Review of Patient Gene Profiles Obtained through a Non-Negative Matrix Factorization-Based Framework to Determine the Role Inflammation Plays in Neuroblastoma Pathogenesis.

Neuroblastoma is the most common extracranial solid tumor in children. It is a highly heterogeneous tumor consisting of different subcellular types and genetic abnormalities. Literature data confirm the biological and clinical complexity of this cancer, which requires a wider availability of gene targets for the implementation of personalized therapy. This paper presents a study of neuroblastoma samples from primary tumors of untreated patients. The focus of this analysis is to evaluate the impact that the inflammatory process may have on the pathogenesis of neuroblastoma. Eighty-eight gene profiles were selected and analyzed using a non-negative matrix factorization framework to extract a subset of genes relevant to the identification of an inflammatory phenotype, whose targets (PIK3CG, NFATC2, PIK3R2, VAV1, RAC2, COL6A2, COL6A3, COL12A1, COL14A1, ITGAL, ITGB7, FOS, PTGS2, PTPRC, ITPR3) allow further investigation. Based on the genetic signals automatically derived from the data used, neuroblastoma could be classified according to stage rather than as a "cold" or "poorly immunogenic" tumor.

A Critical Appraisal of the Protective Activity of Polyphenolic Antioxidants against Iatrogenic Effects of Anticancer Chemotherapeutics.

Polyphenolic compounds, encompassing flavonoids (e.g., quercetin, rutin, and cyanidin) and non-flavonoids (e.g., gallic acid, resveratrol, and curcumin), show several health-related beneficial effects, which include antioxidant, anti-inflammatory, hepatoprotective, antiviral, and anticarcinogenic properties, as well as the prevention of coronary heart diseases. Polyphenols have also been investigated for their counteraction against the adverse effects of common anticancer chemotherapeutics. This review evaluates the outcomes of clinical studies (and related preclinical data) over the last ten years, with a focus on the use of polyphenols in chemotherapy as auxiliary agents acting against oxidative stress toxicity induced by antitumor drugs. While further clinical studies are needed to establish adequate doses and optimal delivery systems, the improvement in polyphenols' metabolic stability and bioavailability, through the implementation of nanotechnologies that are currently being investigated, could improve therapeutic applications of their pharmaceutical or nutraceutical preparations in tumor chemotherapy.

A second life for MAO inhibitors? From CNS diseases to anticancer therapy.

Monoamine oxidases A and B (MAO A, B) are ubiquitous enzymes responsible for oxidative deamination of amine neurotransmitters and xenobiotics. Despite decades of studies, MAO inhibitors (MAOIs) find today limited therapeutic space as second-line drugs for the treatment of depression and Parkinson's disease. In recent years, a renewed interest in MAOIs has been raised up by several studies investigating the role of MAOs, particularly MAO A, in tumor insurgence and progression, and the efficacy of MAOIs as coadjutants in the therapy of chemoresistant tumors. In this survey, we highlight the implication of MAOs in the biochemical pathways of tumorigenesis and review the state-of-the-art of preclinical and clinical studies of MAOIs as anticancer agents used in monotherapy or in combination with antitumor chemotherapeutics.

Chemical and Biological Evaluation of Novel 1H-Chromeno[3,2-c]pyridine Derivatives as MAO Inhibitors Endowed with Potential Anticancer Activity.

About twenty molecules sharing 1H-chromeno[3,2-c]pyridine as the scaffold and differing in the degree of saturation of the pyridine ring, oxidation at C10, 1-phenylethynyl at C1 and 1H-indol-3-yl fragments at C10, as well as a few small substituents at C6 and C8, were synthesized starting from 1,2,3,4-tetrahydro-2-methylchromeno[3,2-c]pyridin-10-ones (1,2,3,4-THCP-10-ones, 1) or 2,3-dihydro-2-methyl-1H-chromeno[3,2-c]pyridines (2,3-DHPCs, 2). The newly synthesized compounds were tested as inhibitors of the human isoforms of monoamine oxidase (MAO A and B) and cholinesterase (AChE and BChE), and the following main SARs were inferred: (i) The 2,3-DHCP derivatives 2 inhibit MAO A (IC50 about 1 µM) preferentially; (ii) the 1,2,3,4-THCP-10-one 3a, bearing the phenylethynyl fragment at C1, returned as a potent MAO B inhibitor (IC50 0.51 µM) and moderate inhibitor of both ChEs (IC50s 7-8 µM); (iii) the 1H-indol-3-yl fragment at C10 slightly increases the MAO B inhibition potency, with the analog 6c achieving MAO B IC50 of 3.51 µM. The MAO B inhibitor 3a deserves further pharmacological studies as a remedy in the symptomatic treatment of Parkinson's disease and neuroprotectant for Alzheimer's disease. Besides the established neuroprotective effects of MAO inhibitors, the role of MAOs in tumor insurgence and progression has been recently reported. Herein, antiproliferative assays with breast (MCF-7), colon (HCT116) and cisplatin-resistant ovarian (SK-OV-3) tumor cells revealed that the 10-indolyl-bearing 2,3,4,10-THCP analog 6c exerts anti-tumor activity with IC50s in the range 4.83-11.3 µM.

