bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3508: A diazirine-based photoaffinity etoposide probe for labeling topoisomerase II
Authors: Chee Gaik-Lean , Yalowich Jack , Hasinoff Brian B. 
Published: February 2011

Abstract
Etoposide is a widely used anticancer drug that targets topoisomerase II, an essential nuclear enzyme. However, despite the fact that it has been in use and studied for more than 30 years the specific site on the enzyme to which it binds is unknown. In order to identify the etoposide binding site(s) on topoisomerase II, a diazirine-based photoaffinity etoposide analog probe has been synthesized and its photoreactivity and biological activities have been characterized. Upon UV irradiation, the diazirine probe rapidly produced a highly reactive carbene species that formed covalent adducts containing stable carbon-based bonds indicating that it should also be able to form stable covalent adducts with amino acid residues on topoisomerase II. The human leukemia K562 cell growth and topoisomerase II inhibitory properties of the diazirine probe suggest that it targets topoisomerase II in a manner similar to etoposide. The diazirine probe was also shown to act as a topoisomerase II poison through its ability to cause topoisomerase IIα-mediated double-strand cleavage of DNA. Additionally, the diazirine probe significantly increased protein-DNA covalent complex formation upon photoirradiation of diazirine probe-treated K562 cells, as compared to etoposide-treated cells. This result suggests that the photoactivated probe forms a covalent adduct with topoisomerase IIα. In conclusion, the present characterization of the chemical, biochemical, and biological properties of the newly synthesized diazirine-based photoaffinity etoposide analog indicates that use of a proteomics mass spectrometry approach will be a tractable strategy for future identification of the etoposide binding site(s) on topoisomerase II through covalent labeling of amino acid residues. This work was supported by institutional grants from the University of Manitoba, Canadian Institutes of Health Research, National Institutes of Health grant CA090787 to J.C.Y. and a Canada Research Chair for Drug Development for B.B.H
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 3508.
Abstract 3510: The molecular docking-based design and biological evaluation of a novel series of bisintercalating DNA-binding bisanthrapyrazole compounds containing amine linkers
Authors: Wu Xing , Zhang Rui , Guziec Lynn , Guziec Frank , Yalowich Jack C. , Hasinoff Brian B. 
Published: February 2011

Abstract
Anticancer drugs that bind to DNA and inhibit DNA-processing enzymes represent an important class of anticancer drugs. In order to find stronger DNA binding and more potent cytotoxic compounds, a series of bisanthrapyrazole derivatives containing amine linkers were designed and evaluated by molecular docking techniques. Because the anthrapyrazoles are unable to be reductively activated like doxorubicin and other anthracyclines, they should lack the cardiotoxicity exhibited by this class of antitumor agent. The concentration dependent increase in DNA melting temperature was used to determine the strength of DNA binding and the bisintercalation potential of the newly synthesized analogs. These compounds were also assessed for their ability to inhibit: 1) the growth of the human erythroleukemic K562 cell line; 2) the decatenation activity of DNA topoisomerase IIα; 3) the relaxation activity of DNA topoisomerase I. Finally, the compounds were evaluated as topoisomerase IIα poisons by measuring the topoisomerase IIα-mediated double strand cleavage of DNA. All of the bisanthrapyrazoles inhibited K562 cell growth in the low to submicromolar concentration range and also strongly inhibited the decatenation activity of topoisomerase IIα. However, none of the bisanthrapyrazole compounds act as topoisomerase IIα poisons. In conclusion, a novel group of bisanthrapyrazole compounds were designed, synthesized, and biologically evaluated as potential anticancer agents. Support: CIHR, a Canada Research Chair in Drug Development to B.B.H., a National Institutes of Health grant CA090787 to J.C.Y. and the Dishman Foundation at Southwestern University.
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 3510.
Abstract 352: Preclinical evaluation of LYS6K1, a novel, highly selective, orally bioavailable inhibitor of p70 S6 kinase currently in phase I clinical trials for cancer
Authors: Geeganage Sandaruwan , Sams Lillian L. , Joseph Sajan , Brail Leslie , Wang Tao , Rodgers George , Akunda Jackie , Huang Jianping , Perkins Everett J. , Ajamie Rose 
Published: February 2011

