bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3500: Nucleolytic processing of Topoisomerase 2 covalent complexes
Authors: Nitiss John L. , Bahmed Karim , Mishina Margarita , Berk Jeffrey , Nitiss Karin C. 
Published: February 2011

Abstract
The generation of elevated levels of enzyme: DNA covalent complexes is the key event in cell killing by many drugs targeting DNA topoisomerases. These agents, termed topoisomerase poisons generate protein linked DNA strand that block transcription and replication, leading to cell death. A critical step in the repair of topoisomerase mediated DNA damage is the removal of protein that is covalently attached to DNA. Several specialized repair enzymes, including Tdp1 (tyrosyl DNA phosphodiesterase I) and TTRAP (TRAF and TNF receptor-associated protein) can hydrolyze phosphotyrosyl: DNA linkages. We previously reported that yeast Tdp1 could hydrolyze 5′ as well as 3′ phosphotyrosyl linkages. Human Tdp1 can also hydrolyze 5′ phosphotyrosyl linkages, although the efficiency of the reaction with the human enzyme is much less than that seen with the yeast enzyme. Interestingly, the human enzyme processes adducts bearing a seven amino acid peptide linked to an oligonucleotide with greater efficiency than a 5′ biotin linked oligonucleotide, suggesting that the nature of the adduct at DNA ends influences Tdp1 reaction kinetics. We also used substrates derived from Top2 trapped covalent complexes to assess the ability of other DNA repair enzymes to remove peptides covalently bound to DNA. We found that the heterodimeric nuclease Slx1/Slx4 is able to remove Top2 peptides that are covalently bound to DNA. This result is consistent with our genetic data from yeast that a mutation in the subunit that includes the nuclease (Slx1) is hypersensitive to Top2 poisons, but not sensitive to other DNA damaging agents. Our results indicate that there are multiple pathways for repairing Top2 covalent complexes and suggest that the Slx1/Slx4 dependent pathway may be particularly relevant to repairing topoisomerase mediated damage at replication forks.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3500.
Abstract 3503: CCT241533 is a novel, potent and selective inhibitor of CHK2 and potentiates the cellular effects of PARP inhibitors
Authors: Anderson Victoria E. , Eve Paul D. , Walton Michael I. , Caldwell John J. , Pearl Laurence H. , Oliver Antony W. , Collins Ian , Garrett Michelle D. 
Published: February 2011

Abstract
CHK2 is a checkpoint kinase involved in the ATM-mediated response to double stranded DNA breaks (DSB). Detection of DSB by the MRE11-RAD50-NBS1 (MRN) complex leads to activation of ataxia telangiectasia mutated (ATM) kinase, which can then phosphorylate CHK2 on threonine 68. This facilitates CHK2 to dimerisation and autophosphorylation in trans at threonine 383/387, resulting in full activation and subsequent phosphorylation in cis at serine 516, a biomarker read out of CHK2 activation. Once activated, CHK2 phosphorylates a range of targets involved in DNA damage repair, cell cycle arrest and apoptosis.
It has been suggested that inhibitors of CHK2 may increase the efficacy of genotoxic cancer therapies. However, the evidence so far is inconsistent. We have therefore developed a CCT241533, a potent and selective inhibitor of CHK2, as a molecular tool and potential therapeutic agent (the structure will be disclosed in the presentation). The co-crystal structure of CCT241533 bound to the kinase domain of CHK2 confirms that the compound binds the ATP binding pocket. CCT241533 inhibits CHK2 with an IC50 of 3 nM and shows minimal inhibitory activity against a panel of known kinases at 1 μM, including CHK1 (IC50 = 245 nM). We show that CCT241533 blocks CHK2 activity in three human tumor cell lines (HT29, HeLa, MCF7) in which we have confirmed functional activation of CHK2. We also show that CCT241533 potentiates the growth inhibitory effect of two structurally distinct Poly (ADP-ribose) polymerase (PARP) inhibitors in p53 defective human cancer cells. We further demonstrate that this cellular effect correlates with inhibition of PARP inhibitor-mediated induction of CHK2 activity, as assessed by the phospho-serine 516 biomarker and CHK2 mobility shift. This adds strength to the conclusion that the potentiation between the two compounds is due to their effects on CHK2.
To summarize, we have developed a potent and selective CHK2 inhibitor and show, for the first time, potentiation between CHK2 inhibition and PARP inhibition.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3503.
Abstract 3515: Gefitinib-resistant cell line derived from PC-9 has high sensitivity to SN-38
Authors: Sakai Asao , Kimura Hideharu , Sone Takashi , Ohmori Tohru , Kasahara Kazuo , Fujimura Masaki 
Published: February 2011