Cluster of resistance-inducing genes in MCF-7 cells by estrogen, insulin, methotrexate and tamoxifen extracted via NMF.

Breast cancer has become a leading cause of death for women as the economy has grown and the number of women in the labor force has increased. Several biomarkers with diagnostic, prognostic, and therapeutic implications for breast cancer have been identified in studies, leading to therapeutic advances. Resistance, on the other hand, is one of clinical practice's limitations. In this paper, we use Nonnegative Matrix Factorization to automatically extract two gene signatures from gene expression profiles of wild-type and resistance MCF-7 cells, which were then investigated further using pathways analysis and proved useful in relating resistance pathways to breast cancer regardless of the stimulus that caused it. A few extracted genes (including MAOA, IL4I1, RRM2, DUT, NME4, and SUMO3) represent new elements in the functional network for resistance in MCF-7 ER+ breast cancer. As a result of this research, a better understanding of how resistance occurs or the pathways that contribute to it may allow more effective therapies to be developed.

Colorectal cancer in Crohn's disease evaluated with genes belonging to fibroblasts of the intestinal mucosa selected by NMF.

Crohn's disease (CD) is a type of chronic, inflammatory bowel disease (IBD) which affects any part of the gastrointestinal tract. This study aims to understand the mechanism which activate mucosal fibroblasts in the microenvironment of the colon in CD and colorectal carcinomas and to extract fibroblasts phenotypes via a novel framework based on non-negative factorization of matrix (NMF). The results identify a fibroblast phenotype characterized by intense pro-inflammatory activity ensured by the presence of genes belonging to the APOBEC1 family, such as APOBEC3F and APOBEC3G. These results demonstrated that there is a difference in fibroblast response in producing a pro-tumorigenic effect in CD. The different activation mechanisms could represent useful biomarkers in controlling CD development without generalizing its significance as IBD.

Analysis of fibroblast genes selected by NMF to reveal the potential crosstalk between ulcerative colitis and colorectal cancer.

Patients with ulcerative colitis (UC) have an increased risk of developing colorectal cancer (CRC). The CRC risk extent raises with increasing age, duration of symptoms, severity of inflammation and dysplasia. CRC is a complex multi-stage process and associated with UC represents 2% of all colon cancers. With the aim of clarifying some aspects of the evolution of UC towards CRC, we characterized the phenotype of fibroblasts present in the mucosa of subjects affected by UC to verify whether they can contribute to the genesis of a microenvironment favorable to tumor transformation. The fibroblast phenotype was obtained with the help of transcriptome analysis adopting a novel framework based on Nonnegative Matrix Factorization (NMF) which automatically extracts a limited number of genes from fibroblast gene expression profiles of patients with UC and CRC. These genes may be considered possible candidates in generating a permissive microenvironment for the evolution of disease under study.

Reductive domino reaction to access chromeno[2,3-c]isoquinoline-5-amines with antiproliferative activities against human tumor cells.

An interaction of homophthalonitrile with salicylaldehydes proceeds as a novel domino reaction and results in the formation of nineteen 12H-chromeno[2,3-c]isoquinoline-5-amine derivatives. Four new bonds and two cycles are forged in a single synthetic operation, employing cheap and eco-friendly ammonium formate, acting both as a catalyst and a reducing agent. The in vitro cytotoxicity tests revealed antiproliferative activities against five human tumor cell lines, including the cisplatin-resistant ovarian carcinoma one (A2780cp8), with inhibitory potency data (IC50) in the low micromolar range in most cases. Molecular docking calculations and fluorescence quenching studies revealed possible binding properties with DNA of the active compounds.