Abstract
PI3K/AKT/mTOR/S6K signaling pathway (AKT pathway) controls cell survival, cell-cycle progression, cell growth and metabolism through a cascade phosphorylation of a number of key substrates. This pathway is regulated by three well characterized tumor suppressors; pten, tsc2, and lkb1. Deletion of these genes results in activation of the AKT pathway and proliferative disorders. Similarly, activating mutations of the receptor tyrosine kinases or PI3 Kinase result in the activation of the pathway. Therefore, multiple nodes of the pathway have become drug targets. As part of a comprehensive drug discovery platform aimed at targeting the PI3K pathway, we have developed a potent small molecule inhibitor of p70 S6 kinase that is a downstream effector in this pathway.
LYS6K1 is a potent, highly selective ATP competitive inhibitor against p70 S6 kinase with an IC50 of 0.002 uM. In vitro, LYS6K1 inhibits the phosphorylation of S6 ribosomal protein in HCT116 colon cancer cells with an IC50 of 0.2 uM and similar activity is seen in a broad range of other cell lines. In vivo, LYS6K1.tosylate demonstrates potent phospho-S6 inhibition in nude mice bearing HCT116 colon carcinoma cells, with an ED50 value of 2.2 mg/kg and a ED90 value of 10 mg/kg 4 hours after a single oral dose. In these studies, LYS6K1.tosylate did not show statistically significant elevation of phospho-AKT, in spite of potent p70 S6 kinase inhibition. Proportional dose, exposure, and pharmacodynamic relationships were observed for LYS6K1 in dose- and time- dependent studies. In vivo, LYS6K1.tosylate effectively inhibits the growth of HCT116 colon carcinoma xenografts in mice and the growth of U87MG glioblastoma tumor as a single agent at 2.5 mg/kg given twice daily.
Overall, LYS6K1.tosylate has high permeability that resulted in good oral absorption and PK properties. Based on these pre-clinical observations, LYS6K1.tosylate has advanced to Phase I studies.
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 352.
Abstract 3520: Pegylated nanoplatinates: A novel re-engineered cisplatin for cancer chemotherapy
Authors: Soni Shivani , Sengupta Shiladitya , Paraskar Abhimanyu , Chaudhuri Padmaparna 
Published: February 2011

Abstract
Cis-diamminedichloroplatinum (II) (CDDP) is a platinum based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas, lymphomas, and germ cell tumors. There are two major concerns of cisplatin based chemotherapy: first is relapse of cancer in majority of pateints with cisplatin resistant disease and second is cisplatin associated nephrotoxicity (kidney damage). In the present study, we have demonstrated that cisplatin can be complexed using a carboxylato bond with poly-isobutylene-maleic acid, derivatized with a polyethylene glycol moiety. We found that at unique cisplatin to polymer ratio, this conjugate self-assembles into nanoparticles, and exhibits enhanced therapeutic efficacy without any nephrotoxicity as compared with cisplatin in murine lewis lung carcinoma model. The PIMA-PEG-CDDP conjugate inhibited proliferation and induced apoptosis in Lewis lung carcinoma and 4T1 breast cancer cells in vitro. The nanoparticles were taken up by cancer cells through endocytosis within 6 hours and retained in subcellular compartment over 24 hours in 4T1 breast cancer cells. Furthermore, in an in vivo 4T1 breast cancer model, PIMA-PEG-CDDP nanoparticles reduce tumor growth drastically with no side effects, thus increasing the survival rate of the mice as compared to free cisplatin treated mice. Thus our studies showed that pegylated-PIMA-CDDP can be harnessed for lung and breast cancer chemotherapy with increased therapeutic index compared with cisplatin.
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 3520.
Abstract 3530: OATP1B3 in pancreatic cancer tissue as a potential target for anticancer drug transport
Authors: Obaidat Amanda , Hagenbuch Bruno 
Published: February 2011