Abstract
Most non-small cell lung cancer (NSCLC) tumors with EGFR mutations are responsive to EGFR tyrosine kinase inhibitors such as gefitinib. Preliminary experiments with PC-9/MET, a gefitinib resistant cell line derived from PC-9 showed a higher sensitivity to SN-38, which is an active metabolite of CPT-11, in comparison to parental PC-9. The mechanisms of the collateral sensitivity to SN-38 were investigated in the resistant cell line. The WST-1 assay showed that PC-9/MET was more sensitive, with an IC50 of 0.027 ± 0.014 μM, to SN-38 than that to PC-9 with an IC50 of 0.093 ± 0.049 μM. Topoisomerase-I (Topo-I) mRNA expression value in PC-9/MET to increase 9.2 times in comparison to that of PC-9. The Topo-I activity of PC-9/MET was higher than that of PC-9 and the Topo-I protein expression was also higher in PC-9/MET. PC-9/MET has a greater expression of MET in comparison to PC-9. The suppression of MET expression by an MET-specific siRNA resulted in a decrease in the Topo-I activity and Topo-I protein expression in PC-9/MET.
In conclusion, the Topo-I activity and protein expression in PC-9/MET is elevated via the mRNA expression, thus resulting in collateral sensitivity to SN-38. The MET over-expression in PC-9/MET may therefore be one of the mechanisms which cause an increase in the Topo-I activity and expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3515.
Abstract 3518: Preclinical pharmacology of the novel, potent & selective CHK1 inhibitor SAR-020106
Authors: Walton Michael I. , Eve Paul D. , Hayes Angela , Valenti Melanie , Brandon Alexis De Haven , Box Gary , Aherne G Wynne , Eccles Suzanne A. , Raynaud Florence I. , Williams David H. , Reader John C. , Collins Ian , Garrett Michelle D. 
Published: February 2011

Abstract
Genotoxic antitumor agents continue to be the mainstay of current cancer chemotherapy. These drugs cause DNA damage and activate numerous cell cycle checkpoints facilitating DNA repair and the maintenance of genomic integrity. Most human tumors lack functional p53 and consequently have compromized G1/S checkpoint control. This has led to the hypothesis that S and G2/M checkpoint abrogation may selectively enhance genotoxic cell killing in a p53 deficient background, as normal cells would be rescued at the G1/S checkpoint. CHK1 is a serine/threonine kinase associated with DNA damage linked S and G2/M checkpoint control. SAR-020106 (the structure will be shown on the poster) is an ATP competitive, potent and selective CHK1 inhibitor with an IC50 of 13.3nM on the isolated human enzyme. This compound abrogates an etoposide-induced G2 arrest with an IC50 of 55nM in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0 to 29-fold in a number of colon tumor lines in vitro and in a p53 dependent fashion. Biomarker studies have shown that SAR-020106 inhibits cytotoxic drug induced autophosphorylation of CHK1 at S296 and blocks phosphorylation of CDK1 at Y15 in a dose-dependent fashion both in vitro and in vivo. Cytotoxic drug combinations were associated with increased γH2AX and PARP cleavage consistent with SAR-020106 enhanced DNA damage and tumor cell death. Irinotecan and gemcitabine antitumor activity was enhanced by SAR-020106 in vivo with minimal toxicity. Orally bioavailable analogues of SAR-02106 are currently under development. In conclusion SAR-020106 represents a novel class of CHK1 inhibitors which can enhance antitumor activity with selected anticancer drugs in vivo and may therefore have clinical utility.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3518.
Abstract 3522: A Phase 0 microdosing trial to identify chemoresistance: From bench to bedside
Authors: Wang Sisi , He Miaoling , Li Tao , de Vere White Ralph , Lara Primo N. , Gandara David , Mack Philip C. , Turteltaub Kenneth , Henderson Paul T. , Pan Chong-xian 
Published: February 2011