Novel Antiproliferative Biphenyl Nicotinamide: NMR Metabolomic Study of its Effect on the MCF-7 Cell in Comparison with Cisplatin and Vinblastine.

A 1H-NMR-based metabolomic study was performed on MCF-7 cell lines treated with a novel nicotinamide derivative (DT-8) in comparison with two drugs characterized by a well-established mechanism of action, namely the DNA-metalating drug cisplatin (cis-diamminedichloridoplatinum(II), CDDP) and the antimitotic drug vinblastine (vinblastine, VIN). The effects of the three compounds, each one at the concentration corresponding to the IC50 value, were investigated, with respect to the controls (K), by the 1H-NMR of cells lysates and multivariate analysis (MVA) of the spectroscopic data. Relevant differences were found in the metabolic profiles of the different treatments with respect to the controls. A large overlap of the metabolic profiles in DT-8 vs. K and VIN vs. K suggests a similar biological response and mechanism of action, significantly diverse with respect to CDDP. On the other hand, DT8 seems to act by disorganizing the mitotic spindle and ultimately blocking the cell division, through a mechanism implying methionine depletion and/or S-adenosylmethionine (SAM) limitation.

An NMF-Based Methodology for Selecting Biomarkers in the Landscape of Genes of Heterogeneous Cancer-Associated Fibroblast Populations.

The rapid development of high-performance technologies has greatly promoted studies of molecular oncology producing large amounts of data. Even if these data are publicly available, they need to be processed and studied to extract information useful to better understand mechanisms of pathogenesis of complex diseases, such as tumors. In this article, we illustrated a procedure for mining biologically meaningful biomarkers from microarray datasets of different tumor histotypes. The proposed methodology allows to automatically identify a subset of potentially informative genes from microarray data matrices, which differs either in the number of rows (genes) and of columns (patients). The methodology integrates nonnegative matrix factorization method, a functional enrichment analysis web tool with a properly designed gene extraction procedure to allow the analysis of omics input data with different row size. The proposed methodology has been used to mine microarray of solid tumors of different embryonic origin to verify the presence of common genes characterizing the heterogeneity of cancer-associated fibroblasts. These automatically extracted biomarkers could be used to suggest appropriate therapies to inactivate the state of active fibroblasts, thus avoiding their action on tumor progression.

Translational impact of novel widely pharmacological characterized mofezolac-derived COX-1 inhibitors combined with bortezomib on human multiple myeloma cell lines viability.

A set of novel diarylisoxazoles has been projected using mofezolac (1) as a lead compound to investigate structure-inhibitory activity relationships of new compounds and the cyclooxygenases (COXs) catalytic activity. Mofezolac was chosen because is the most potent and selective reversible COX-1 inhibitor [COX-1 IC50 = 0.0079 µM and COX-2 IC50 > 50 µM, with a selectivity index (SI) in favor of COX-1 higher than 6300]. Seventeen new compounds were synthesized in fair to good yields and evaluated for their COXs inhibitory activity and selectivity. SIs ranged between 1 and higher than 1190.3,4-Bis(4-methoxyphenyl)-5-vinylisoxazole (22) has the highest SI with COX-1 IC50 = 0.042 µM and COX-2 IC50 > 50 µM. 1 and 22 were superior to aspirin in inhibiting platelet aggregation (IC50 = 0.45, 0.63 and 1.11 µM, respectively) in human platelet rich plasma (hPRP) assay. They did not induce blood coagulation and hemolysis, and are neither genotoxic nor mutagen. 1 and 22 slightly increase bortezomib cytotoxic effect on multiple myeloma (MM) cell lines (NCI-H929 and RPMI-8226) and affects MM cell cycle and apoptosis when co-administered with the proteasome inhibitor bortezomib, a drug clinically used to treat plasma cell neoplasms including MM. In addition, structure-based binding mode of 1 and 22, through Fingerprints for Ligands and Proteins (FLAG) calculation, allowed to explain the one order of magnitude difference between COX-1 IC50 values of the two compounds. Specifically, the higher inhibitory potency seems due to the formation of a H-bond between COX-1 S530 and the carboxyl, present in 1 and absent in 22.

