Mcl-1 Antisense Therapy Chemosensitizes Human Melanoma in a SCID Mouse Xenotransplantation Model

It is well established that high expression of the antiapoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL can significantly contribute to chemoresistance in a number of human malignancies. Much less is known about the role the more recently described Bcl-2 family member Mcl-1 might play in tumor biology and resistance to chemotherapy. Using an antisense strategy, we here address this issue in melanoma, a paradigm of a treatment-resistant malignancy. After in vitro proof of principle supporting an antisense mechanism of action with specific reduction of Mcl-1 protein as a consequence of nuclear uptake of the Mcl-1 antisense oligonucleotides employed, antisense and universal control oligonucleotides were administered systemically in combination with dacarbazine in a human melanoma SCID mouse xenotransplantation model. Dacarbazine, available now for more than three decades, still remains the most active single agent for treatment of advanced melanoma. Mcl-1 antisense oligonucleotides specifically reduced target protein expression as well as the apoptotic threshold of melanoma xenotransplants. Combined Mcl-1 antisense oligonucleotide plus dacarbazine treatment resulted in enhanced tumor cell apoptosis and led to a significantly reduced mean tumor weight (mean 0.16 g, 95% confidence interval 0.08–0.26) compared to the tumor weight in universal control oligonucleotide plus dacarbazine treated animals (mean 0.35 g, 95% confidence interval 0.2–0.44) or saline plus dacarbazine treated animals (mean 0.39 g, 95% confidence interval 0.25–0.53). We thus show that Mcl-1 is an important factor contributing to the chemoresistance of human melanoma in vivo. Antisense therapy against the Mcl-1 gene product, possibly in combination with antisense strategies targeting other antiapoptotic Bcl-2 family members, appears to be a rational and promising approach to help overcome treatment resistance of malignant melanoma

A Novel Small-Molecule Integrin Antagonist Inhibits Cells Adhesion Followed By Anoikis in Endothelial Cells - A Comparative Analysis with Cilengitide

Background: Despite the crucial role of integrin receptors in cancer pathogenesis and massive efforts towards establishing clinically relevant drugs, to the present no effective integrin antagonist for the treatment of malignant diseases has been introduced into the clinic.Context and purpose of the study: The purpose of the study was to examine the cellular effects and molecular mechanisms of a novel anti-integrin compound designated AV-398/38 and to compare it with cilengitide, one of the most advanced and best characterized αVβ3/αVβ5 integrin antagonists. AV-398/38 is a small molecule integrin antagonist that is currently in an early phase of pre-clinical evaluation. It was identified by virtual screening of chemical databases with the aim to detect novel integrin αVβ3 antagonist-like candidates. Based on preliminary in vitro data, the compound was recognized as a potential anti-neoplastic drug candidate, displaying high specificity and binding affinity in the nanomolar range towards the αVβ3 receptor, as well as showing potentially favorable drug-like properties.Results: Our studies revealed that its anti-neoplastic properties are most likely mediated by inhibition of integrin-mediated cell attachment to the extracellular matrix resulting in anoikis in a TP53 independent manner. Additionally, we observed inhibition of integrin-linked pathways involved in cell proliferation, survival and migration such as FAK, Akt, and MAPK as well as direct inhibitory effects on cell migration. We compared the effects of the compound with cilengitide, which is one of the bestcharacterized αVβ3 antagonists available.Main findings: The main finding was the observation, that AV-398/38 is capable of inducing cell death via induction of anoikis in a TP53 independent manner.&nbsp;Conclusions: Integrin αVβ3/αVβ5 inhibition leads to apoptotic cell death most likely triggered by a loss of adherence. Brief summary and potential implications: Our data indicate that compound AV-398/38 or structurally similar molecules may be promising candidates for preclinical development.&nbsp;</p

4-({(Z)-5-[(Z)-3-Ethoxy-4-hydroxybenzylidene]-3-methyl-4-oxo-1,3-thiazolidin-2-ylidene}amino)benzoic acid dimethylformamide monosolvate

The molecular structure of the title compound, C20H18N2O5S&amp;#183;C3H7NO, represents an essentially planar 5-benzylidene-thiazolidine moiety (r.m.s. deviation from planarity without ring substituents = 0.095&amp;#8197;&amp;#197;) to which the 4-aminobenzoic acid fragment is inclined at 76.23&amp;#8197;(1)&amp;#176;. In the crystal, the benzoic acid molecules are arranged in layers parallel to [001] which are built up from inversion dimers held together by head-to-tail phenol&amp;#8211;carboxy O&amp;#8212;H...O hydrogen bonds and head-to-tail &amp;#960;&amp;#8211;&amp;#960; stacking interactions between the 5-benzylidene-thiazolidine moieties (ring centroid distance = 3.579&amp;#8197;&amp;#197;). These layers are separated by the dimethylformamide solvent molecules which are firmly anchored via a short O&amp;#8212;H...O hydrogen bond [O...O = 2.5529&amp;#8197;(10)&amp;#8197;&amp;#197;] donated by the &amp;#8211;COOH group

NVX-412, a new oncology drug candidate, induces S-phase arrest and DNA damage in cancer cells in a p53-independent manner.

