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Further studies on the mechanism of intracellular induction of active oxygen species and selective oncolysis with metal oxide nanoparticles (NPs), as well as the discussion of alternative mechanisms of the NPs impact on tumor cells, are needed to introduce nanotechnologies into antitumor therapy. The paper concerns the inhibition of oxidation processes in tumor cells under the action of manganese oxide-based NPs (size 10–60 nm) as the mechanism of a tumor cell death. When manganese (II) hydroxide-based NPs enter the cells, they are oxidized with oxygen to Mn4+ compounds; the oxidation processes being blocked in the tumor cells. Hence, the MnO NPs cytotoxicity can be due to the possible direct reduction of O2 in the presence of manganese compounds in the cells. [ABSTRACT FROM AUTHOR]

The optimal conditions of sorption of Ag(NH3)2+ ions under the dynamic conditions by the Transcarpathian clinoptilolite (Western Ukraine) were: temperature of clinoptilolite thermal pre-treatment—150 °C; sorbent grain diameter—0.20 to 0.31 mm; flow rate of Ag(I) solution with the concentration of 1.0 µg mL−1 through the sorbent—3 mL min−1; concentration of NH3—0.05 mol L−1; pH 10.8. The sorptive capacity value of clinoptilolite under the optimal conditions is 4.1 mg of Ag per 1 g of zeolite. The best desorbent of Ag(I) from clinoptilolite is 3.5 M HNO3. This desorbent removes 100% of sorbed Ag(I). The solid-phase extraction procedure with clinoptilolite was used to pre-concentrate trace amounts of silver ions in water-ammonia solutions to be finally determined by the atomic absorption method. The proposed method allows to pre-concentrate trace amounts of Ag(NH3)2+ from solutions with a high content of Cl− ions and other macro-components of natural waters. The linearity of the proposed method was evaluated in the range of 1.2–400 ng mL−1 with the detection limit 0.4 ng mL−1. The intact clinoptilolite and its composites with silver were used for the treatment of human tumor cells (HepG2, HCT116, КB3-1 lines) and pseudonormal cells (human HEК293 cells and murine J774.2 cells). Silver doping increased cytotoxicity of the intact clinoptilolite, while thermal (500 °C, 2.5 h) pretreatment of silver-containing clinoptilolite decreased its cytotoxicity. These effects depended on tissue origin of the treated cells. Ag(NH3)2+-zeolite was more toxic comparing with zeolite treated with aqueous NH3 for all studied mammalian cells. [ABSTRACT FROM AUTHOR]

Cage-like amines with norbornane and adamantane frameworks were studied in a versatile, convenient one-pot green synthetic experiment for pyrimidine core annulation via cleavage of a 1H-tetrazole ring. The transannulation was performed without an excess of the reagents and solvent under optimized conditions. As a result, 11 new thieno[2,3-dpyrimidinones with bulky substituents were obtained in high yields without the need of further purification and with excellent selectivity of the process. The introduced сage-like framework is regarded as a bioisostere of the 2-arylamino moiety. Preliminary screening of the biological activity was performed and 2-{[1-(bicyclo[2.2.1]heptan-2-yl)ethyl]amino}-5,6,7,8-tetrahydro[1]benzothieno[2,3-dpyrimidin-4(3H)-one demonstrated high toxicity toward human leukemia HL-60, cervix carcinoma KB3-1, and colon carcinoma HCT116 cells that correlates well with the results obtained previously for the activity of the compounds with benzylamino substituents. [ABSTRACT FROM AUTHOR]

We studied cytotoxic activity of new tetranitrosyl NO-generating binuclear iron—sulfur [Fe—S] complexes containing different ligands in the molecule against tumor cells in vitro. Cytotoxic activity of the most active complex with cysteamine (CysAm) was compared with that of antitumor drug cisplatin. Caspase activation and morphological changes in cells were visualized by fluorescence microscopy. Fluorescence of active caspases 3 and 7 and changes in nuclear DNA in cells in the presence of CyAm were detected by using fluorochrome-labeled inhibitor of caspases (FLICA) and Hoechst and propidium iodide reagents. Similar cytotoxic activities of CyAm and cisplatin were demonstrated in various human tumor cell lines of different histogenesis. Therefore, a new class of NO-donating [Fe—S] complexes can provide the base of potential drugs for chemotherapy with a new mechanism of action. [ABSTRACT FROM AUTHOR]

Abstract Background Tumour radiosensitivity would be particularly useful in optimizing the radiation dose during radiotherapy. The aim of the current study was to evaluate the potential value of phosphorylated H2AX (γH2AX) and ATM (pATM) in assessing 12C6+ radiosensitivity of tumour cells. Methods Human cervical carcinoma HeLa cells, hepatoma HepG2 cells, and mucoepidermoid carcinoma MEC-1 cells were irradiated with different doses of 12C6+. The survival fraction was assayed with clonogenic survival method and the foci of γH2AX and pATM was visualized using immunocytochemical methods. Flow cytometry was used to assay γH2AX, pATM and the cell cycle. Results The survival fraction decreased immediately in dose-dependent manner, but in turn, significantly increased during 24 h after 12C6+ irradiation. Both γH2AX and pATM foci accumulated linearly with doses and with a maximum induction at 0.5 h for γH2AX and 0.5 or 4 h for pATM, respectively, and a fraction foci kept for 24 h. The expression of γH2AX and pATM was in relation to cell cycle. The G0/G1 phase cells had the highest expression of γH2AX after 0.5 h irradiation and then decreased to a lower level at 24 h after irradiation. An obvious increase of pATM in G2/M phase was shown after 24 h of 2 and 4 Gy irradiation. The significant G2/M phase arrest was shown. There was a close relationship between the clonogenic survival and γH2AX and pATM expression both in timing and dose in response to 12C6+. Conclusions The rate of γH2AX and pATM formation and loss may be an important factor in the response of cells to 12C6+. pATM and γH2AX are effective radiation biomarkers in assessing the radiosensitivity of 12C6+ in human tumor cells.

