bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 740: PINCH is an independent prognostic factor in rectal cancer patients without preoperative radiotherapy: A study in a Swedish rectal cancer trial of preoperative radiotherapy
Authors: Holmqvist Annica Elisabet , Holmlund Birgitta , Ardsby Malin , Gao Jingfang , Adell Gunnar , Johansson Ann-Charlotte , Carstensen John , Langford Dianne , Sun Xiao-Feng 
Published: August 2012

Abstract
Background: Particularly interesting new cysteine-histidine rich protein (PINCH) connected to integrins of the cell surface, is involved in cell spreading, motility and proliferation. The expression of PINCH and its relationship to outcome have been studied, however, the clinical significance between PINCH and preoperative radiotherapy (RT) in tumors is unknown. In this study, PINCH expression and its relationship to RT, clinical, histological and biological factors were investigated in rectal cancer patients, and in colon cancer and fibroblast cell lines. Material and Methods: PINCH expression was immunohistochemically examined at the invasive margin and inner tumour area in 137 primary rectal adenocarcinomas (72 cases without RT and 65 cases with RT). PINCH expression in colon cancer (KM12C) and fibroblast (CCD18 Co) cell lines was examined by real time PCR. The KM12C and CCD 18 Co cell lines, cultured separately and co-cultured, were analyzed over time at 8h, 24h, 48h and 72h after radiation. Results: In patients without RT, strong PINCH expression at the invasive margin of tumors was related to worse survival, compared to patients with weak expression, independent of both TNM stage and differentiation (p = 0.03). No survival relationship in patients with RT was observed (p = 0.64). Real time PCR analyzes showed that KM12C irradiated cells tended to have a higher expression of PINCH at 24h compared to cells without radiation, while in co-cultured KM12C cells, PINCH tended to increase at 8h. PINCH seemed to increase at 8h in CCD 18 Co cells with radiation compared to cells without radiation, while in co-cultured CCD 18 Co cells, PINCH seemed to be lower at 8h in radiated cells than in non-radiated cells. Conclusions: PINCH expression at the invasive margin was an independent prognostic factor in patients without RT. RT might up-regulate the expression of PINCH, which may help us to select the best-suited patients for RT in the future. The levels of PINCH differ when separately cultured and co-cultured cells were compared, which might indicate that PINCH is involved in the crosstalk between tumor cells and their surrounding fibroblasts.
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 740. doi:1538-7445.AM2012-740
Abstract 750: Impairment of clofarabine (CLO) clearance (CL) in the presence of cimetidine: Evidence of a drug-drug interaction between clofarabine and inhibitors of human organic cation transporter-2 (hOCT2)
Authors: Foster Matthew C. , Walko Christine , Kumar Parag , Huang Jeffrey , Ivanova Anastasia , Garcia Reynaldo , Deventer Hendrik Van , Ewesuedo Reginald , Shea Thomas C. 
Published: August 2012

Abstract
Background: CLO is a nucleoside analog with efficacy in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical studies using an isolated, perfused rat-kidney model suggested that CLO may be a substrate of OCT2, a channel that mediates the transport of cations across the renal tubular basolateral membrane. Evidence of this mechanism is lacking in humans, though this property could contribute to drug interactions with compounds such as cimetidine that inhibit hOCT2. Methods: Eligible patients were: 1) untreated AML ≤ 60 years of age unsuited for intensive induction therapies, 2) relapsed or refractory AML, or 3) MDS patients who failed ≤ 1 prior regimen. Patients were treated with CLO according to the schedule: CLO 15 mg/m2 IV day 1, CLO 30 mg/m2 PO day 3, CLO 15 mg/m2 IV day 5 preceded by two doses of oral cimetidine (800 mg PO 8-10 hours apart), and CLO 30 mg/m2 PO on days 6 and 7. Pharmacokinetic (PK) studies were obtained after CLO dosing on days 1, 3 and 5. CLO plasma concentration was determined, and concentration-time data was analyzed by non-compartmental methods. Oral bioavailability (F) was determined for each patient. The geometric means of area under the curve, 0-infinity (AUC), and CL for intravenous CLO administered after cimetidine doses were compared with AUC and CL for intravenous CLO administered without cimetidine. Results: To date, 8 patients have been treated. Mean F = 0.66, 90% confidence interval (CI) (0.49, 0.87). Comparisons of PK parameters between IV dosing with and without cimetidine are shown in the table. Conclusions: Co-administration of the hOCT2 inhibitor cimetidine with CLO appears to increase CLO AUC by impairing renal CL. Enrollment continues in an attempt to further support the putative mechanism of CLO renal clearance by hOCT2-mediated tubular secretion, and to further investigate the clinical import of this drug-drug interaction.

