bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3733: Combined effect of linalool as component of Humulus lupulus on doxorubicin-induced antitumor activity
Authors: Miyashita Michiko , Sadzuka Yasuyuki 
Published: August 2012

Abstract
[Purpose] Cancer chemotherapy has been applied to advanced tumors and intractable tumors, playing an important role in their treatments. However, there are many problems including the appearance of adverse reactions and acquirement of drug resistance. The increased numbers of medications resulted in a decreased quality of life for the patients. However, food and food components can be used to increase the activity of antitumor agents without increasing the number of medicines. In this study, the effects of some components in Humulus lupulus (Hop) were examined on the doxorubicin (DOX) induced antitumor activity in vitro and in vivo. [Methods] The effects of Hop components (linalool, myrcene, α-humulene, α-caryophyllene) on DOX permeability and DOX cytotoxicity in P388 leukemia cells in vitro were examined. P388 leukemia cells (5 x 105 cells per animal) were transplanted onto the backs of BDF1 mice, and DOX (2.0mg/kg/day x 4 days, i.p.) and linalool (1.0mg/kg/day x 4 days, p.o.) were administered. The solid tumor and normal tissues were removed and measured DOX concentrations in each tissue. [Results and Discussion] In vitro, myrcene, α-humulene and α-caryophyllene did not have beneficial effects on DOX permeability in tumor cells. In contrast, the addition of linalool was shown to significantly promote on DOX influx and increased DOX concentration in tumor cells. The combination of DOX with linalool (0.1 μM) showed 3.5-fold (P&lt;0.05) cytotoxicity, compared to treatment with DOX alone. Therefore, the combined linalool with DOX enhanced DOX cytotoxicity by the increase of DOX concentration in tumor cells. In vivo, the tumor weight in the DOX alone group decreased to 77% of the control level, whereas the combination of linalool with DOX decreased the tumor weight by 53% (P&lt;0.05) of that in DOX alone group. In the tumor, the DOX concentration in the linalool combined group increased by 1.8-fold (P&lt;0.05) compared to DOX alone group. In the normal tissue, the DOX concentration after combined linalool and DOX treatment tended to decrease. In particular, the DOX concentration in the heart decreased by 49% (P&lt;0.05) of that in DOX alone group, expecting that linalool may decrease DOX-induced cardiotoxicity. Thus, the combination of linalool with DOX increased DOX concentration in the tumor, consequently enhanced antitumor activity of DOX. In conclusion, linalool is expected effectiveness as DOX modulator.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3733. doi:1538-7445.AM2012-3733
Abstract 3739: TAK-733, an investigational, selective MEK1/2 inhibitor, in combination with alisertib (MLN8237), an investigational, selective Aurora A kinase inhibitor is tolerated and results in additive to synergistic antitumor activity: Results from In Vivo Studies
Authors: Fabrey Robyn , O'Connell Shawn , Stanton Andrew , Chakravarty Arijit , Gangolli Esha , Ecsedy Jeffery , Zarycki Jodi , Vincent Patrick 
Published: August 2012

Abstract
MEK and Aurora A kinase inhibitors (AAK) have profound impacts on cell cycle progression. Inhibition of MEK leads to defects in cell-cycle progression followed by cell cycle arrest and/or apoptosis. These cell-cycle progression defects may in part be due to the role of MEK in the DNA replication or damage checkpoint responses through positive regulation of DNA repair mechanisms. AAK inhibition leads to chromosome congression and segregation defects leading to DNA damage followed by apoptosis or senesence. The overlapping biological effects of inhibition of AAK and MEK kinases in cell cycle progression and chromosomal integrity raise the possibility that inhibiting both targets would provide added benefit over the inhibition of either target alone. The in vivo antitumor activity of TAK-733, an investigational potent, selective, non-ATP-competitive allosteric inhibitor of MEK, in combination with alisertib, an investigational potent, selective, reversible, ATP-competitive inhibitor of Aurora A kinase, was examined in experimental human solid tumor xenograft models including NSCLC (NCI H23 [KRAS and LKB1 mutations]), CRC (SW620 [KRAS, APC, p53 mutations]), and pancreatic cancer (Panc 1 and Capan 1 [KRAS mutations] and BxPC-3 [No MAPK mutations]) models in immunocompromised mice. The previously established maximally efficacious doses for the single agents dosed once daily (QD) orally (PO) (10 mg/kg TAK-733 and 30-mg/kg alisertib) were examined. A lower dose of 20 mg/kg alisertib was also examined in the event the maximally efficacious dose of each agent was not tolerated in combination. The once daily (QD) concurrent oral administration of TAK-733 and alisertib resulted in additive to synergistic antitumor activity and in prolonged inhibition of tumor regrowth after terminating treatment compared to single agent treatment in all xenograft models examined. Concurrent administration of TAK-733 and alisertib daily for 21 days was well tolerated. Treatment with TAK-733 alone and in combination with alisertib clearly inhibited phosphorylated ERK and produced a slight increase in phosphorylated histone H3. The results from the nonclinical models examined demonstrate considerable improvement in nonclinical antitumor activity over either single agent alone and provide a biological rationale for clinical evaluation of a TAK-733/alisertib combination in patients with advanced malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3739. doi:1538-7445.AM2012-3739
Abstract 3756: Structure activity relationship studies of novel FAK inhibitor C4
Authors: Agharkar Priyanka A. , Ethirajan Manivannan , Liao Jianqun , Yemma Michael , Cance William , Pandey Ravindra , Kurenova Elena 
Published: August 2012