Three new metal-organic coordination complexes, namely [Cu(4,4′-bipy)2(NCS)2]n (I), [Cu(HCOO)2(4,4′—bipy)] (II), and [Cu(2,2′-bipy)2]2(V6O17) (III) (4,4′-bipy and 2,2′-bipy = 4,4′-bipyridine and 2,2′-bipyridine, respectively) are successfully prepared by using two similar pyridine ligands with different orientations of N atoms under different reaction conditions (slow volatilization for I, solvothermal for II and III). Their structures and compositions are characterized by both single crystal X-ray diffraction and elemental analysis. Additionally, the newly synthesized compounds are evaluated to identify the molecular characteristics contributing to their cytotoxicity. They are tested against three human multiple myeloma cells (NCI-H929, MM1S, and MM1R) with the MTT assay. [ABSTRACT FROM AUTHOR]

C‑X‑C motif chemokine 12 (CXCL12) promotes metastasis of several tumors by affecting cell migration and invasion via its receptors, C‑X‑C chemokine receptor type (CXCR)4 and CXCR7. Current therapeutic approaches focus on the selective inactivation of either CXCR4 or CXCR7 in patients with cancer. Alternative strategies may emerge from the analysis of downstream events that mediate the migratory effects of CXCL12 in cancer cells. While CXCR4 activates cell signaling through both G proteins and arrestins, CXCR7 is believed to preferentially signal through arrestins. The present study analyzed the CXCL12‑dependent chemotaxis of A549, C33A, DLD‑1, MDA‑MB‑231 and PC‑3 cells, in which either the activity of G proteins, EGFR or Src kinase was inhibited pharmacologically or the expression of arrestins was inhibited by RNA interference. The results demonstrated that CXCL12‑induced migration of A549, C33A, DLD‑1, MDA‑MB‑231 and PC‑3 cells was attenuated by the Gα i/o ‑inhibitor pertussis toxin (PTX), but was unaffected by small interfering RNA‑mediated gene silencing of β‑arrestin1/2. In particular, the sensitivity of DLD‑1 migration to PTX was unexpected, as it is solely dependent on the non‑classical chemokine receptor, CXCR7. Furthermore, chemotactic responses to CXCL12 were additionally prevented by inhibiting EGFR activity via AG1478 and Src kinase activity via Src inhibitor‑1. In conclusion, the results of the present study suggest that G protein‑ and Src‑dependent transactivation of EGFR is a common mechanism through which CXCL12‑bound CXCR4 and/or CXCR7 control cancer cell migration and metastasis. These findings highlight EGFR as a potential therapeutic target that interferes with CXCL12‑induced cancer expansion.

Multidrug resistance (MDR) of tumors occurs when tumor cells exhibit reduced sensitivity to a large number of unrelated drugs. The molecular mechanism of MDR commonly involves overexpression of the plasma membrane drug efflux pump P-glycoprotein (P-gp). Overexpression of P-gp may be induced by the selection and/or adaptation of cells during exposure to chemotherapeutic drugs, referred to as acquired P-gp-mediated MDR. This study aimed to establish a P-gp quantification method by Ultra Performance Liquid Chromatography and Tandem Mass Spectrometry (UPLC-MS/MS) to better understand the regulation of P-gp expression and its relationship with the level of drug resistance. Absolute P-gp expression was determined in the human tumor cells MCF-7, HepG-2, and SMMC-7721 and their corresponding drug-resistant subclones MCF-7/ADMs, MCF-7/MXs, MCF-7/MTXs, HepG-2/ADMs, HepG-2/MXs, HepG-2/MTXs, SMMC-7721/ADMs, SMMC-7721/MXs and SMMC-7721/MTXs. A unique 10-mer tryptic peptide (IATEAIENFR) of P-gp was synthesized for developing the quantitative UPLC-MS/MS method with the stable isotope labeled signature peptide IATEAI ( 13 C 6, 15 N 1 ) ENFR as the internal standard (IS). The detection signal was linear in the range of 0.1–100 ng mL −1 . Quality control (QC) data showed that the within-run and between-run precision (%RSD) and accuracy (%RE) conformed to acceptable criteria of ±15% for the calibration standards and QCs (±20% at the LLOQ). The UPLC-MS/MS method was first applied to quantify P-gp in HepG-2 and SMMC-7721 cells and their drug-resistant subclones. The results confirmed that P-gp expression in most drug-resistant subclones increase significantly compared to parental tumor cells but varied among different types of drugs or tumor cells. This outcome was then compared with published reports and discrepancy was observed in HepG2 cell lines mainly due to different sample types and samples sources. Additionally, P-gp mRNA results ascertained that overexpression of P-gp in subclones was not only regulated by MDR1. The linear correlation between RI and logarithm-transformed P-gp expression was moderate or high and statistically significantly different in subclones, except for SMMC-7721/ADMs. The present study is the first to demonstrate the quantitative relationship between RI and P-gp expression by linear regression modeling and expanded the number of efflux transporters related to MDR quantifiable by LC-MS/MS to better understand the biological significance of effluent transporter expression. [ABSTRACT FROM AUTHOR]

Metallic nanoparticles have emerged as an important class of nanomaterials for a wide range of industrial and medical applications. Because of the intensive commercial applications, risk assessment of these nanoparticles is of great importance. In the present study, the human hepatoma and leukemia cells were used to characterize the apoptotic effects of silver nanoparticles (4.7 and 42 nm) and gold nanoparticles (30 nm). Apoptotic cells were identified by chromatin condensation and flow cytometry analysis, using Annexin V/PI, TUNEL and caspase activation assays. Flow cytometry analysis showed that the three metallic nanoparticles induced apoptotic cell death in a concentration and time dependent-manner. Moreover, the three nanoparticles induced activation of caspase-3 and -7 in hepatoma and leukemia cells. Apoptotic effects were stronger after exposure of both cell lines with 4.7 nm silver nanoparticles than those obtained with 42 nm silver and 30 nm gold nanoparticles. In conclusion, silver (4.7 and 42 nm) and gold (30 nm) nanoparticles induced apoptosis in hepatoma and leukemia cells via the caspase dependent pathway. The smaller silver nanoparticles (4.7 nm) had a greater ability to induce apoptosis in both cell lines. [ABSTRACT FROM AUTHOR]

Diterpenoid alkaloids are isolated from plants of the genera Aconitum, Delphinium, and Garrya (Ranunculaceae) and classified according to their chemical structures as C18-, C19- or C20-diterpenoid alkaloids. The extreme toxicity of certain compounds, e.g., aconitine, has prompted a thorough investigation of how structural features affect their bioactivities. Therefore, natural diterpenoid alkaloids and semi-synthetic alkaloid derivatives were evaluated for cytotoxic effects against human tumor cells [A549 (lung carcinoma), DU145 (prostate carcinoma), MDA-MB-231 (triple-negative breast cancer), MCF-7 (estrogen receptor-positive, HER2-negative breast cancer), KB (identical to cervical carcinoma HeLa derived AV-3 cell line), and multidrug-resistant (MDR) subline KB-VIN]. Among the tested alkaloids, C19-diterpenoid (e.g., lipojesaconitine, delcosine and delpheline derivatives) and C20-diterpenoid (e.g., kobusine and pseudokobusine derivatives) alkaloids exhibited significant cytotoxic activity and, thus, provide promising new leads for further development as antitumor agents. Notably, several diterpenoid alkaloids were more potent against MDR subline KB-VIN cells than the parental drug-sensitive KB cells.