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 750. doi:1538-7445.AM2012-750
Abstract 751: Mass balance, excretion and metabolism of [14C] ASA404 in cancer patients in a phase I trial
Authors: McKeage Mark , Fong Peter , Hong Kevin , Flarakos Jimmy , Mangold James , Du Yancy , Tanaka Chiaki , Schran Horst 
Published: August 2012

Abstract
Purpose: To determine the mass balance, excretion and metabolism of the small molecule flavonoid tumor vascular disrupting agent ASA404 in patients with advanced cancer. Methods: Seven cancer patients were given a single dose of 3000 mg [14C] ASA404 by intravenous infusion over 20 minutes prior to collection of samples of plasma, urine and faeces. Pharmacokinetic samples were analysed by HPLC, liquid scintillation counting, mass spectrometry, glusulase treatment and comparison to authentic standards. Descriptive pharmacokinetic parameters were generated by non-compartmental analysis. Results: Mass balance was achieved (mean recovery of radioactivity in excreta = 86.9% of the dose) with balanced excretion between urine (mean recovery of radioactivity in urine = 53.9% of dose) and faeces (mean recovery of radioactivity in faeces = 33.3% of dose). ASA404 was eliminated as parent drug, three known metabolites (6-hydroxy-ASA404, ASA404 acyl glucuronide and 6-hydroxy-ASA404 acyl glucuronide) and as two novel metabolites (an ASA404 dimer and an ASA404 dimer glucuronide conjugate). Unchanged ASA404 was the major radioactivity component detected in plasma within the first 24 hours after dosing. At later time-points, irreversibly protein bound ASA404 and all of the metabolites that had been detected in excreta, contributed to total plasma radioactivity. Conclusion: This study defined the substantial excretion of ASA404, mainly as metabolites, in both urine (over half of the dose) and faeces (about one third of the dose) after intravenous administration. Two novel metabolites were identified that were not reported by previous studies using nonradioactive techniques.
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 751. doi:1538-7445.AM2012-751
Abstract 769: Restoration of c-Cbl function, by inhibiting Cdc42, confers tamoxifen sensitivity on basal-like (triple negative) breast cancer cells
Authors: Chen Hsing-Yu , Yang Yin , Noble Mark D. 
Published: August 2012

Abstract
Our present work offers a new means by which cancer cells become resistant to anti-cancer treatments and mechanism-driven approaches for overcoming such resistance. Specifically, here we demonstrate a previously unrecognized mechanism of tamoxifen (TMX) resistance distinct from loss of estrogen receptor on basal-like (triple negative) breast cancer cells, which are among the most challenging tumors to treat with current therapies. Our present finding emerged from trying to understand the puzzling differences in regulation of receptor tyrosine kinase (RTK) degradation in normal progenitor cells and in breast cancer cells. When glial progenitor cells become slightly more (15-20%) oxidized, such as by exposing them to TMX, we find sequential activation of Fyn (a member of the Src-family of kinases) and c-Cbl (an E3 ubiquitin ligase) is activated. Phosphorylation of c-Cbl causes ubiquitylation of its target proteins and thus increases the degradation of its target proteins, such as particular RTKs, including the epidermal growth factor receptor (EGFR, our specific target in this study). In contrast to normal progenitor cells, basal-like breast cancer cells exposed to TMX show increased Fyn activation but no increase in c-Cbl phosphorylation. We now have found that oxidation-induced activation of c-Cbl in basal-like breast cancer cells is inhibited due to expression of Cdc42. Cdc42 sequestered c-Cbl, prevented its activation and prevented EGFR from being degraded. Restoration of c-Cbl function, by genetically or pharmacologically inhibiting Cdc42 activation, reduced EGFR levels in these cells. More critically, restoring c-Cbl function sensitized these cells to TMX both in vitro and in vivo. Analysis of tumor growth in vivo showed that reducing the levels of Cdc42 both reduced the size of tumors and made them more sensitive to TMX. The results provide a novel defense mechanism that basal-like breast cancer cells utilize to prevent EGFR degradation which may have high relevance to treatment of these tumors. Of particular importance is the ability of Cdc42 knockdown to confer TMX sensitivity on these otherwise resistant tumor cells.
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 769. doi:1538-7445.AM2012-769
Abstract 770: Overcoming Trastuzumab resistance with the novel pan-erbb inhibitor AZD8931
Authors: Balachandran Banujan , Chabot Catherine , Hamel Sophie , Chan Carmel T. , Kane Susan , Buchanan Marguerite , Aguilar-Mahecha Adriana , Basik Mark 
Published: August 2012