Abstract
Organic Anion Transporting Polypeptides (OATPs) are multispecific transporters that are expressed in normal and cancerous tissue (e.g. colon, prostate, breast and bone cancers). Several anticancer drugs have been shown to be transported by certain OATPs. The aim of the study was to determine the expression of OATPs in pancreatic cancer tissue and functionally characterize anticancer drug transport via the expressed OATPs. Ten pancreas tissue samples were obtained for analysis: 6 normal pancreas, 3 pancreatic cancer and 1 metastatic tissue. Expression of OATPs was analyzed at the mRNA level using the Quantigene assay. Protein expression and localization were determined by immunofluorescence with OATP specific antibodies. Transport of the radiolabeled anticancer drugs paclitaxel and docetaxel was measured in an OATP-expressing Chinese Hamster Ovary (CHO) cell system. Among the 11 human OATPs, expression in pancreatic cancer tissue at the mRNA level was highest for OATP4A1 followed by OATP3A1, OATP2A1 and OATP1B3. Expression of OATP4A1, OATP3A1 and OATP1B3 was confirmed at the protein level. In addition, transport of paclitaxel and docetaxel was observed in OATP1B3-expressing CHO cells with Km values of 2.2 μM for both substrates. In summary, OATP4A1, OATP3A1 and OATP1B3 are expressed in pancreatic cancer. OATP1B3 transports the anticancer drugs paclitaxel and docetaxel with relatively high affinities. In conclusion, given that OATP1B3 is exclusively expressed in normal human hepatocytes, which are generally resistant to the effects of anticancer therapy, transport of anticancer drugs via this transporter might be a feasible approach to target the killing of OATP1B3-expressing cancer cells.
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 3530.
Abstract 3535: Retinoblastoma cerebrospinal fluid metastases treatable by intensive intraventricular and multidrug resistance-reversal systemic chemotherapy without radiation
Authors: Chan Helen S. L. , Héon Elise , Doyle John J. , Dimaras Helen , Gallie Brenda L. 
Published: February 2011

Abstract
PURPOSE: Despite combining chemotherapy with peripheral stem cell transplant, cerebrospinal fluid (CSF) metastasis is the most difficult type of retinoblastoma (RB) metastasis to cure, since most drugs that can be given safely into the CSF are anti-leukemia agents that are ineffective against solid tumors. Most metastatic RB cells also express P-glycoprotein causing multidrug resistance (MDR). Drugs do not readily enter into the central nervous system because of the blood-brain barrier formed by P-glycoprotein-rich blood vessels. High-dose craniospinal radiation is too morbid for treatment of young children. Radiation also greatly increases the secondary malignancy risk for patients with germline RB1 mutations. To cure CSF metastases without craniospinal radiation, we designed an intensive multimodality chemotherapy regimen.
METHOD: Since 2000, we treated 4 children with CSF metastases: Child A, with germline bilateral RB, and optic nerve involvement (1 eye enucleated but no radiation); Child B, with germline trilateral RB (no enucleation and no surgery or radiation for the huge suprasellar tumor); Child C, with germline trilateral RB (1 eye enucleated but no surgery or radiation for the huge suprasellar tumor); and Child D, with nongermline unilateral RB with orbital and intracranial recurrence (only localized orbital radiation). All children were treated with 6 or 7-cycle high-dose carboplatin and etoposide, standard-dose vincristine, and high-dose/3-hour-infusion cyclosporine to inhibit both tumor-cell and blood-brain barrier P-glycoprotein. Intraventricular drugs, cytarabine, which is not a substrate of P-glycoprotein but effective against RB cell line in vitro, and topotecan, which is less susceptible to MDR, contributed to treatment of the CSF metastases. On achieving significant responses, supralethal-dosage carboplatin, etoposide and cyclophosphamide were used for consolidation, with the bone marrow rescued with autologous peripheral blood stem cells.
RESULTS: Child A and C are relapse-free 9.1 and 2.3 years post-diagnosis (8.6 and 1.8 years post-transplant). Child B and D died of disease 2.7 and 1.8 years post-diagnosis (2 and 1.4 years post-transplant).
CONCLUSION: Two of the 4 children with CSF metastases, who in the past would have died, are now surviving after intensive multimodality chemotherapy without radiation.
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 3535.
Abstract 354: PI-103 and TCN as proliferative inhibitors of the RTK/PI3K/ATK signaling pathways in astrocytomas
Authors: Connell-Albert Yvette , Gursel Demir , Tuskan Robert , Anastassiadis Theonie , Hawes Jessica , Van Schaick Jessica , Reilly Karlyne 
Published: February 2011

