kinase receptor, which is a clinically validated target for treating gastrointestinal stromal tumors. The KIT promoter contains a G-rich domain within a ...relatively long sequence potentially able to form three adjacent G-quadruplex (G4) units, namely, K2, SP, and K1. These G4 domains have been studied mainly as single quadruplex units derived from short truncated sequences and are currently considered promising targets for anticancer drugs, alternatively to the encoded protein. Nevertheless, the information reported so far does not contemplate the interplay between those neighboring G4s in the context of the whole promoter, possibly thwarting drug-discovery efforts. Here we report the structural and functional study of the KIT promoter core sequence, in both single- and double-stranded forms, which includes all three predicted G4 units. By preventing the formation of alternatively one or two G4 units and by combining biophysical techniques and biological assays, we show for the first time that these quadruplexes cannot be analyzed independently, but they are correlated to each other. Our data suggest that, while K2 and K1 G-rich sequences retain the ability to fold into parallel G4 motifs within a long sequence, the SP G-rich domain contributes to G4 structure only together with K2. Remarkably, we have found that, in the context of a dynamic equilibrium between the three G4 units, the G4 formed by K1 has the most significant influence on the structure stability and on the biological role of the whole promoter.
Thirty years after the onset of the first clinical studies with cisplatin, the development of antineoplastic platinum drugs continues to be a productive field of research. This article reviews the ...current preclinical and clinical status, including a discussion of the molecular basis for the activity of the parent drug cisplatin and platinum drugs of the second and third generation, in particular their interaction with DNA. Further emphasis is laid on the development of third generation platinum drugs with activity in cisplatin-resistant tumours, particularly on chelates containing 1,2-diaminocyclohexane (DACH) and on the promising and more recently evolving field of non-classic ( trans- and multinuclear) platinum complexes. The development of oral platinum drugs and drug targeting strategies using liposomes, polymers or low-molecular-weight carriers in order to improve the therapeutic index of platinum chemotherapy are also covered.
Ruthenium anticancer drugs belong to the most promising non-platinum anticancer metal compounds in clinical evaluation. However, although the clinical results are promising regarding both activity ...and very low adverse effects, the clinical application is currently hampered by the limited solubility and stability of the drug in aqueous solution. Here, we present a new nanoparticle formulation based on polymer-based micelles loaded with the anticancer lead ruthenium compound KP1019. Nanoprepared KP1019 was characterised by enhanced stability in aqueous solutions. Moreover, the nanoparticle formulation facilitated cellular accumulation of KP1019 (determined by ICP-MS measurements) resulting in significantly lowered IC50 values. With regard to the mode of action, increased cell cycle arrest in G2/M phase (PI-staining), DNA damage (Comet assay) as well as enhanced levels of apoptotic cell death (caspase 7 and PARP cleavage) were found in HCT116 cells treated with the new nanoformulation of KP1019. Summarizing, we present for the first time evidence that nanoformulation is a feasible strategy for improving the stability as well as activity of experimental anticancer ruthenium compounds.
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