Abstract
Approximately 15-20% of all invasive breast carcinomas overexpress the HER-2 receptor, a membrane surface-bound receptor tyrosine kinase upstream of critical proliferation and cell survival pathways. Trastuzumab, a humanized monoclonal antibody to the extracellular domain of HER-2, has proven to be a beneficial treatment for patients diagnosed as HER-2+, but does have its limitations. A majority of advanced HER-2 positive breast cancer patients will develop resistance to the therapy within the first year while many others do not respond to the drug when used alone. The purpose of this study was to determine whether AZD8931, a reversible pan-ERBB inhibitor that equipotently inhibits the tyrosine kinase-activity of EGFR, HER-2, and HER-3, could reverse this resistance in established trastuzumab-resistant BT474 and SKBR3 cell lines. To account for tumor heterogeneity in HER-2+ tumors, response to AZD8931 was examined in both ER-positive (BT474) and ER-negative (SKBR3) cell lines. Proliferation assays were used to assess the efficacy of AZD8931 alone and in combination with trastuzumab. Results showed significantly diminished cell growth in all tested cell lines, including those resistant to trastuzumab, at clinically relevant concentrations of AZD8931 (&lt;2µM). Furthermore, when AZD8931 was tested in conjunction with trastuzumab, the resistance to trastuzumab was reversed using clinically relevant doses of trastuzumab. Using combination indices, it was found that AZD8931 synergizes well with trastuzumab and could be used as a combination therapy for both trastuzumab-sensitive and trastuzumab-resistant breast cancer patients. Western blot analyses confirmed the results of cell proliferation assays as p-EGFR, p-HER-2, p-HER-3, p-Akt, and p-MAPK, were all reduced after treatment with AZD8931. Thus, AZD8931 alone or in combination with trastuzumab may be an effective therapy in HER2+ breast cancers.
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 770. doi:1538-7445.AM2012-770
Abstract 772: Notch1 affects ABCC1-mediated drug efflux and drug sensitivity in MCF7 breast cancer cells
Authors: Lu Meiling , Majumdar Neena , Jiang Ruixuan , Cho Sungpil , Beck William T. 
Published: August 2012

Abstract
Development of multidrug resistance is a major impediment to the successful treatment of cancer. Although many cellular mechanisms are involved in multidrug resistant cancers, overexpression of ATP-binding cassette (ABC) membrane transporters represents one of the main determinants of the multidrug resistance phenotype. We have previously demonstrated a positive correlation of expression of intracellular Notch1 (NIC) and the ABCC1 transporter; we found that NIC contributes to multidrug resistance by upregulation of ABCC1 (S Cho, M Lu et al, PNAS, in press, 2011). In order to determine whether there is a functional relationship between the two proteins, we performed drug efflux experiments. We treated drug-sensitive MCF-7 and multidrug resistant (MDR) MCF-7/VP breast cancer cells with the anticancer drug doxorubicin and measured the amount of drug efflux by flow cytometry over time. The MDR MCF-7/VP cells, which have high levels of activated Notch1 and ABCC1 proteins, exhibited increased doxorubicin efflux, compared to the drug-sensitive MCF-7 cells. Since γ-secretase (GS) is required for the processing of Notch into its active form, NIC, we blocked GS activity using a GS inhibitor, DAPT, in MCF-7/VP cells and assayed drug efflux from them. We found that inhibition of Notch signaling by DAPT blocks ABCC1 mediated drug efflux. To better understand the connection between Notch, ABCC1, and drug efflux, we compared drug efflux in MCF-7 cells stably overexpressing NIC (ICN1-c4, which also overexpress ABCC1), and the “empty vector” control MCF-7 cells (pcDNA3). As expected, we saw increased drug efflux in the ICN1-c4 cells compared to MCF7/pcDNA3 cells. To establish whether the observed drug efflux is ABCC1-specific, we treated ICN1-c4 cells with either the ABCC1-specific inhibitors reversan or probenecid, or with an ABCC1 siRNA to knockdown ABCC1 expression, and then examined these cells for changes in drug efflux. We found that inhibition of ABCC1, by reducing ABCC1 activity or levels in the presence of activated Notch1, blocks drug efflux from ICN1-c4 cells. In addition, we also found that the ABCC1 inhibitor reversan sensitizes ICN1-c4 cells to doxorubicin, and knockdown of ABCC1 reverses the resistance of ICN1-c4 cells to doxorubicin. These results strongly support the idea that Notch1 exerts its effect on ABCC1-mediated drug efflux to a large extent through its induction of ABCC1. Overall, our results reveal a novel functional relationship between expression of Notch and ABCC1. (Supported in part by CA40570 [to WTB] and in part by UIC.)
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 772. doi:1538-7445.AM2012-772
Abstract 773: Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein
Authors: Zhou Wen-jing , Wang Fang , Zhang Xu , To Kenneth Kin Wah , Huang Hong-bing , Fu Li-Wu 
Published: August 2012