Abstract
INTRODUCTION: Glioblastomas (GBMs), the most aggressive of malignant astrocytomas, are recurrent, infiltrative, and fatal. In GBMs, receptor tyrosine kinases (RTKs) are often mutated and activated, leading to the dysregulation of normal cell signaling pathways. The PI3K/Akt1/mTOR pathway, which is important in normal biological events such as proliferation, survival, invasion, migration and angiogenesis, is often deregulated in malignant cancers, resulting from the simultaneous loss of tumor suppressor PTEN, and the hyperactivation of the Akt pathway. Therefore, pharmacological inhibition of the PI3K/Akt1/mTOR may prove beneficial in arresting the proliferation of astrocytomas and glioblastomas.
METHODS: In order to determine if the selected inhibitors PIA-6, OSU03012, Rapamycin, Tricribine (TCN), and PI-103 had an effect on the PI3K/Akt-1/mTOR pathway, we examined their inhibitory effects on mouse astrocytoma cell lines K1861-10 Grade II; KR158 Grade III; K130G#3 Grade IV; human astrocytoma cell lines, U87MG and SF295, both Grades IV; and normal proliferating mouse primary astrocytes using the Alamar blue assay as a measure of metabolic activity and proliferation. Inhibitors with low IC50 values in tumor cells as compared to normal primary astrocytes were favored.
RESULTS: From the select panel of inhibitors, only the AKT inhibitor TCN and dual PI3K/mTor inhibitor PI-103 showed low IC50 values in the nM or pM range, suggesting strong inhibition of proliferation in the astrocytoma cell lines tested. Rapamycin, an mTOR inhibitor, showed inconsistent inhibition of cell proliferation on the cell lines tested, although mTor activity was effectively inhibited, suggesting that inhibitory effects of rapamycin at higher concentrations may be acting via different pathways.
CONCLUSIONS: Our results support the hypothesis that the PI3K/Akt1/mTOR pathway is a potential druggable target in astrocytomas and glioblastomas.
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 354.
Abstract 3541: Pharmacological chaperones increase membrane expression of ABCG2 harboring the Q141K single nucleotide polymorphism
Authors: Tamaki Akina , Caterina Ierano , Shukla Suneet , Robey Robert W. , Ambudkar Suresh V. , Bates Susan E. 
Published: February 2011