In order to study the possibility of using a metal complex of the porphyrin series, FeIIICl-tetraphenylporphyrin (FeClTPP), and its polymeric form as antitumor agents for binary catalytic therapy, the technology of preparation of polymer particles containing FeClTPP was developed for the first time. The experimental data obtained allow one to conclude that the developed form using a copolymer of lactic and glycolic acids (ratio of monomer units 50: 50), ultrasonic homogenization, D-mannitol (as a cryoprotectant), the active agent to polymer ratio 1: 10, and the organic to aqueous phase ratio 1: 10 and 1: 20, respectively, has the optimal physicochemical parameters. It was found that the free substance of FeClTPP and polymer particles with FeClTPP are active against MCF-7 (human breast adenocarcinoma), HeLa (human cervical carcinoma), and MG-63 (human osteosarcoma) cell lines. The polymer particles containing FeClTFP exhibit the highest cytotoxic effect against MCF-7 lines as compared to the free substance. The results of the study indicate that both the substance of tetraphenylporphyrin and its resulting polymeric form are promising for the treatment of tumor diseases in binary catalytic therapy. [ABSTRACT FROM AUTHOR]

By the use of thermodynamics formalism of irreversible processes, complex systems theory and systems biology, it is derived a relationship between the production of entropy per unit time, the fractal dimension and the tumor growth rate for human tumors cells. The thermodynamics framework developed demonstrates that, the dissipation function is a Landau potential and also the Lyapunov function of the dynamical behavior of tumor growth, which indicate the directional character, stability and robustness of the phenomenon. The entropy production rate may be used as a quantitative index of the metastatic potential of tumors. The current theoretical framework will hopefully provide a better understanding of cancer and contribute to improvements in cancer treatment. [ABSTRACT FROM AUTHOR]

Background Tumour radiosensitivity would be particularly useful in optimizing the radiation dose during radiotherapy. The aim of the current study was to evaluate the potential value of phosphorylated H2AX (γH2AX) and ATM (pATM) in assessing 12C6+ radiosensitivity of tumour cells. Methods Human cervical carcinoma HeLa cells, hepatoma HepG2 cells, and mucoepidermoid carcinoma MEC-1 cells were irradiated with different doses of 12C6+. The survival fraction was assayed with clonogenic survival method and the foci of γH2AX and pATM was visualized using immunocytochemical methods. Flow cytometry was used to assay γH2AX, pATM and the cell cycle. Results The survival fraction decreased immediately in dose-dependent manner, but in turn, significantly increased during 24 h after 12C6+ irradiation. Both γH2AX and pATM foci accumulated linearly with doses and with a maximum induction at 0.5 h for γH2AX and 0.5 or 4 h for pATM, respectively, and a fraction foci kept for 24 h. The expression of γH2AX and pATM was in relation to cell cycle. The G0/G1 phase cells had the highest expression of γH2AX after 0.5 h irradiation and then decreased to a lower level at 24 h after irradiation. An obvious increase of pATM in G2/M phase was shown after 24 h of 2 and 4 Gy irradiation. The significant G2/M phase arrest was shown. There was a close relationship between the clonogenic survival and γH2AX and pATM expression both in timing and dose in response to 12C6+. Conclusions The rate of γH2AX and pATM formation and loss may be an important factor in the response of cells to 12C6+. pATM and γH2AX are effective radiation biomarkers in assessing the radiosensitivity of 12C6+ in human tumor cells. [ABSTRACT FROM AUTHOR]

Application of special systems for drug delivery into target cells might be useful for overcoming several problems in treatment of dangerous diseases. These are: consequences of nonspecific negative effects of drugs towards healthy cells, low sensitivity of cancer cells to anticancer drugs used in doses that are non-toxic for the organism, resistance of tumor cells to anticancer drugs and of the pathogenic microorga­nisms to the antibiotics. Here we studied the efficiency of application of novel nanoscale drug delivery system in tumor cell lines, including drug-resistant ones. The polyethylene glycol (PEG)-modified polymeric carrier VEP-GMA used in this study, was synthesized at the Department of Organic Chemistry of Lviv National Polytechnic University. We compared the effect of free doxorubicin and of this anticancer drug immobilized on the polymeric carrier, towards human tumor cells. It was found that such immobilization of doxorubicin significantly enhanced the cytotoxic action of this drug towards human lung carcinoma A549 cells, human colorectal carcinoma HCT116 cells, human breast carcinoma MCF-7 cells and their doxorubicin-resistant MCF-7/ADR subline. The results of our studies demonstrated that using doxorubicin complex with novel polymeric nanoscale carrier VEP-GMA-PEG permitted reducing the active dose of doxorubicin in cancer cells at least 10 times, comparing with such dose of this anticancer drug used in free form. Since the antineoplastic effect of carrier-immobilized doxorubicin was maintained, these results suggest a potential reduction of negative side effects of the corresponding chemotherapy. It was shown that the uptake by tumor cells of the carrier- immobilized doxorubicin was significantly enhanced comparing with such uptake of free doxorubicin. Our data demonstrated that neither macropinocytosis, nor endocytosis can be responsible for the uptake of doxorubicin that is immobilized on the nanosized polymeric carrier. Our future experiments are focused on the improvement of characteristics of this carrier by means of its specific functionalization aimed at reaching its addressed action towards tumor cells in vitro and in vivo.

Pseudo-spectral approximations areconstructed for the model equations describing the populationkinetics of human tumor cells in vitro and their responses toradiotherapy or chemotherapy. These approximations are moreefficient than finite-difference approximations. The spectralaccuracy of the pseudo-spectral method allows us to resolve themodel with a much smaller number of spatial grid-points thanrequired for the finite-difference method to achieve comparableaccuracy. This is demonstrated by numerical experiments which show agood agreement between predicted and experimental data.