The new molecular entity quinoxalinhydrazide derivative NVX-412 was identified as a promising drug candidate for the treatment of various cancer types due to its strong cytotoxic activity and relative specificity. Here, we provide first data about the mechanisms of action of NVX-412. We show that NVX-412 exerts its anti-neoplastic activity in a p53-independent manner and induces S-phase arrest and DNA damage as assessed by γH2AX staining. We suggest a bi-modal (dose-dependent) mode of action of NVX-412, being primarily cytostatic at lower and predominantly cytotoxic at higher concentrations. Based on the broad and consistent anti-neoplastic activity observed, NVX-412 holds promise as an effective drug candidate for the treatment of various cancer types, especially for hematological malignancies with highly unmet medical need

Osteosarcoma of the jaw – experience at the Medical University Vienna and comparative study with international tumor registries

OBJECTIVES: Osteosarcoma of the jaw (OSAJ) is fundamentally different in clinical practice from its peripheral counterparts. Studies are difficult to conduct due to low incidence rates. The primary aim of this study was to provide for the first time a comprehensive retrospective analysis of the treatment concepts and outcome data of OSAJ patients treated at the University Hospital Vienna and to compare these with two recently published studies on OSAJ. The clinical study was accompanied by a biomarker study investigating the prognostic relevance of melanoma-associated antigen-A (MAGE-A) in OSAJ specimens. METHOD: Eighteen patients were included, and their outcomes were compared to published data. Immunohistochemistry was performed with mouse monoclonal antibodies against MAGE-A. Survival rates were estimated by the Kaplan-Meyer method. The log-rank test was used to analyze potential prognostic parameters. Fisher’s exact test was performed to define the significant differences between the survival rates of the current study and the DOESAK registry. RESULTS: Disease-specific survival was 93.8% after five and 56.3% after ten years. The development of metastases (p=0.033) or relapse (p=0.037) was associated with worsened outcomes in our group as well as in the comparative group. Despite the different treatment concepts of the study groups, survival rates were comparable. MAGE-A failed to show prognostic relevance for OSAJ patients. CONCLUSIONS: Uncertainties about the optimal treatment strategies of OSAJ patients will currently remain. Thus, prospective studies of OSAJ are needed but are only feasible in a multicenter study setting, conducted over a prolonged time period

Relationships between Molecular Complexity, Biological Activity, and Structural Diversity.

Following the theoretical model by Hann et al. moderately complex structures are preferable lead compounds since they lead to specific binding events involving the complete ligand molecule. To make this concept usable in practice for library design, we studied several complexity measures on the biological activity of ligand molecules. We applied the historical IC50/EC50 summary data of 160 assays run at Novartis covering a diverse range of targets, among them kinases, proteases, GPCRs, and protein-protein interactions, and compared this to the background of "inactive" compounds which have been screened for 2 years but have never shown any activity in any primary screen. As complexity measures we used the number of structural features present in various molecular fingerprints and descriptors. We found generally that with increasing activity of the ligands, their average complexity also increased, and we could therefore establish a minimum number of structural features in each descriptor needed for biological activity. Especially well suited in this context were the Similog keys and circular substructure fingerprints. These are those descriptors, which also perform especially well in the identification of bioactive compounds by similarity search, suggesting that structural features encoded in these descriptors have a high relevance for bioactivity. Since the number of features correlates with the number of atoms present in the molecule, also the number of atoms serves as a reasonable complexity measure and larger molecules have, in general, higher activities. Due to the relationship between feature counts and densities on one hand and biological activity on the other, the size bias present in almost all similarity coefficients becomes especially important. Diversity selections using these coefficients can influence the overall complexity of the resulting set of molecules, which has an impact on the biological activity that they exhibit. Using sphere-exclusion based diversity selection methods, such as OptiSim together with the Tanimoto dissimilarity, the average feature count distribution of the resulting selections is shifted toward lower complexity than that of the original set, particularly when applying tight diversity constraints. This size bias reduces the fraction of molecules in the subsets having the complexity required for a high, submicromolar activity. None of the diversity selection methods studied, namely OptiSim, divisive K-means clustering, and self-organizing maps, yielded subsets covering the activity space of the IC50 summary data set better than subsets selected randomly

NCI-60 DTP human tumor cell line screen shows strong anti-cancer activity in various cancer types.

<p>A panel of 59 human tumor cell lines of diverse tumor entities was included in a NCI screen. This table shows the mean IC₅₀ values in nM after 48 hours incubation for the various cancer types for 57 of them. Results for two cell lines were identified as outliers and were not included in the calculation of the mean IC₅₀. Numbers in brackets indicate the number of cell lines tested within a certain cancer type. NCI, National Cancer Institute; DTP, Developmental Therapeutics Program.</p

Chemical structure of NVX-412.

<p><b>A:</b> Pyrazine-2-carboxylic acid N’-(7-fluoro-pyrrolo[1,2-α]quinoxalin-4-yl)-hydrazide-oxalic acid co-crystal; Molecular Formula: C₁₈H₁₃FN₆O₅, Molecular Weight: 412 g/mol <b>B:</b> Solvent accessible mesh model. White: carbon; yellow: fluorine; blue: nitrogen; red: oxygen. Both structures were generated with ChemBio 3D Ultra 12.0 (CambridgeSoft, MA, USA).</p