Improving knowledge on the activation of bone marrow fibroblasts in MGUS and MM disease through the automatic extraction of genes via a nonnegative matrix factorization approach on gene expression profiles.

BACKGROUND: Multiple myeloma (MM) is a cancer of terminally differentiated plasma that is part of a spectrum of blood diseases. The role of the micro-environment is crucial for MM clonal evolution. METHODS: This paper describes the analysis carried out on a limited number of genes automatically extracted by a nonnegative matrix factorization (NMF) based approach from gene expression profiles of bone marrow fibroblasts of patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. RESULTS: Automatic exploration through NMF, combined with a motivated post-processing procedure and a pathways analysis of extracted genes, allowed to infer that a functional switch is required to lead fibroblasts to acquire pro-tumorigenic activity in the progression of the disease from MGUS to MM. CONCLUSION: The extracted biologically relevant genes may be representative of the considered clinical conditions and may contribute to a deeper understanding of tumor behavior.

A New Class of 1-Aryl-5,6-dihydropyrrolo[2,1-a]isoquinoline Derivatives as Reversers of P-Glycoprotein-Mediated Multidrug Resistance in Tumor Cells.

A number of aza-heterocyclic compounds, which share the 5,6-dihydropyrrolo[2,1-a]isoquinoline (DHPIQ) scaffold with members of the lamellarin alkaloid family, were synthesized and evaluated for their ability to reverse in vitro multidrug resistance in cancer cells through inhibition of P-glycoprotein (P-gp) and/or multidrug-resistance-associated protein 1. Most of the investigated DHPIQ compounds proved to be selective P-gp modulators, and the most potent modulator, 8,9-diethoxy-1-(3,4-diethoxyphenyl)-3-(furan-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carbaldehyde, attained sub-micromolar inhibitory potency (IC50 : 0.19 µm). Schiff bases prepared by the condensation of some 1-aryl-DHPIQ aldehydes with p-aminophenol also proved to be of some interest, and one of them, 4-((1-(4-fluorophenyl)-5,6-dihydro-8,9-dimethoxypyrrolo[2,1-a]isoquinolin-2-yl)methyleneamino)phenol, had an IC50 value of 1.01 µm. In drug combination assays in multidrug-resistant cells, some DHPIQ compounds, at nontoxic concentrations, significantly increased the cytotoxicity of doxorubicin in a concentration-dependent manner. Studies of structure-activity relationships and investigation of the chemical stability of Schiff bases provided physicochemical information useful for molecular optimization of lamellarin-like cytotoxic drugs active toward chemoresistant tumors as well as nontoxic reversers of P-gp-mediated multidrug resistance in tumor cells.

Effect of mofezolac-galactose distance in conjugates targeting cyclooxygenase (COX)-1 and CNS GLUT-1 carrier.

Neuroinflammation is the earliest stage of several neurological and neurodegenerative diseases. In the case of neurodegenerative disorders, it takes place about 15-20 years before the appearance of specific neurodegenerative clinical symptoms. Constitutive microglial COX-1 is one of the pro-inflammatory players of the neuroinflammation. Novel compounds 3, 14 and 15 (Galmof0, Galmof5 and Galmof11, respectively) were projected, and their synthetic methodologies developed, by linking by an ester bond, directly or through a C5 or C11 unit linker the highly selective COX-1 inhibitor mofezolac (COXs selectivity index > 6000) to galactose in order to obtain substances capable to cross blood-brain barrier (BBB) and control the CNS inflammatory response. 3, 14 and 15 (Galmofs) were prepared in good to fair yields. Galmof0 (3) was found to be a selective COX-1 inhibitor (COX-1 IC50 = 0.27 µM and COX-2 IC50 = 3.1 µM, selectivity index = 11.5), chemically and metabolically stable, and capable to cross Caco-2 cell monolayer, resembling BBB, probing that its transport is GLUT-1-mediated. Furthermore, Galmof0 (3) powerfully inhibits PGE2 release higher than mofezolac (1) in LPS-stimulated mouse BV2 microglial cell line, a worldwide recognized neuroinflammation model. In addition, Fingerprints for Ligands and Proteins (FLAP) was used to explain the different binding interactions of Galmofs with the COX-1 active site.

Investigating Structural Requirements for the Antiproliferative Activity of Biphenyl Nicotinamides.