Abstract
Introduction: FAK and VEGFR3 have stirred considerable interest in recent years as attractive anti-cancer targets, owing to their high expression across several tumor types and relatively low levels in normal tissues. Our lab has shown that VEGFR3 binds to FAK and the physical interaction between the two proteins confers a significant survival advantage to tumor cells. We discovered small molecule C4 that specifically targets and disrupts FAK-VEGFR3 interaction to exert anti-tumor effects, but does so at moderate concentrations. This prompted us to design C4 analogs that display enhanced potency, minimum toxicity and high specificity for the target site. Here, we have shown that some C4 analogs disrupt FAK-VEGFR3 interaction and dramatically inhibit pancreatic tumor growth at low concentrations as single agents as well as in combination with Gemcitabine. Methods: The structure of C4 was modified at various positions by substituting alkyl and aryl moieties. The resulting analogs were screened for anti-cancer inhibitory effects in different cancer cell lines by MTS assay. Effects of C4 analogs on pancreatic cancer cell lines were determined by MTS assay (viability), Clonogenecity assay, Western blot (phosphorylation, apoptosis) and TUNEL assay. Target specificity (immunoprecipitation) and binding confirmation (Forte-Bio's Octet Red assay) of all analogs were performed. In vivo anti-tumor activity of lead analogs was done using a subcutaneous xenograft mouse model of pancreatic cancer. Results: Twenty C4 analogs were screened and four were selected for further analyses. These four analogs strikingly decreased survival of six pancreatic cancer cell lines. Analog C9 showed highest cytotoxic effects, inhibited colony formation of Panc-1 cells at 1µM, induced dose dependent cleavage of caspase-3 and PARP and decreased phosphorylated forms of Akt and Erk within 24h treatment. Disruption of FAK-VEGFR3 interaction was seen with 1µM C9. Octet method revealed that 20µM C9, KD (M) = 1.29×10-7. In vivo, 30 days treatment with low doses of the four analogs led to massive reduction in tumor growth when treated as single agents (60%) and in combination with Gemcitabine (80%)(P&lt;0.05). Conclusions: Targeting the FAK-VEGFR3 protein-protein interaction site highlights a unique approach for molecular-targeted highly specific cancer therapeutics. The outcomes from this project could potentially widen the spectrum of oral-based treatment options for pancreatic cancer, which yet remains a formidable disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3756. doi:1538-7445.AM2012-3756
Abstract 3770: PK/PD/Efficacy characterization of AZ285, a selective CK2 kinase inhibitor
Authors: Schroeder Patricia , Alimzhanov Marat , Brassil Patrick , Denz Christopher R. , Dowling James E. , Lyne Paul D. , Cooke Emma L. 
Published: August 2012

Abstract
Casein Kinase 2 (CK2) is an abundant, highly conserved protein serine/threonine kinase with numerous physiological targets and participates in the maintenance of cell viability with a role in cell growth and proliferation. While the expression level of CK2 in normal cells is tightly regulated, there is an increasing body of evidence demonstrating it's over expression in cancerous cells, thereby making inhibition a viable chemotherapeutic target. Here we will describe a mathematical tumor growth inhibition model describing the relationship between systemic exposure to a potent inhibitor of CK2 (AZ285) and efficacy in the HCT116 xenograft model. Furthermore, a PK/PD model describing the onset, intensity, and duration of the pAKT and cleaved caspase 3 response as function of concentration and time is described and linked to pre-clinical xenograft efficacy outcomes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3770. doi:1538-7445.AM2012-3770
Abstract 3790: Preclinical profile of LGX818: A potent and selective RAF kinase inhibitor
Authors: Stuart Darrin D. , Li Nanxin , Poon Daniel J. , Aardalen Kimberly , Kaufman Susan , Merritt Hanne , Salangsang Fernando , Lorenzana Edward , Li Allen , Ghoddusi Majid , Caponigro Giordano , Sun Frank , Kulkarni Swarupa , Kakar Shefali , Turner Nancy , Zang Richard , Tellew John , Pryer Nancy 
Published: August 2012