We studied cytotoxic activity of a new NO-releasing tetranitrosyl binuclear iron complex with cysteamine (CysAm) for human tumor cells, the relationship between the expression of O6-methylguanine-DNA methyltransferase (MGMT) and cell sensitivity to CysAm, and apoptosis-inducing capacity of this preparation. It was found that histogenetically different cell lines are characterized by different sensitivity to CysAm, and this parameter correlated with the basal level of MGMT. CysAm induced apoptosis via activation of caspases 3 and 7. These data suggest that CysAm can be considered as a potential antitumor agent, but definitive conclusions can be made after preclinical trials. [ABSTRACT FROM AUTHOR]

Crambescins are guanidine alkaloids firstly isolated in the early 90s from the encrusting Mediterranean sponge Crambe crambe (Schmidt, 1862) (Bondu et al., 2012, Laville et al., 2009, Berlinck et al., 1990). C. crambe derivatives are divided in two families named crambescins and crambescidins (Gerlinck et al., 1992). Although data on the bioactivity of these compounds is scarce, crambescidins have recognized cytotoxic, antifungal, antioxidant, antimicrobial and antiviral activities (Buscema and Van de Vyver, 1985, Jares-Erijman., 1998, Olszewski et al., 2004, Lazaro et al., 2006, Suna et al., 2007, AOKI et al., 2004). Recently we have carefully evaluated the cytotoxic activity of C816 over several human tumor cell types and characterized some of the cellular mechanisms responsible of the anti-proliferative effect of this compound on human liver-derived tumor cells (Rubiolo et al., 2013). Taking this into account, and to better understand the mechanism of action of crambescins and their potential as therapeutic agents, we made a comparative gene expression profiling of HepG2 cells after crambescin C1 (C1) and crambescin A1 (CA1) exposures. Results have shown that C1 induces genes involved in sterol and glucose metabolisms and metabolism involving growth factors. It also down regulates genes mainly involved in cell cycle control, DNA replication, recombination and repair, and drug metabolism. Flow cytometry assays revealed that C1 produces a G0/G1 arrest in HepG2 cell cycle progression. CA1 also down-regulates genes involved in cell cycle regulation, DNA recombination and pathways related to tumor cells proliferation with lower potency when compared to C1.

β- d -Glucopyranoside,(3β,12β,20E)-12,25-dihydroxydammar-20(22)-en-3-yl (pseudo-ginsenoside Rh2) and its 20Z-isomer were synthesized from ginsenoside Rh2 under a mild condition, via a simple three-step called acetylation, elimination–addition and saponification. In addition, their activities were evaluated by eight different human tumor cells, compared with ginsenoside Rh2 group. Results indicated that the reaction in the side chain might greatly enhance the anti-proliferative activity of ginsenosides. [ABSTRACT FROM AUTHOR]

Purpose: To review the results from previous studies aiming at the molecular characterization of circulating tumor cells (CTC), to specifically address the role of epithelial-mesenchymal-transition (EMT) and stemness features of CTC in their contribution to tumor progression and to summarize potential interference of CTC with the efficacy of radiotherapy. Conclusions: Detection of CTC has been reported for most epithelial tumors and has been associated with an increased risk of local and regional recurrence as well as the development of distant metastases. Given a causal relationship between the presence of CTC and tumor progression at the primary or distant sites, several distinct features have to be postulated for these cells: First, a change from an epithelial to a mesenchymal cell-like phenotype which should alleviate the disconnection of individual tumor cells from tight cell-to-cell junctions within the epithelial cell layer and endow single tumor cells with the capacity to migrate into blood vessels; secondly, the presence of stem-cell properties which contribute to the re-establishment of bulk tumor tissue at the primary or metastatic site upon tumor recurrence or distant progression, respectively. Indeed, EMT and stem-cell features were frequently observed in CTC and the phenotype of CTC was established as a stronger predictor of outcome than sole enumeration of CTC in a defined volume of blood. The exploitation of CTC above their use as prognostic marker is still a subject of many ongoing investigations as are the identification of suitable therapeutic targets for this small cell subpopulation. [ABSTRACT FROM AUTHOR]

Abstracts: Ethnopharmacological relevance: Himatanthus articulatus (Vahl) Woodson (Apocynaceae) is a tree occurring in the Amazon region. The local population uses its bark against to external tumors and cancer. Aim of the study: evaluated the antiproliferative activity of the crude extract and their fractions against human tumors cells. Materials and methods: the antiproliferative responses of the crude extract and their fractions were colorimetrically evaluated by sulforhodamine B (SRB) assay against HT-29 (colon adenocarcinoma); NCI-H460 (non-small cell lung carcinoma); MCF-7 (breast cancer); OVCAR-3 (ovarian adenocarcinoma) and RXF-393 (renal cell carcinoma) as well as against NIH-3T3 (mouse embryo fibroblast cell). Results: The cytotoxicity data from the crude extract allowed considering active only in the NCI-H460 cell line. However, the antiproliferative activity was much more pronounced at the chloroformic fraction in all cell lines tested. The butanolic fraction demonstrated activity against to HT-29, MCF-7, RXF-393 and OVCAR-3 cells. The ethyl acetate fraction demonstrated activity only in RXF-393 and the aqueous residue did not present antiproliferative effect. Conclusions: Through the popular use we find that the crude extracts of Himatanthus articulatus bark displayed weak cytotoxic. However, the butanolic fraction showed to be active only against to tumor cell lines while chloroformic fraction possesses high activity being similar to the positive control. Both fractions have been selected for future bio-guided fractionation and isolation of active compounds. [Copyright &y& Elsevier]

Purpose: We compared clonogenic survival in 27 human tumor cell lines that vary in genotype after low-dose-rate (LDR) or high-dose rate (HDR) irradiation. We measured susceptibility to LDR-induced redistribution in the cell cycle in eight of these cell lines. Methods and Materials: We measured clonogenic survival after up to 96 hours of LDR (0.25 Gy/h) irradiation. We compared these with clonogenic survival after HDR irradiation (50 Gy/h). Using flow cytometry, we measured LDR-induced redistribution as a function of time during LDR irradiation in eight of these cell lines. Results: Coefficients that describe clonogenic survival after both LDR and HDR irradiation segregate into four radiosensitivity groups that associate with cell genotype: mutant (mut)ATM, wild-type TP53, mutTP53, and an unidentified gene in radioresistant glioma cells. The LDR and HDR radiosensitivity correlates at lower doses (∼2 Gy HDR, ∼6 Gy LDR), but not at higher doses (HDR > 4 Gy; LDR > 6 Gy). The rate of LDR-induced loss of clonogenic survival changes at approximately 24 hours; wild-type TP53 cells become more resistant and mutTP53 cells become more sensitive. Redistribution induced by LDR irradiation also changes at approximately 24 hours. Conclusions: Radiosensitivity of human tumor cells to both LDR and HDR irradiation is genotype dependent. Analysis of coefficients that describe cellular radiosensitivity segregates 27 cell lines into four statistically distinct groups, each associating with specific genotypes. Changes in cellular radiosensitivity and redistribution in the cell cycle are strongly time dependent. Our data establish a genotype-dependent time-dependent model that predicts clonogenic survival, explains the inverse dose-rate effect, and suggests possible clinical applications. [Copyright &y& Elsevier]