A number of trimethoxybenzoic acid anilides, previously studied as permeability glycoprotein (P-gp) modulators, were screened with the aim of identifying new anticancer agents. One of these compounds, which showed antiproliferative activity against resistant MCF-7 cell line, was selected as the hit structure. Replacement of the trimethoxybenzoyl moiety with a nicotinoyl group, in order to overcome solubility issues, led to a new series of N-biphenyl nicotinoyl anilides, among which a nitro derivative, N-(3',5'-difluoro-3-nitro-[1,1'-biphenyl]-4-yl)nicotinamide (3), displayed antiproliferative activity against MCF-7 and MDA-MB-231 cells in the nanomolar range. The search for a bioisostere of the nitro group led to nitrile analogue N-(3-cyano-4'-fluoro-[1,1'-biphenyl]-4-yl)nicotinamide (36), which shows a strong increase in activity against MCF-7 and MDA-MB-231 cells. Compound 36 induced a dose-dependent accumulation of G2 - and M-phase MCF-7 cell populations, and a decrease in S-phase cells. Relative to vinblastine, a well-known potent antimitotic agent, compound 36 also induced G1 -phase arrest at low doses (20-40 nm), but did not inhibit in vitro tubulin polymerization.

Effect of cisplatin containing liposomes formulated by unsaturated chain-containing lipids on gynecological tumor cells.

Gynecological tumors are major therapeutic areas of platinum-based anticancer drugs. Here, we report the characterization and in vitro biological assays of cisplatin-containing Egg L-α-phosphatidylcholine liposomes with different amounts of cholesterol. Dynamic light scattering estimated sizes of all obtained liposomes in the 100 nm range that are suitable for in vivo use. On the basis of these data and of the drug loading values, the best formulation has been selected. Stability and drug release properties of platinum-containing liposomes have been verified in serum. The growth inhibitory effects of both liposomal and free drug in a panel of ovarian and breast human cancer cell lines, characterized by a different drug sensitivity, give comparable or better results with respect to free cisplatin drug.

Novel targeting of phospho-cMET overcomes drug resistance and induces antitumor activity in multiple myeloma.

PURPOSE: The aim of the study was to verify the hypothesis that the cMet oncogene is implicated in chemio- and novel drug resistance in multiple myeloma. EXPERIMENTAL DESIGN: We have evaluated the expression levels of cMET/phospho-cMET (p-cMET) and the activity of the novel selective p-cMET inhibitor (SU11274) in multiple myeloma cells, either sensitive (RPMI-8226 and MM.1S) or resistant (R5 and MM.1R) to anti-multiple myeloma drugs, in primary plasma cells and in multiple myeloma xenograft models. RESULTS: We found that resistant R5 and MM.1R cells presented with higher cMET phosphorylation, thus leading to constitutive activation of cMET-dependent signaling pathways. R5 cells exhibited a higher susceptibility to the SU11274 inhibitory effects on viability, proliferation, chemotaxis, adhesion, and to its apoptogenic effects. SU11274 was able to revert drug resistance in R5 cells. R5 but not RPMI-8226 cells displayed cMET-dependent activation of mitogen-activated protein kinase pathway. The cMET and p-cMET expression was higher on plasma cells from patients with multiple myeloma at relapse or on drug resistance than on those from patients at diagnosis, complete/partial remission, or from patients with monoclonal gammopathy of unknown significance. Viability, chemotaxis, adhesion to fibronectin or paired bone marrow stromal cells of plasma cells from relapsed or resistant patients was markedly inhibited by SU11274. Importantly, SU11274 showed higher therapeutic activity in R5- than in RPMI-8226-induced plasmocytomas. In R5 tumors, it caused apoptosis and necrosis and reverted bortezomib resistance. CONCLUSION: Our findings suggest that the cMET pathway is constitutively activated in relapsed and resistant multiple myeloma where it may also be responsible for induction of drug resistance, thus providing the preclinical rationale for targeting cMET in patients with relapsed/refractory multiple myeloma.

Platinum complexes can inhibit matrix metalloproteinase activity: platinum-diethyl[(methylsulfinyl)methyl]phosphonate complexes as inhibitors of matrix metalloproteinases 2, 3, 9, and 12.