Abstract
ABCG2 is an ATP-binding cassette half-transporter that functions as a xenobiotic transporter. Since ABCG2's discovery in multidrug-resistant cancer cells, the transporter has garnered interest in pharmacogenomics as a component of the blood-brain barrier and the maternal-fetal barrier as well as a modulator of oral drug absorption. A single nucleotide polymorphism (SNP) C421A in ABCG2, resulting in a glutamic acid to leucine mutation at amino acid 141 (Q141K), has been extensively studied and has been found to affect protein expression and ATPase activity, but may also affect protein folding. As misfolded ABCG2 has been shown to be degraded through the endoplasmic reticulum associated protein degradation (ERAD) system (T. Furukawa et al., Pharm Res., 26(2): 469-479, 2008), we postulated that pharmacological chaperones such as mitoxantrone, a known substrate of ABCG2, might increase surface expression of Q141K ABCG2. In this study, we used HEK293 stably transfected with Q141K ABCG2 to examine whether incubating cells expressing the mutated transporter with mitoxantrone or other ABCG2 substrates would serve to “rescue” Q141K ABCG2 and improve trafficking to the cell surface, as we have demonstrated in other mutations that impair trafficking (O. Polgar et al., Biochemistry, 43(29): 9448-9456, 2004). Expression of ABCG2 in cells transfected with wild-type or Q141K ABCG2 was measured by immunoblot analysis and flow cytometry. After treatment with 5 μM of mitoxantrone, cell surface expression of ABCG2 in cells transfected with vector containing Q141K ABCG2 increased, while cells transfected with wild-type ABCG2 showed no change. Increased ABCG2 expression was also observed in membrane preparations from mitoxantrone-treated cells transfected with Q141K ABCG2 compared to wild-type ABCG2 transfected cells. Interestingly, immunoblot analysis showed that when cells transfected with Q141K ABCG2 were incubated with 50 μM of the dietary compounds tert-butyl hydroquinone (TBHQ) and dibenzoylmethane (DBM), increased expression of ABCG2 was observed in membrane preparations, while no change was observed for cells expressing wild-type ABCG2. These results suggest that some dietary compounds may promote proper folding and membrane localization of mutant forms of ABCG2.
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 3541.
Abstract 3542: Analysis of miRNA mediated Cisplatin resistant mechanisms
Authors: Suzuki Toshihiro , NIshio Kazuto , Togawa Tadayasu , Sugawara Kanako , Sakuraba Hitoshi 
Published: February 2011

Abstract
Cisplatin is an effective anticancer agent that is widely used in the treatment of testicular, ovarian, bladder and lung cancers. However, the development of resistance to cisplatin is a major obstacle to treatment. To understand the clinically relevant mechanisms of resistance, many studies have been aimed at clarifying the biochemical/molecular alterations of cisplatin-resistant cells. However, these studies did not conclusively identify the basis of cellular resistance to cisplatin.
Recently some studies have shown that micro RNAs play an important role in cancer cell resistance to chemotherapeutic agents and cancer development.
In this study, micro RNA expression profiles of cisplatin resistant non small cell lung cancer cell lines were analyzed using microarray and real time RT-PCR. We found some of micro RNAs were similarly regulated in couple of cisplatin resistant cell lines. These finding are useful for understanding the miRNA mediated cisplatin resistance mechanisms. Now, functional analyses on miRNAs involving cisplatin resistance are in progress.
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 3542.
Abstract 3545: Alterations of molecular mechanisms in newly selected 5-fluorouracil resistant pancreatic cancer cell line and the effect of biochanin A thereon
Authors: Bhardwaj Vikas , Lai James C.K. , Bhushan Alok 
Published: February 2011

Abstract
Resistance to drugs is one of the major contributor to the high mortality rate of pancreatic cancer. The molecular mechanisms of pancreatic cancer drug resistance are not well understood. We generated and characterized a 5FU resistant pancreatic cancer cell line (AsPC1/R). 5FU resistant pancreatic cancer cells (AsPC1/R) were selected with the increasing concentration of the drug till 6-fold resistance was achieved. Our dose response studies show that the resistant cells were cross-resistant to the gefitinib; however, the sensitivity to gemcitabine was not altered. Western blot analysis shows lower level of EGFR in the AsPC1/R as compared to AsPC1 cells. In addition, our results indicate that the resistant cells have high levels of activated Erk 1 and Akt. Levels of c-fos and c-jun in the nuclear fraction were upregulated in the resistant cells. Furthermore, invasive mechanisms such as uPAR and MMP activity are upregulated in the AsPC1/R cells compared to the parent cells. We also determined the effect of biochanin A on 5FU resistance and found that it reverses the 5FU resistance in AsPC1/R cells. Our previous studies have shown that biochanin A reduces the levels of thymidylate synthase and the levels of activated Erk and Akt. We conclude that biochanin A may overcome 5FU resistance in pancreatic cancer and could be used in combination with other chemotherapeutic agents in treating pancreatic cancer.
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 3545.