Abstract: We previously observed that in yeast cisplatin activates different pathways accounting for stress response. Here, we investigated whether genes involved in yeast drug response were modulated by cisplatin in human tumor cell lines (A2780, IGROV-1, A431, U2-OS) including cisplatin-resistant sublines (A2780/BBR, IGROV-1/Pt1, A431/Pt and U2-OS/Pt). Factors and pathways involved in stress response (glutathione-S-transferase, proteasome, checkpoint control and recombinational repair) were increased by cisplatin in human tumor sensitive and resistant cells. Moreover, sensitization to cisplatin by pharmacologically targeting glutathione or proteasome was observed in sensitive and resistant cells. Interestingly, only in IGROV-1/Pt1 cells, in which cisplatin up-regulated HSP70 and HSP90, targeting of HSP90 resulted in sensitization of resistant cells, suggesting a protective role of stress response. In conclusion, the present findings support the potential relevance of interfering with heat shock protein response to increase cisplatin cytotoxicity in resistant cells. Overall, pathways activated by cisplatin in human tumor cells appear cell-type specific, at least in part reflecting the stress response observed in yeast. [Copyright &y& Elsevier]

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS, RAF, mitogen/extracellular signal-regulated kinase, extracellular signal-regulated kinase and mitogen-activated protein kinase pathway. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation, it may provide possible diagnostic and therapeutic targets in human malignant tumors. We analyzed exon 15 of the BRAF gene for mutations in 58 lung, 12 breast, six kidney, 14 cervical, four endometrial and 10 ovarian carcinoma cell lines by PCR-SSCP and direct sequencing. The T1796A transversion was found in one (2.9%) of 34 small cell lung carcinoma and one (8.3%) of 12 breast carcinoma cell lines, resulting in a valine-to-glutamate substitution at residue 599 (V599E). One (4.2%) of 24 non-small cell lung carcinoma cell line showed the C1786G transversion, leading to a leucine-to-valine substitution at residue 596 (L596V). No BRAF point mutations were found in any of the other cell lines examined. Our present results suggest that BRAF may not be a frequent target of mutations involved in the pathogenesis of human lung, breast, kidney, cervical, endometrial and ovarian carcinomas. [ABSTRACT FROM AUTHOR]

Purpose: We have previously shown in a limited number of tumor cell lines derived from only two histological types that clonogenic survival patterns fall into radiosensitivity groups, each group associating with a specific genotype. We now establish a global, quantitative description of human tumor cells based on genotype-dependent radiosensitivity across histological types. Methods: We measure clonogenic radiosensitivity in 39 human tumor cell lines that vary in histological type (colorectal, glioblastoma, prostate, bladder, teratoma, breast, melanoma and liver) and expression of several genes purported to influence radiosensitivity: ATM (ataxia telangiectasia mutated), TP53 (tumor protein 53), CDKN1A (cyclin-dependent kinase N1A), 14-3-3σ (an isoform of the 14-3-3 gene) and DNA mismatch repair genes . For each survival curve we use the linear-quadratic model and a linear-linear model to extract multiple coefficients and seek correlation across histological types. Results: Under one-parameter analysis, survival rate at circa 2 Gy, cell lines segregate into two major, statistically-significant groups that correlate with TP53 status (wildtype versus mutant). Under two-parameter analysis, cell lines segregate into four radiosensitivity groups based on correlations between response at lower doses (ca. 2 Gy) and a component of response to higher doses (>4 Gy). Conclusions: Intrinsic radiosensitivity of 39 human tumor cell lines segregate into distinct genotype-dependent radiosensitivity groups that associate with mutATM, wtTP53, mutTP53, and an unidentified factor in some glioblastoma cells. Genotype-dependent radiosensitivity underlies histology-dependent variation in radiosensitivity. Our analysis establishes a quantitative overview of radiosensitivity that can predict possible response of human tumors to radiotherapy protocols. [ABSTRACT FROM AUTHOR]

Abstract: Paclitaxel and etanidazole are hypoxic radiosensitizers that exhibit cytotoxic action at different mechanisms. The poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles containing paclitaxel, etanidazole and paclitaxel+etanidazole were prepared by o/w and w/o/w emulsification-solvent evaporation method. The morphology of the nanoparticles was investigated by scanning electron microscope (SEM). The drug encapsulation efficiency (EE) and release profile in vitro were measured by high-performance liquid chromatography (HPLC). The cellular uptake of nanoparticles for the human breast carcinoma cells (MCF-7) and the human carcinoma cervicis cells (HeLa) was evaluated by transmission electronic microscopy and fluorescence microscopy. Cell viability was determined by the ability of single cell to form colonies in vitro. The prepared nanoparticles were spherical shape with size between 80 and 150nm. The EE was higher for paclitaxel and lower for etanidazole. The drug release was controlled over time. The cellular uptake of nanoparticles was observed. Co-culture of the two tumor cell lines with drug-loaded nanoparticles demonstrated that released drug effectively sensitized hypoxic tumor cells to radiation. The radiosensitization of paclitaxel+etanidazole nanoparticles was more significant than that of single drug-loaded nanoparticles. [Copyright &y& Elsevier]

Abstract: The efficacy of anthracycline based anticancer drugs is limited by pleiotropic drug resistance of tumor cells. Aiming at the design of anthracyclinone congeners capable of circumventing drug resistance, we synthesized naphthoindole containing derivatives of tryptophan and tryptamine. In doing so we adapted the traditional, gramine based approach for tryptophan and tryptamine synthesis. The most potent new compound, 3-(2-aminoethyl)-4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione (16), was equally cytotoxic (IC50 within low micromolar concentrations) for human K562 leukemia and HCT116 colon carcinoma cell lines and their isogenic sublines with genetically defined determinants of altered drug response, that is, the expression of the multidrug transporter P-glycoprotein and loss of pro-apoptotic p53. Each of these mechanisms conferred resistance to the reference drug adriamycin. In contrast, naphthotryptamine 16, although less potent than adriamycin, was equally toxic for wild type cell lines and drug resistant counterparts. Moreover, at 3–5μM 16 inhibited topoisomerase I in vitro. Thus, our novel naphthoindole based derivative of tryptamine gained new activities important for anticancer therapy, namely, suppression of topoisomerase I and the ability to overcome resistance mediated by P-glycoprotein expression and p53 dysfunction. [Copyright &y& Elsevier]

The goal of the paper is to compute efficiently solutions for model equations that have the potential to describe the growth of human tumor cells and their responses to radiotherapy or chemotherapy. The mathematical model involves four unknown functions of two independent variables: the time variable t and dimensionless relative DNA content x. The unknown functions can be thought of as the number density of cells and are solutions of a system of four partial differential equations. We construct solutions of the system, which allow us to observe the number density of cells for different t and x values. We present results of our experiments which simulate population kinetics of human cancer cells in vitro. Our results show a correspondence between predicted and experimental data. [ABSTRACT FROM AUTHOR]