Platinum complexes able to inhibit matrix metalloproteinases (MMPs) through a noncompetitive mechanism are reported for the first time in this study. [PtCl2(SMP)] and [Pt(dimethylmalonato)(SMP)], characterized by the bisphosphonate-analogue ligand diethyl[(methylsulfinyl)methyl]phosphonate (SMP), are slight inhibitors of MMP-2 (IC50 = 258 +/- 38 and 123 +/- 14 microM, respectively) but markedly inhibit MMP-9 (IC50 = 35.5 +/- 6 and 17 +/- 4 microM), MMP-3 (IC50 = 5.3 +/- 2.9 and 4.4 +/- 2.2 microM), and MMP-12 (IC50 = 10.8 +/- 3 and 6.2 +/- 1.8 microM). In contrast, cisplatin, carboplatin, and the SMP ligand are inactive, and the bisphosphonate clodronate shows a broad-spectrum inhibitory activity in the high micromolar range (mean IC50 > 200 microM). These results, along with mechanistic investigations (DNA interaction and tumor cell growth inhibition), demonstrate that ligand modifications of platinum compounds can be exploited to target also biological substrates distinct from DNA.

Sterically hindered complexes of platinum(II) with planar heterocyclic nitrogen donors. A novel complex with 1-methyl-cytosine has a spectrum of activity different from cisplatin and is able of overcoming acquired cisplatin resistance.

A very interesting series of water soluble platinum compounds violating some of the classical structure-activity relationships, but still showing antitumor activity, was reported by Hollis and collaborators some 25 years ago [L.S. Hollis, A.R. Amundsenm, E.W. Stern. J. Med. Chem. 32 (1989) 128-136]. The compounds, having formula [PtClA(2)L](+) (A(2)=two monodentate or a bidentate amine, L=a secondary or tertiary amine or a N-donor heterocycle), were characterized by a positive charge and three non-labile N-donor ligands. We have extended the investigation to analogous compounds in which 2,9-dimethyl-1,10-phenanthroline has taken the place of the A(2) ligand(s) and L is 2-picoline (1), 6-amino-2-picoline (2), or 1-methyl-cytosine (3). The X-ray analysis of 2 has revealed a bow-like distortion of the phenanthroline plane, a sloping of the phenanthroline plane with respect to the coordination plane, and an overall shielding of the metallic core by the ortho substituents of the phenanthroline and pyridine ligands. In vitro grow inhibition assays have been performed on the most water soluble complex 3. The results indicate that this complex is characterized by a potent growth inhibitory activity with mean IC(50) value (in a panel of 11 human tumor cell lines) of 1.1 microM to be compared with a mean value of 3.8 microM for cisplatin. The same compound also appears to completely overcome the acquired cisplatin resistance stemming from reduced uptake or a multifocal mechanism, thus pointing to a mechanism of action distinctly different from that of cisplatin.

Differential processing of antitumour-active and antitumour-inactive trans platinum compounds by SKOV-3 ovarian cancer cells.

In order to compare the mechanistic properties of the antitumour-active trans platinum complex trans-[PtCl(2){Z-HN=C(OMe)Me}(NH(3))] (trans-Z) and of the antitumour-inactive isomer of cisplatin trans-[PtCl(2)(NH(3))(2)] (trans-DDP), the differential processing of the two compounds by SKOV-3 ovarian cancer cells has been investigated. trans-Z and trans-DDP enter cells with the same efficacy, but trans-Z shows a two-fold higher affinity for cellular DNA. The treatment with trans-DDP IC(50) determines an initial and transient cytostatic effect, paralleled by a moderate increase of apoptosis and by sequential and reversible arrests in S and G(2)/M phases of cell-cycle. In contrast, trans-Z IC(50) determines an initial cytotoxic effect, a more persistent and marked increase of apoptosis, and a more marked and prolonged arrest in S and G(2)/M phases of the cell-cycle. Treatment-induced gene expression modifications indicate that phenotypic effects of trans-DDP are driven by an initial and transient up-regulation of some genes related to cell-cycle checkpoint and arrest networks, whereas the more dramatic phenotypic effects of trans-Z are driven by a persistent up-regulation of more numerous genes involved in cell-cycle checkpoint and arrest networks, and in genome stability and DNA repair. Therefore, molecular and cellular events have been identified which are produced by trans-Z but not by trans-DDP, and which likely represent the mechanistic basis of antitumour activity of trans-Z in the SKOV-3 system.