Abstract
Selective RAF inhibitors have significant activity in patients with metastatic melanoma whose tumors express BRAFV600E. However, not all patients respond equally well to treatment and the duration of response is often limited to less than 6 months. LGX818 was developed with the hypothesis that a more potent inhibitor with excellent pharmacological properties would maximize the degree and duration of patient response. LGX818 is a highly potent RAF inhibitor with selective anti-proliferative and apoptotic activity in cells expressing BRAFV600E. In the A375 (BRAFV600E) human melanoma cell line LGX818 suppresses phospho-ERK (EC50 = 3 nM) leading to potent inhibition of proliferation (EC50 = 4 nM). No significant activity was observed against a panel of 100 kinases (IC50 &gt; 900 nM) and LGX818 did not inhibit proliferation of &gt; 400 cell lines expressing wild-type BRAF. Contributing to the high potency of LGX818 is the extremely slow off-rate from BRAFV600E which is not observed with other RAF inhibitors. In biochemical assays the dissociation half-life was &gt;24 hours which translated into sustained target inhibition in cells following drug wash-out. Single dose PK/PD studies in human melanoma xenograft models (BRAFV600E) indicated that LGX818 treatment at oral doses as low as 6 mg/kg resulted in strong (75%) and sustained (&gt;24 hours) decrease in phospho-MEK, even following clearance of drug from circulation. Decreases in phospho-ERK were consistent with phospho-MEK but markers of downstream transcriptional output (DUSP6 and SPRY4) appeared to provide a more sensitive measure of pathway activation. LGX818 induced tumor regression in multiple BRAF mutant human tumor xenograft models grown in immune compromised mice and rats at doses as low as 1 mg/kg. Consistent with the in vitro data, LGX818 was inactive against BRAF wild-type tumors at doses up to 300 mg/kg bid, with good tolerability and linear increase in exposure. Efficacy was also achieved in a more disease-relevant spontaneous metastatic melanoma and a model of melanoma brain metastasis. LGX818 is a potent and selective RAF kinase inhibitor with unique biochemical properties that contribute to an excellent pharmacological profile. A Phase I clinical trial in patients with BRAF mutant tumors is ongoing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3790. doi:1538-7445.AM2012-3790
Abstract 3792: Population Pharmacokinetic (PPK) modeling of ProLindac™ (AP5346), a nanopolymer prodrug of diaminocyclohexane (DACH)-platinum (Pt) in recurrent advanced ovarian cancer (AOC) patients
Authors: Rezaï Keyvan , Urien Saik , Weill Sophie , Bekradda Mohamed , Bourdel Fabrice , Nowotnik David P. , Cvitkovic Esteban , Lokiec François 
Published: August 2012

Abstract
Background: ProLindac™ (PL) is a 25 kDa hydroxypropylmethacrylamide copolymer linked to a DACH-Pt. The DACH-Pt complex is thought to be biologically inert while attached to the polymer, with slow in vivo Pt release accelerated in low pH environments (extracellular space of hypoxic tumor and intracellular lysosomal compartment). Methods: 9/35 patients (pts) with recurrent OAC treated with single-agent PL via 2-h IV infusion at doses of 900 mg/m*2 q2w (3 pts), 1400 mg/m*2 q3w (3 pts) and 1680 mg/m*2 q3w (3 pts) were assessable for full PK analysis. 8 time point samples were collected on cycle 1, and 2 samples at cycles 2, 3 and 4. The ultrafiltration procedure used Ultra-4 filters (Amicon) with 50 kDa for unbound PL (U-PL) and 3 kDa for unbound Pt (U-Pt) cut-off. Urine was collected every 6 h from day 1 to 5 of dosing 1. Pt levels were measured by a validated Flameless Atomic Absorption Spectrometry Method (concentration range: 12.5 - 500 ng/mL). PPK was modeled using a nonlinear mixed effect model program (Monolix version 3.1s) by computing the maximum likelihood estimation of the parameters without any approximation of the model. Results: A 3-compartment open model adequately described the total PL time-concentration curve with linear elimination while a 2-compartment model satisfactorily described U-PL and U-Pt time-concentration curves with linear elimination. Mean PPK parameters with SD are summarized below: The mean recovery of PL dose in urine was at least 60% within 5 days. Conclusion: The central Vd for total PL Pt is rather small, close to the circulating blood volume suggesting that the major part of parent drug is restrained in the circulatory space with weak tissue diffusion probably due to a high protein binding rate. However, for U-PL and U-Pt, the Vd is much higher suggesting: 1) a significant tissue diffusion of active species (free-Pt), 2) PL is bound to plasma proteins with low-energy bonds.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3792. doi:1538-7445.AM2012-3792
Abstract 3813: DNA polymerase eta and a novel anticancer selenophene compound
Authors: Chen Yih-wen , Chang Jang-yang , Chou Kai-Ming 
Published: August 2012