The influence of inhibitors of different lipoxygenases (LOX) on the growth of human tumor cells with different profiles of synthesized eicosanoids was studied. The studied LOX inhibitors had virtually no influence on the growth of A549 cells actively synthesizing cyclooxygenase and lipoxygenase metabolites of arachidonic acid (AA). The inhibitor of 12-LOX, baicalein, significantly inhibited proliferation in cultures of A431 epidermoid carcinoma cells with a characteristic domination of the major lipoxygenase metabolite of AA, 12-hydroxyeicosatetraenoic acid (12-HETE), in the profile of synthesized eicosanoids and reduced to 70% the incorporation of [3H]thymidine into DNA. Treatment of these cultures with 12-HETE virtually restored the growth potential of the tumor cells. The findings suggest that the lipoxygenase metabolite of AA, 12-HETE, is a growth-limiting factor for tumor cells of definite type. [ABSTRACT FROM AUTHOR]

Abstract: Cytotoxic and antiproliferative effects of halothane, isoflurane, and sevoflurane in anesthetic doses on human colon carcinoma (Caco-2), larynx carcinoma (HEp-2), pancreatic carcinoma cells (MIA PaCa-2), poorly differentiated cells from lymph node metastasis of colon carcinoma (SW-620), and normal fibroblasts were investigated. Cells were exposed to anesthetic gas mixture consisting of O2: N2O (35:60 vol.%), halothane (1.5 vol.%) or isoflurane (2.0 vol.%) or sevoflurane (3.0 vol.%), and CO2 (5 vol.%), for 2, 4, and 6 h. Cytotoxicity of anesthetics was analyzed by validated tetrazolium dye assay MTT test. All anesthetics expressed cytotoxic effects on treated tumor cells in time and cell line dependent manner. Growth suppression in cells exposed to halothane was enhanced in HEp-2 (to 67.7%), Caco-2 (to 76.3%), and SW620 cells (to 80.9%), and was minimal in normal fibroblasts (to 89.4%). Antiproliferative activity of halothane was measured via radioactive precursors incorporation assay. In Caco-2 cells treated by halothane, decrease in DNA synthesis (52.4%, p =0.001), RNA synthesis (39.2%, p <0.001), and protein synthesis (19.2%, p =0.004) was observed. In HEp-2 cells, DNA and RNA syntheses were decreased to 72.5% and 79.9%, whereas protein synthesis was 14.0% of control (p <0.001). In SW620 cells, protein synthesis after 4 h was 24.4% (p =0.007). A DNA fragmentation was observed in Caco-2 and MIA PaCa-2 cells. Exposition of phosphatidylserine on outer lipid bilayer plasma membrane of tumor cell treated by halothane proved apoptosis as mode of cell death. [Copyright &y& Elsevier]

We have recently demonstrated that overexpression of dihydrodiol dehydrogenase (DDH) in human ovarian carcinoma cells (2008/C13*) is associated with cisplatin and carboplatin resistance. Furthermore, we have also elucidated that transfection of parental human ovarian carcinoma cells with a full-length DDH1 cDNA leads to induction of resistance to the platinum drugs. The development of cisplatin resistance in the transfected cells is associated with an increase in DDH enzyme activity. Previous studies have identified several different mechanisms for development of cisplatin resistance, including altered DNA repair capacity, increased GSH-based detoxification, and increased metallothionein content. However, none of these mechanisms has been found to be universally associated with the development of cisplatin resistance in tumor cells from different tissue sources. The present study was undertaken to assess whether overexpression of DDH1 or DDH2 (in human ovarian, cervical, lung and germ-cell tumor cell lines) could specifically induce resistance to the platinum drugs in these cell lines. We demonstrated a ubiquitous association of increased expression of DDH1 or DDH2 (as judged by increased enzyme activity in transfected clones) with development of resistance to cisplatin and carboplatin. Moreover, we also found a lack of cross-resistance to anticancer drugs that have a different mode of action including paclitaxel, vincristine, doxorubicin hydrochloride, and melphalan. Although at present it is not clear how DDH is involved in platinum drug resistance, the identification of this gene as a causal factor in a series of cell lines derived from different tumors with different intracellular compositions indicates the importance of deciphering this hitherto undefined pathway which can produce resistance to platinum drugs. [ABSTRACT FROM AUTHOR]

The genes of the glutathione S-transferase (GST) family encode enzymes that appear to be critical in cellular protection against the cytotoxic effects, whereas p53 is a tumor suppressor gene. Despite a large number of studies on germline polymorphisms of GSTM1, GSTT1 and p53 genes, there have been very few reports on genotyping of these genes in human malignant tumor cells. In this study, we investigated GSTM1, GSTT1 and p53 codon 72 polymorphisms in a variety of human tumor cell lines originating from different organs to clarify tissuespedic polymorphic frequency of these genes in human solid tumors. The GSTM1 and GSTT1 genetic polymorphisms were evaluated using multiplex PCR techniques and PCR-RFLP analysis was conducted to identify p53 codon 72 genotypes. Gene expression of GSTM1 or GSTT1 was detected by RT-PCR in the cells with respective present genotype for each. Polymorphisms of p53 codon 72 detected by PCR-RFLP were also confirmed using SSCP and sequence analyses. GSTM1 and GSTT1 genotypes were various in 104 cell lines examined. Null GSTM1 genotype was dominant in small cell lung, kidney and ovarian carcinoma cells, whereas null GSTT1 genotype was dominant in cervical and endometrial Carcinoma cells. GSTM1 and GSTT1 genotypes in ovarian carcinoma cells were quite similar to those in small cell lung carcinoma cells. Polymorphic frequency of p53 codon 72 was also various among the cells, however, the Pro allele was found in only 1 of 6 kidney, 14 cervical and 4 endometrial carcinoma cell lines. There was a significant difference in GSTM1 and p53 genotypes between 34 small cell and 24 non small cell lung carcinoma cells (P < 0.01). Combined study on the distribution of GSTM1, GSTT1 and p53 genotypes revealed that null GSTM1 genotype was associated with the Arg allele of p53 codon 72 in 58 lung carcinoma cells and null GSTT1 genotype was associated with the Pro/Pro homozygote in 104 tumor cell lines examined. This is the first study examining GSTM1, GSTT1 and p53 codon 72 polymorphisms in a variety of human solid tumor cells and suggesting that polymorphic frequency of these genes may be tissue- and organ-specific. The molecular interaction between GST gene defects and p53 codon 72 genotype in the development of human malignant tumors should be further investigated. [ABSTRACT FROM AUTHOR]

