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Antitumor Drugs (antitumor + drug)
Selected AbstractsMethionine Can Favor DNA Platination by trans -Coordinated Platinum Antitumor Drugs,ANGEWANDTE CHEMIE, Issue 45 2009Chan Li Schneller ans Ziel: Die Bindung von Methionin an trans -koordinierte Platinkomplexe führt zu einer drastisch beschleunigten Komplexierung mit DNA (siehe Schema). Platin-Methionin-Spezies wurden auch als Zwischenstufen in einem Zellsystem gebildet und könnten eine wichtige Rolle im Wirkmechanismus von trans -Komplexen spielen. [source] Microwave-Assisted "Green" Synthesis of 2-Alkyl/Arylbenzothiazoles in One Pot: A Facile Approach to Antitumor Drugs.CHEMINFORM, Issue 12 2007Sukanta Kamila Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Carbonyl reductase 1 as a novel target of (,)-epigallocatechin gallate against hepatocellular carcinoma,HEPATOLOGY, Issue 2 2010Weixue Huang Human carbonyl reductase 1 (CBR1) converts the antitumor drug and anthracycline daunorubicin (DNR) into the alcohol metabolite daunorubicinol (DNROL) with significantly reduced antitumor activity and cardiotoxicity, and this limits the clinical use of DNR. Inhibition of CBR1 can thus increase the efficacy and decrease the toxicity of DNR. Here we report that (,)-epigallocatechin gallate (EGCG) from green tea is a promising inhibitor of CBR1. EGCG directly interacts with CBR1 and acts as a noncompetitive inhibitor with respect to the cofactor reduced nicotinamide adenine dinucleotide phosphate and the substrate isatin. The inhibition is dependent on the pH, and the gallate moiety of EGCG is required for activity. Molecular modeling has revealed that EGCG occupies the active site of CBR1. Furthermore, EGCG specifically enhanced the antitumor activity of DNR against hepatocellular carcinoma SMMC7721 cells expressing high levels of CBR1 and corresponding xenografts. We also demonstrated that EGCG could overcome the resistance to DNR by Hep3B cells stably expressing CBR1 but not by RNA interference of CBR1-HepG2 cells. The level of the metabolite DNROL was negatively correlated with that of EGCG in the cell extracts. Finally, EGCG decreased the cardiotoxicity of DNR in a human carcinoma xenograft model with both SMMC7721 and Hep3B cells in mice. Conclusion: These results strongly suggest that EGCG can inhibit CBR1 activity and enhance the effectiveness and decrease the cardiotoxicity of the anticancer drug DNR. These findings also indicate that a combination of EGCG and DNR might represent a novel approach for hepatocellular carcinoma therapy or chemoprevention. (HEPATOLOGY 2010;) [source] Mechanisms involved in hydroxycamptothecin-induced apoptosis of gastric cancer cellsJOURNAL OF DIGESTIVE DISEASES, Issue 1 2002Shui Ping TU OBJECTIVE: Hydroxycamptothecin (HCPT) is a unique antitumor drug that acts directly on topoisomerase I and inhibits its activity. However, the mechanism of HCPT-induced apoptosis is unclear. In the present study, the mechanism of HCPT-induced apoptosis in gastric cancer cells was investigated by detecting the expression of p53, c - myc, bcl-2, bcl-xl and bcl-xs genes in gastric cancer cells. METHODS: Apoptosis of gastric cancer cells (SGC-7901, MKN-45) was determined by terminal deoxyribonucleotidyl transferase-mediated dUTP, digoxigenin nick-end labeling (TUNEL) and flow cytometry. The mRNA and protein levels of the p53, c-myc, bcl-2, bcl-xl and bcl-xs genes were tested by reverse transcription,polymerase chain reaction analysis and immunocytochemical stain, respectively. RESULTS: Hydroxycamptothecin may induce apoptosis in different differentiated gastric cancer cells. The effect of HCPT-induced apoptosis on gastric cancer cells was dependent on the dose of HCPT used and the time of exposure to HCPT. Both SGC-7901 and MKN-45 cells manifested some morphological features of apoptosis after 12 h exposure to HCPT, including cell shrinkage, nuclear condensation, DNA fragmentation and formation of apoptotic bodies. Some typical subdiploid peaks