Abstract
Human DNA polymerase ≤ (pol α) plays a key role in replicating across the UV radiation induced cyclobutane pyrimidine dimers (CPD) in DNA and mutations in pol ≤ gene result in a syndrome called Xeroderma Pigmentosum Variant (XP-V). In the absence of pol β, the DNA replication forks collapse after prolonged stalling at CPD sites, which consequently lead to DNA breakages and cell death. Therefore, pol ≤ has been considered to serve as a cellular protection mechanism to enhance cell survival and reduce mutagenesis. In addition to UV-induced CPD lesion, pol ≤ has the ability to handle DNA lesions introduced by chemotherapeutic anticancer agents, such as platinum based compounds and nucleoside analogs. Such damage tolerance ability of pol ≤ has been shown to reduce cell sensitivity to these DNA targeting agents. D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole] is a selenophene compounds that demonstrated promising antitumor activity against various human cancer cells and in vivo xenograft mouse model. Mechanistic studies have shown that D-501036 induced DNA adduct(s) and caused genome instability, which result in cell cycle accumulation in the S-phase, DNA breakage, and subsequently lead to cell death. Interestingly, the IC50 for human fibroblast XP30RO cells derived from XP-V patients was &gt;50 fold higher than the XP30RO cells that stably transfected with a pol ≤ expressing vector (XP30RO-EGFP-pol α). In addition, D-501036 caused an increased amount of DNA breakage in the XP30RO-EGFP-pol ≤ cells as compared to its parental XP30RO cells in both DNA fragmentation and comet assays. These results revealed a novel role of pol ≤ in the action of D-501036 that is very different from its protective role against UV irradiation or cisplatin.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3813. doi:1538-7445.AM2012-3813
Abstract 3820: Reduced migration and enhanced killing of glioblastoma multiforme by mefloquine via alteration of sphingolipid levels
Authors: Sharma Natasha , Cho Heeyon Y. , Thomas Simmy , Chen Thomas C. , Hofman Florence M. , Petasis Nicos A. , Schonthal Axel H. , Louie Stan G. 
Published: August 2012

Abstract
Purpose: Glioblastoma multiforme (GBM) is one of the most aggressive and common brain tumors. Current therapy for GBM is limited to surgery, radiation therapy and chemotherapy using temozolomide (TMZ). However, the emergence of resistance to TMZ and the ability of malignant gliomas to migrate away from the primary tumor site often results in recurrence of the tumor and failure of the initial therapy. This dire scenario illustrates the urgent need to identify novel agents that will be effective in TMZ-resistant tumors. In this study, we investigated the anticancer potential of an FDA approved antimalarial drug, mefloquine (MQ), in the in vitro model of GBM. MQ's impact on glioma viability, proliferation and migration was studied in a number of wild type and TMZ-resistant cells lines. We also evaluated the effects of MQ on intracellular levels of sphingolipids, which are bioactive lipids and have been recognized as the mediators of cellular proliferation and invasion in GBM. Method: To study the effect of MQ on TMZ resistance in vitro, we generated TMZ-resistant cell lines from established GBM cells. We evaluated the effects of MQ on cellular viability and proliferation by MTT assay and colony formation assay. Moreover, cell death was determined by analyzing the effect of MQ on various markers of apoptosis (e.g. cleavage of caspase 7 and PARP) using western blot. The effect of MQ on the migration of both TMZ-sensitive and -resistant cells was evaluated using wound healing scratch assay and Boyden chamber. To evaluate the impact of MQ on sphingolipids, we employed a validated LC-MS lipidomic assay to quantify the levels of various sphingolipids. Results: MQ was able to reduce cellular viability and proliferation in both TMZ-sensitive and -resistant GBM cells. MQ exerted its antitumor activity through induction of apoptosis. Our results further demonstrate the ability of MQ to reduce the migration of both TMZ-sensitive and -resistant GBM cell lines. In addition MQ was able to reduce the intracellular levels of sphingosine-1-phosphate (S1P), a pro-survival and pro-migratory sphingolipid and increased the levels of ceramide, a pro-apoptotic sphingolipid. Conclusion: Altogether our results demonstrate the ability of MQ to reduce cellular viability and proliferation and to induce apoptotic cell death in both TMZ-sensitive and -resistant GBM cells. It is conceivable that MQ exerts these effects by altering sphingolipid metabolism. These preliminary data suggests that MQ should be further investigated for cancer therapeutic purposes for TMZ-resistant GBM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3820. doi:1538-7445.AM2012-3820