Purpose: To determine cross-resistance to anti-tumor treatments in 2′,2′difluorodeoxycytidine (dFdC, gemcitabine)-resistant human tumor cells.Methods and Materials: Human lung carcinoma cells SW-1573 (SWp) were made resistant to dFdC (SWg). Sensitivity to cisplatin (cDDP), paclitaxel, 5-fluorouracil (5-FU), methotrexate (MTX), cytarabine (ara-C), and dFdC was measured by a proliferation assay. Radiosensitivity and radioenhancement by dFdC of this cell panel and the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000 were determined by clonogenic assay. Bivariate flowcytometry was performed to study cell cycle changes.Results: In the SWg, a complete deoxycytidine kinase (dCK) deficiency was found on mRNA and protein level. This was accompanied by a 10-fold decrease in dCK activity which resulted in the >1000-fold resistance to dFdC. Sensitivity to other anti-tumor drugs was not altered, except for ara-C (>100-fold resistance). Radiosensitivity was not altered in the dFdC-resistant cell lines SWg and AG6000. High concentrations (50–100 μM dFdC) induced radioenhancement in the dFdC-resistant cell lines similar to the radioenhancement obtained at lower concentrations (10 nM dFdC) in the parental lines. An early S-phase arrest was found in all cell lines after dFdC treatment where radioenhancement was achieved.Conclusions: In the dFdC-resistant lung tumor cell line SWg, the deficiency in dCK is related to the resistance to dFdC and ara-C. No cross-resistance was observed to other anti-tumor drugs used for the treatment in lung cancer. Sensitivity to ionizing radiation was not altered in two different dFdC-resistant cell lines. Resistance to dFdC does not eliminate the ability of dFdC to sensitize cells to radiation. [Copyright &y& Elsevier]

The role of individual eicosanoids of the arachidonic acid (AA) cascade in the growth control of A549 human lung adenocarcinoma cells has been studied. Cyclooxygenase and lipoxygenase metabolites of [14C]AA incorporated were actively synthesized in the cultures of tumor cells with full confluence unaccomplished. In such cultures inhibitors of AA metabolism (indomethacin and esculetin) and also a lipoxygenase metabolite of AA, 15-hydroxyeicosatetraenoic acid (15-HETE), significantly suppressed the incorporation of [3H]thymidine and biosynthesis of prostaglandin E2(PGE2). Other lipoxygenase metabolites of AA (5-HETE and 12-HETE) had no effect on these parameters. The basic fibroblast growth factor (bFGF) had practically no affect on the growth of A549 cells and the PGE2 production in cultures with 5% fetal calf serum (FCS); however, in the presence of 0.5% FCS this factor significantly increased the number of tumor cells. The growth-stimulating effect of bFGF was completely abolished by a cyclooxygenase inhibitor indomethacin. The data suggest a key role of PGE2 in the growth control of A549 cells with an active synthesis of cyclooxygenase and lipoxygenase metabolites of AA, its importance in realization of the mitogenic effect of bFGF, and specific features of 15-HETE as a down-regulator of the PGE2-dependent proliferation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel potent antineoplastic azolidinone-indole hybrid molecules. • 5-Fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1 H -indole-2-carboxylic acid methyl ester (3a) affected cell membranes of HepG2 cells. • Cytotoxicity of 3a is related to the induction of apoptosis via caspase 3, PARP1 cleavage, Bax up-regulation and DNA damage. • Compound 3a did not affect the transition of G1/S phases in HepG2 cells. A series of novel indole-azolidinone hybrids has been synthesized via Knoevenagel reaction of 5-fluoro-3-formyl-1 H -indole-2-carboxylic acid methyl ester and some azolidinones differing in heteroatoms in positions 1, 2 and 4. Their anticancer activity in vitro was screened towards MCF-7 (breast cancer), HCT116 (colon cancer), HepG2 (hepatoma), HeLa (cervical cancer), A549 (lung cancer), WM793 (melanoma) and THP-1 (leukemia) cell lines, and a highly active 5-fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1 H -indole-2-carboxylic acid methyl ester (3a) was identified and subjected to in-depth investigation of cytotoxicity mechanisms. This compound was found to possess the highest cytotoxic action towards tumor cells comparing with the action of other derivatives (1 , 3b , 3c , 3d , 3e). Compound 3a exhibited toxicity toward MCF-7, HCT116, and A549, HepG2 cancer cells, while the non-malignant cells (human keratinocytes of HaCaT line and murine embryonic fibroblasts of Balb/c 3T3 line) possessed moderate sensitivity to it. The compound 3a induced apoptosis in studied tumor cells via caspase 3-, PARP1-, and Bax-dependent mechanisms; however, it did not affect the G1/S transition in HepG2 cells. The compound 3a impaired nuclear DNA in HepG2, HCT116, and MCF-7 cells without intercalating this biomolecule, but much less DNA damage events were induced by 3a in normal Balb/c 3T3 fibroblasts compared with HepG2 carcinoma cells. Thus, 5-fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1 H -indole-2-carboxylic acid methyl ester 3a was shown to trigger DNA damage and induce apoptosis of human tumor cells and it might be considered as an anticancer agent perspective for in-depth studies. [ABSTRACT FROM AUTHOR]

• Natural cytisine was used for transannulation of tetrazoles to thienopyrimidinones. • Solvent-free protocol allowed to obtain cytisine-thienopyrimidinones in high yields. • Single crystal X-ray diffraction and Hirshfeld surface analysis were performed. • Cytisine-thienopyrimidinones demonstrated high affinity to EGFR tyrosine kinase. • Primary anticancer assays were performed against sixty cancer cell lines. [Display omitted] For the first time, natural product Cytisine was successfully used as a reagent for thermal-activated transannulation of 1 H -tetrazoles and a series of cytisine-thienopyrimidinone conjugates were obtained in high yields (85-95%). Structures of conjugates were analysed by 1H and 13C NMR. Moreover, the structure of compound 3c was also proven by a single crystal X-ray diffraction analysis and intermolecular interactions were studied by the Hirshfeld surface analysis. The molecular docking studies and primary anticancer activity screening of selected synthesised conjugates have been performed. [ABSTRACT FROM AUTHOR]