before the G0/G1 phase were observed. The apoptotic rates induced by 10 ,g/mL HCPT in SGC-7901 and MKN-45 cells were 21.88 and 12.34%, respectively. The mRNA and protein levels of p53 and bcl-2 were downregulated after treatment with HCPT in SGC-7901 cells. However, the c-myc, bcl-xl and bcl-xs protein levels were unchanged in SGC-7901 cells. In MKN-45 cells, the mRNA and protein levels of p53 increased after treatment with HCPT, whereas the protein levels of bcl-2, c-myc, bcl-xl and bcl-xs remained unchanged. CONCLUSIONS: Our results indicate that HCPT-induced apoptosis in gastric cancer cells may be regulated through modulation of the expression of p53 and bcl-2 genes. [source] Liquid chromatographic assay for the cyclic depsipeptide aplidine, a new marine antitumor drug, in whole blood using derivatization with trans -4,-hydrazino-2-stilbazoleBIOMEDICAL CHROMATOGRAPHY, Issue 1 2004Rolf W. Sparidans Abstract A sensitive bio-analytical assay for the depsipeptide aplidine in plasma has been modi,ed and tested for human whole blood samples. The adapted method is based on reversed-phase liquid chromatography and ,uorescence detection of the trans -4,-hydrazino-2-stilbazole derivative of the analyte. Aplidine is isolated from the matrix by solid-phase extraction on an octadecyl modi,ed silica stationary phase. After evaporation of the acetone eluate, the derivatization with the hydrazino reagent is performed in a water,acetonitrile mixture at pH = 4. The reaction mixture is injected directly into the chromatograph and the analyte is quanti,ed by ,uorescence detection at 410 and 560 nm for excitation and emission, respectively. The method has been validated in the 2,100 ng/mL range, with 2 ng/mL being the lower limit of quanti,cation. Precision and accuracy both meet the current requirements for a bioanalytical assay. The stability of aplidine in whole blood at ambient temperature and at 37°C is limited; recoveries in the range 60,85% were observed after 7 h. Further, adequate stability of aplidine in plasma at ,80 and ,20°C for 35 months could now be demonstrated. Copyright © 2003 John Wiley & Sons, Ltd. [source] Cyclooxygenase-2 inhibitor celecoxib augments chemotherapeutic drug-induced apoptosis by enhancing activation of caspase-3 and -9 in prostate cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2005Devendra S. Dandekar Abstract Many tumors constitutively express high levels of the inducible form of proinflammatory enzyme, cyclooxygenase-2 (COX-2). Increased COX-2 expression is associated with tumor cell resistance to many cytotoxic chemotherapy drugs. Furthermore, increased resistance to cytotoxic antitumor drugs is also known to be dependent on associated stromal cells in many tumors. We investigated whether prostate tumor-associated stromal cells, marrow-derived osteoblasts, affect cytotoxicity of 2 antitumor drugs, COL-3 and docetaxel (TXTR), and whether it is dependent on COX-2 activity. We further examined whether inhibiting the activity of COX-2 negate the stroma-induced decrease in drug sensitivity in tumor cells. COX-2-specific inhibitor celecoxib (CXB) was used to inhibit COX-2 activity and associated alteration in cell death signaling was investigated. Coculturing PC-3ML cells with osteoblasts decreased the cytotoxicity of the tested antitumor drugs and was associated with increased COX-2 activity in PC-3ML cells. A significant decrease in drug-induced PGE2 increase and an increase in cytotoxicity were observed when cells were treated with COL-3 or TXTR combined with CXB. Cytotoxicity of single or combination treatment increased apoptosis, which was associated with caspase-3 and -9 activation, PARP cleavage, increased BAD protein, but decreased protein levels of XIAP and BCL- xL. Oral administration of CXB (40 mg/kg) to mice with PC-3ML tumors for 42 days increased tumor latency, decreased tumor growth and enhanced tumor control with COL-3 or TXTR. Overall, a synergistic enhancement of antitumor activity in combination treatment was observed