Abstract
BACKGROUND: DNA damage is the critical step in cancer cell response to platinum (Pt) chemotherapy. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring radiocarbon. By measuring 14C bound to DNA, AMS can detect carboplatin-induced DNA damage after patients receive one subtoxic microdose of 14C-labeled carboplatin.
METHODS: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1/100th of the therapeutic dose) or one therapeutic dose of [14C]carboplatin. Carboplatin-DNA adducts and other relevant parameters such as drug influx/efflux, intracellular drug inactivation, and repair of DNA damage, were measured and correlated with response to chemotherapy.
RESULTS: AMS detected Pt-DNA damage when cancer cells and mice with tumor xenografts were exposed to one subtoxic microdose of [14C]carboplatin. The levels of microdose-induced DNA damage were linearly proportional to the DNA damage caused by the therapeutic drug dose (R2=0.92, p&lt;0.001); and these levels of DNA damage correlated with chemoresistance. Low DNA damage predicts chemoresistance. Measuring drug uptake/efflux, intracellular inactivation and DNA repair allowed insight into some resistance mechanisms. A Phase 0 microdosing trial has been designed to study patients with non-small cell lung cancer or bladder cancer who are scheduled to receive Pt-based chemotherapy. One subtoxic microdose of 14C-carboplatin will be administered to these patients before biopsy. Pt-induced DNA damage and repair in left-over tumor biopsy specimens and other relevant parameters will be measured and correlated with the response and toxicity of chemotherapy. Molecular analysis of genes such as ERCC1 and RRM1 will be analyzed and compared with this Phase 0 results.
CONCLUSION: The levels of DNA damage induced by nontoxic microdosing carboplatin can potentially predict chemoresistance in patients. A phase 0 microdosing trial is under the IRB review to identify chemoresistance and determine the underlying resistant mechanisms for personalized therapy before patients receive toxic Pt chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3522.
Abstract 3526: Inhibition of ABCB1 (MDR1) expression by an siRNA nanoparticulate delivery system to overcome drug resistance in osteosarcoma
Authors: Susa Michiro , Iyer Arun K. , Liu Xianzhe , Choy Edwin , Hornicek Francis J. , Mankin Henry , Milane Lara , Amiji Mansoor M. , Duan Zhenfeng 
Published: February 2011