Objective: Combination therapies are important in the treatment of many tumor types. This study was undertaken to find candidates for combination therapy with the novel topoisomerase I inhibitor topotecan. Methods: The cytotoxic effect of topotecan alone and in combination with five standard cytotoxic drugs was studied in 27 primary cultures of human tumor cells from patients with various diagnoses using the fluorometric microculture cytotoxicity assay (FMCA). The combinations were analysed according to the multiplicative concept of drug interaction. Results: The additive model was shown to be a better descriptor than the effect of the most effective agent (Dmax) for all drug combinations tested. Topotecan in combination with cisplatin (CisP) was the drug combination showing synergy in the highest percentage of samples (54%), followed by topotecan in combination with doxorubicin (Dox; 39%), etoposide (P16; 23%), paclitaxel in the formulation Taxol (22%) and cytarabine (AraC; 12%). The high percentage of synergistic interactions was especially pronounced in solid tumors. In 28% of the samples tested, drug sensitivity testing of only single drugs failed to predict response to the drugs in combination. Conclusion: Cisplatin and doxorubicin showed promising effects in combination with topotecan, and clinical trials with these combinations seem warranted. The results also indicate the value of testing drug combinations in in vitro drug sensitivity testing. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Cancer Research & Clinical Oncology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A reduced capacity for apoptosis induction is considered to play a significant role both in the development of malignancy and in tumor cell resistance to chemotherapeutic drugs. The Bcl-2 oncoprotein inhibits apoptosis induced by antitumor agents at a point downstream of drug-target interactions. Stable expression of Bcl-2 in the human epithelial tumor (HeLa) cell line results in inhibition of apoptosis following exposure to the topoisomerase II poison, etoposide. However, Bcl-2 is unable to enhance clonogenic survival as a result of alternate pathways to reproductive death induced by the drug. Purpose: The purpose of this study was to further investigate the role of Bcl-2 in human epithelial tumor cell drug resistance using 5-fluoro-2′-deoxyuridine, staurosporine, and doxorubicin, in addition to etoposide. Methods: The ability of Bcl-2 to enhance clonogenic cell survival was studied by colony-forming assays, while delay of cell death induction was assessed by trypan blue viability measurements. The proportion of apoptotic cells was measured by morphological criteria, as well as detection of apoptotic DNA fragmentation using the terminal deoxynucleotidyl transferase assay. Results: Despite profound inhibition to loss of plasma membrane integrity for all agents tested, Bcl-2 was only able to significantly increase clonogenic survival following exposure to 5-fluoro-2′-deoxyuridine and staurosporine, but not following exposure to etoposide or doxorubicin. Furthermore, the time-course of apoptosis induction following exposure of HeLa cells to equitoxic concentrations of staurosporine and etoposide was profoundly different. Conclusions: These results indicate that Bcl-2 enhances clonogenic survival of human epithelial tumor cells in an agent-specific fashion, which may be determined by the initial cytotoxic lesion induced by a particular drug. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine whether resistance to cisplatin [cis-diamminedichloroplatinum (II)] (CDDP) could be overcome by amphotericin B, cyclosporin A and aphidicolin in two sublines of human larynx carcinoma HEp2 cells. The sensitivity of parental and cisplatin-resistant CA3 and CK2 cells to amphotericin B, cyclosporin A and aphidicolin, and also the effects of these drugs (given in maximal nontoxic concentrations) on cisplatin sensitivity were determined by clonogenic survival assay. CA3 and CK2 cells were sensitive to amphotericin B, and resistant to cyclosporin A and aphidicolin, compared with their parental cells. Amphotericin B increased cisplatin toxicity 2-fold in CA3 cells and 2.7-fold in CK2 cells, while it had no effect in parental HEp2 cells. Cyclosporin A did not influence the sensitivity of examined cells to cisplatin. The sensitizing effect of aphidicolin was more obvious in cisplatin-resistant cells. Cisplatin toxicity was increased by aphidicolin: 1.5-fold in HEp2 cells, 2-fold in CA3 cells, and 1.9-fold in CK2 cells. Therefore, the resistance to cisplatin in human larynx carcinoma CA3 and CK2 cells can be partially reversed by amphotericin B and aphidicolin. [ABSTRACT FROM AUTHOR]

Exposing cells to adverse conditions usually elicits expression of stress-response (heat shock) proteins (srp). Here we show that hyperosmolar growth conditions do not uniformly affect srp expression in MCF-7 and HeLa S3 cells, derived from carcinoma of the breast and cervix, respectively. Thus, whereas srp 27 expression was increased in MCF-7, but not in HeLa S3, the opposite was the case with srp 72. On the other hand, hyperosmolality did not induce αB-crystallin or ubiquitin in either cell line. These findings show that srp expression by the human tumor cells studied is non-coordinate, suggesting that each srp is independently modulated. [ABSTRACT FROM AUTHOR]

We established a new complex three-dimensional in vitro model called artificial tumor (ArT), which simulates individual human solid tumors. In contrast to the generally used spheroid models consisting of tumor cells only, the model described in the present report is composed of both tumor cells and tumor stromal cells. We created ArTs as a replica of colon carcinomas, composed of colon carcinoma cells, colon fibro-blasts, and as supportive skeleton fibrous tissue from human colon. All cellular components were established from the same surgically obtained colon carcinoma specimen. The ArTs studied came from 4 types of colon carcinomas; mucinous, well, moderately and undifferentiated colon carcinomas. Among all types of colon carcinomas ArTs could be established with a high rate of success, i.e. 81 %. Cells growing for 5 days on the fibrous tissue under normal culture conditions formed tumors up to 2,000 μm in diameter. Morphological studies showed that tumor cells grown as ArTs maintained the individual characteristics of the original tumor; for example, a comparable heterogeneity in CEA expression and/or maintenance of the differentiation stage. Polarized tumor cells were linked with the tumor stroma-simulating structure by their basal cell membrane, and formed central lumina lined by the apical membranes of the tumor cells, a structure quite similar to the tissue architecture of colon carcinomas in vivo. Copyright © 1995 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Copyright of Archives of Oto-rhino-laryngology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Overexpression of the epidermal growth factor receptor (EGFR) has been observed in human breast tumors and is associated with poor prognosis in breast cancer patients. This would suggest that blocking the activity of the EGFR is a logical approach in the treatment of breast cancer. Three 20 mer phosphorothioate oligodeoxynucleotides were designed to target different regions of the human epidermal growth factor receptor (EGFR) mRNA. Several analogs of these oligodeoxynucleotides (the 2′ fluoro analog, the 2′ propoxy analog, and/or the 5 methyl cytosine analog) were also evaluated. We added these compounds to a human ovarian carcinoma cell line (SKOV3) and a human lung carcinoma line (A549), both of which overexpress the EGFR. All of these antisense oligonucleotides inhibited expression of the 10 kb EGFR mRNA (range: 22–97% inhibition) compared to a scrambled control oligonucleotide or an untreated control. Expression of the less prominent 5.6 kb EGFR mRNA band was also inhibited by all but two of the parent oligonucleotides. No inhibition of this 5.6 kb band was found with the control oligonucleotide. The reduction in the expression of EGFR mRNA by the three most potent antisense compounds was accompanied by a significant reduction of EGFR protein (90–98%) and in vitro growth inhibition of SKOV3 cells as compared to the control oligonucleotide. [ABSTRACT FROM AUTHOR]