in vitro and an additive effect in vivo. These observations suggest a potential clinical use of combined dosing of COX-2 inhibitors and cytotoxic drugs at lower, nontoxic dose than currently used to treat advanced prostate cancer. © 2005 Wiley-Liss, Inc. [source] Determination of binding constants and stoichiometries for platinum anticancer drugs and serum transport proteins by capillary electrophoresis using the Hummel-Dreyer methodJOURNAL OF SEPARATION SCIENCE, JSS, Issue 2 2005Alexander V. Rudnev Abstract A CE method has been developed to evidence and quantitatively characterize the interaction between platinum-based antitumor drugs and human serum proteins. This method is a variant of affinity CE modified regarding both experimental setup and data treatment so as to measure the peaks (or vacancies) that correspond to the bound drug when it slowly binds to the protein. Using the formalism of the Hummel-Dreyer method and cisplatin and oxaliplatin as test compounds, a protocol for determining albumin and transferrin binding constants and stoichiometries, including (and distinguished by) 48 hours of incubation of the reaction mixture, was elaborated. Relative affinities of drugs toward different proteins in aqueous solution at physiological pH, chloride concentration, and temperature were compared in terms of overall binding constants and numbers of drug molecules attached to the protein. The results indicate that both platinum drugs bind to albumin more strongly than to transferrin, supporting the concept that the albumin fraction is a major drug supply route for chemotherapeutical needs. From a comparison with the binding parameters measured previously for cisplatin by other methods, conclusions were drawn about the validity of CE as a simple and convenient method for assaying protein-drug reactions with slow kinetics. [source] Synthesis, Cytotoxicity, and Apoptosis Induction in Human Tumor Cells by Geiparvarin AnaloguesCHEMISTRY & BIODIVERSITY, Issue 9 2004Giampietro Viola A series of geiparvarin analogues modified on the unsaturated alkenyloxy bridge, where a H-atom replaced the 3,-Me group, were synthesized and evaluated against a panel of human tumor cell lines in vitro. These compounds demonstrated a stronger increase in growth inhibitory activity when compared to the parent compound geiparvarin (8). In particular, the activity increased even further in the series of demethylated compounds when a Me substituent in the coumarin moiety is introduced. On the contrary, the same modifications exerted on the parent compound led to an activity reduction. Interestingly, the new derivatives proved to be fully inhibitory to drug-resistant cell lines, thus suggesting that they are not subject to the pump-mediating efflux of antitumor drugs. On the basis of their cytotoxic profiles, the most-active compounds were selected for further biological evaluation. The extracellular acidification rate by the new geiparvarin analogues was measured with the CytosensorTM microphysiometer. The new derivatives significantly increased the acidification rate during the 24,48,h of incubation in a concentration-dependent manner. Cell-cycle analysis, evaluated by flow cytometry, revealed a strong apoptotic induction by these compounds confirmed by DNA laddering and observation by electron microscopy. Interestingly, the apoptotic pathway did not appear to be mediated by the activation of caspase-3. [source] The Gatekeeper: Friend or Foe in Identifying the Next Generation of Kinase InhibitorsCHEMMEDCHEM, Issue 11 2006Olaf Prien Dr. Fighting cancer: The next generation of small-molecule kinase inhibitors might be designed against distinct mutational forms of certain kinases. Current antitumor drugs display remarkable efficacy, but relapse is frequently observed during treatment due to acquired mutation. The gatekeeper plays an important role in this context, and compounds such as 1 that interact with it might be a starting point to design future inhibitors. [source] | |||||||||||||