Abstract
Background: Osteosarcoma accounts for approximately 60% of primary malignant bone tumors diagnosed in the first two decades of life. The use of neo-adjuvant chemotherapy in treating osteosarcoma has improved patients’ average 5 year survival rate from 20% to 70% in the past 30 years. However, for patients who progress after chemotherapy, its effectiveness diminishes due to the emergence of multi-drug resistance (MDR) after prolonged therapy. One of the innovative approaches to addressing MDR is to inhibit MDR1 mRNA expression by RNA interference (RNAi). In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure resulting from MDR, we designed and evaluated a novel drug delivery system for MDR1 siRNA delivery.
Materials and Methods: Novel biocompatible, lipid-modified dextran-based polymeric nanoparticles were used as the platform for MDR1 siRNA delivery; and the efficacy of combination therapy with this system was evaluated. The mean particle size of the MDR1 siRNA loaded nanoparticles as determined by dynamic light scattering (DLS) measurement was 104.4+3.7 nm and the zeta potential was almost neutral (−0.19+1.13 mV). Multi-drug resistant osteosarcoma cell lines (KHOSR2 and U-2OSR2) were treated with the MDR1 siRNA nanocarriers and MDR1 protein (P-gp) expression, drug retention, and immunofluorescence were analyzed. Combination therapy of the MDR1 siRNA loaded nanocarriers with increasing concentrations of doxorubicin was also analyzed.
Results: We observed that MDR1 siRNA loaded dextran nanoparticles efficiently suppresses P-gp expression in the drug resistant osteosarcoma cell lines. With the delivery of nanoparticles loaded with MDR1 siRNA, growth inhibition with doxorubicin was substantially more marked than with the administration of 100 fold higher amounts of free drugs. The results also demonstrated that this approach may be capable of reversing drug resistance by increasing the amount of drug accumulation in MDR cell lines. Furthermore, subcellular distribution of doxorubicin in MDR cells mimicked that of the drug sensitive variant when nanoparticles were utilized.
Conclusions: Lipid-modified dextran-based polymeric nanoparticles are a promising platform for siRNA delivery. Nanocarriers loaded with MDR1 siRNA are a potential treatment strategy for reversing MDR in osteosarcoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3526.
Abstract 3561: The radiosensitizing and cytotoxic effects of PBS-1086, a Rel inhibitor of NF-KB, in breast cancer cells
Authors: Hunter Jill E. , Willmore Elaine , Irving Julie A E , Sliskovic D. Robert , Monie Dileep , Bobb Kathryn , Zhang Jie , Durkacz Barbara W. 
Published: February 2011

Abstract
Recent RNA interference screening has identified p53 and ras mutations to be synthetic lethal with the canonical and non-canonical pathways of NF-κB. We have synthesized inhibitors that antagonize bindings of RelA (p65), RelB and c-rel to the NF-κB sites and thus inhibit both the canonical and non-canonical paths. One such compound, PBS-1086, is evaluated here as a radiosensitizer in wild type and p65−/− mouse embryonic fibroblasts (MEFs), and as a radiosensitizing and chemotherapeutic agent in the p53 deficient and KRAS (G13D) mutant breast cancer cell line, MDA-MB-231.
We found that p65−/− MEFs were ≥ 2-fold more sensitive than p65+/+ MEFs to irradiation (IR) in clonogenic survival assays, thus demonstrating that NF-κB activation conferred radio-resistance. Incubation with PBS-1086 at 1.4 µM, a non-cytotoxic concentration, radiosensitized p65+/+ MEFs (LD50 value of 1.5 Gy for IR + PBS-1086 compared with 2.3 Gy for IR alone). PBS-1086 had no effect on radio-sensitization of p65−/− MEFs, which indicated the radiosensitizing effect of PBS-1086 was mediated through p65. Similar radiosensitizing effects were observed by using RNA interference technique to down-regulate the expression level of p65 by &gt; 95% in p65+/+ MEFs but not in p65−/− MEFs. We also confirmed the inhibition of the NF-κB by PBS-1086 or p65 siRNA in MEFs. NF-κB-dependent luciferase expression increased by 2.5 fold after 10 Gy IR in p65+/+ MEFs. Treatment with PBS-1086 or p65 siRNA reduced luciferase expression significantly. Similarly, IR increased p65+/+ MEFs nuclear extract NF-κB DNA binding activities by 2 fold, which was significantly decreased by either PBS-1086 incubation or p65 siRNA treatment in these cells.
Next, we studied PBS-1086 in MDA-MB-231 breast cancer cells with constitutive NF-κB activation. First, we tested PBS-1086 as a single agent on the growth of the breast cancer cells. Significant cytotoxic effect to PBS-1086 was observed with an LD50 value of 0.4 μM to the MDA-MB-231 cells. Then we tested synergistic effect of PBS-1086 with irradiation in these cells. Incubation with 0.2 µM PBS-1086 significantly enhanced radiation effect by 1.5 fold (LD50 value of 1.66 Gy IR for IR + PBS-1086 compare with 2.55 Gy for IR alone).
In conclusion, we have demonstrated that a Rel inhibitor of NF-KB can potentiate radioactivity through blocking the canonical pathway. It can also selectively kill tumor cells with p53 and KRAS mutations, perhaps through blocking the canonical and non-canonical pathways.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3561.
Abstract 3568: Treatment of Organ-Specific Chloroleukemia by Cytotech Labs API 31510 and Chemotherapy
Authors: Narain Niven R. , Mauro Lucia M. , McCook John P. , Jimenez Joaquin J. 
Published: February 2011

Abstract
The development of chloroleukemia in the rat after transplantation leads to 100% mortality. Recently, two novel clones have been developed. Following intraperitoneal injection, one clone preferentially migrates and forms tumors in the lungs (CHL-L), while another clone forms tumors in the liver (CHL-Li). In vitro, proliferation of both clones were inhibited in a dose-dependent manner by a novel IV solution of API 31510. Accordingly, in the present study we examined the hypothesis that Cytotech Labs API 31510 alone or in combination with cyclophosphamide (CTX) could be effective in the treatment of both clones in vivo. In the first experiments, 24 rats were randomized into 4 groups of six rats each and injected intraperitoneally with CHL-L. In the control group, 100% developed CHL-L. In the group receiving CTX, 5 out of 6 developed CHL-L, while 1 animal remained disease-free. In the group receiving API 31510, 3 out of 6 rats remained disease-free and 3 out of 6 had a partial therapeutic response. In the group which received API 31510 and CTX, 100% of the animals remained disease-free. In a separate experiment, the same protocol was followed using CHL-Li. As observed with the other clone, animals injected with all control animals developed CHL-Li tumors. Similarly, in the group receiving CTX alone, 5 out of 6 developed CHL-Li and 1 remained disease-free. In the group receiving API 31510, 3 out of 6 animals remained disease-free and 3 out of 6 had a partial response. When combining 31510 and CTX, 5 out of 6 animals remained disease-free and 1 had a partial response. No side effects were observed in the animals receiving API 31510 as evidenced by weight gain and behavior. Taken together, these results indicate that API 31510 as a single agent was effective against both chloroma clones used and as an adjuvant to chemotherapy, API 31510 exhibited treatment efficacy in over 90% of animals treated. These data provide a strong foundation for further development of Cytotech Labs API 31510 intravenous formulation as a viable agent for cancer.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3568.
Abstract 3570: Maitake mushroom extract induces apoptosis in breast cancer MCF7 cells through BAK1 activation
Authors: Soares Raquel , Meireles Manuela , Obiol Diego , Alonso Eliana N. , Rocha Ana , Pirraco Ana , Balogh Gabriela Andrea 
Published: February 2011

Abstract
Background: Maitake mushroom has various bioactive compounds. D-fraction, a protein-bound polysaccharide compound, seems to be the most potent for enhancing the immune system via oral administration or injection. In previous studies, the combination of this extract with chemotherapy suggested that the D-Fraction may have the potential to decrease the size of lung, liver, and breast tumors in cancer patients.
Objective: The aim of this study was to examine the in vitro effect of maitake D- Fraction on breast cancer MCF7 cells.
Methods: Cultures of MCF7 cells, incubated with increased concentrations of liquid maitake D-fraction, 0mg/ml; 18,3pg/ml; 36pg/ml; 91pg/ml; 183pg/ml; 367pg/ml, were evaluated for viability, by MTS assay and apoptosis, by TUNEL assay. All experiments were performed in triplicate.
Results: Results seem to indicate that maitake-treated cells have higher apoptosis levels and poorer viability when compared to non-treated cell cultures.
Conclusion: The results obtained in this study, focusing the effect of maitake D- fraction in breast cancer cell proliferation, can drive us to new therapeutic strategies against breast cancer and show that we can find a lot of bioactive compounds in traditional food.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3570.