Abstract
Background and purpose: Besides targeting the well-known oncogenic c-Met, crizotinib is the first oral tyrosine kinase inhibitor (TKI) inhibiting anaplastic lymphoma kinase (ALK) in clinical trials for the treatment of non-small cell lung cancer (NSCLC). In this study, we investigated the potential multidrug resistance (MDR) reversal by crizotinib in vitro and in vivo. Experimental approach: MTT methods were used in vitro and the xenografts in nude mice were used in vivo to investigate crizotinib reversal of MDR. To understand the mechanisms for MDR reversal, the alterations of intracellular doxorubicin(Dox) or rhodamine 123 accumulation, Dox effluxion, ABCB1 expression level, ATPase activity of ABCB1, and crizotinib-induced c-Met, Akt and Erk1/2 phosphorylation were examined. Key results: Crizotinib significantly enhanced the cytotoxicity of ABCB1 substrate chemotherapeutic agents in MDR cells, with no effect found on sensitive cells in vitro and in vivo. In addition, crizotinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin and inhibited the drug efflux in ABCB1-overexpressing MDR cells. Further studies showed that crizotinib enhanced the ATPase activity of ABCB1 in concentration-dependent manner. However, the expressions of ABCB1 were not affected and the reversal activity of crizotinib was not related to the phosphorylation of c-Met, Akt or Erk1/2. Importantly, crizotinib significantly enhanced the effect of paclitaxel against the KBv200 cell xenografts in nude mice. Conclusions and implications: Crizotinib was found to reverse ABCB1-mediated MDR by inhibiting ABCB1 transport function without involvement of ABCB1 expression or blockade of the Akt or Erk1/2 pathways. These findings is useful for combination chemotherapy of crizotinib with conventional chemotherapeutic drugs.
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 773. doi:1538-7445.AM2012-773
Abstract 779: Prodrug-mediated reversal of multidrug resistance in breast cancer cells
Authors: Ajaj Khalid Abu , Lee Yeonju , Graser Ralph , Kratz Felix 
Published: August 2012

Abstract
The P-glycoprotein (P-gp) is a 170 kDa protein that acts as an energy-dependent, transmembrane efflux pump and is encoded by the MDR1 gene. It has been shown to be responsible for multidrug resistance (MDR) in a defined subpopulation of breast cancer patients and thus represents a molecular target for circumventing MDR in this tumor indication. Third generation MDR modulators have been developed that demonstrated high selectivity for P-gp with inhibitory activities in the low nanomolar range. Although some objective responses were achieved in clinical trials, combination therapy with these MDR-modulators caused unacceptable toxicity. Targeting P-gp inhibitors to the tumor site is a means to increase their therapeutic index, and in this context binding tailor-made prodrugs to circulating albumin is an established technology to reduce the toxicity and enhance the efficacy of anticancer drugs. In this work we consequently developed an acid-sensitive albumin-binding prodrug of the P-gp inhibitor zosuquidar (LY335979) in a two-step synthesis using a maleimide hydrazone linker system established in our laboratory that first introduces acetylbenzoic acid at the OH-group of zosuquidar followed by derivatization with 6-maleimidocaproyl hydrazide to form the acid-sensitive hydrazone bond. The maleimide group enables the prodrug to bind rapidly and selectively to the cysteine-34 position of endogenous albumin after intravenous administration. HPLC analysis demonstrated rapid albumin binding of the zosuquidar prodrug as well as the quantitative release of the acetylbenzoic ester derivative of zosuquidar at pH 5.0. Subsequently, its ability to circumvent MDR was tested in two doxorubicin-resistant breast carcinoma cell lines (MCF-7/ADR and MT-3/ADR). The MDR status of these cell lines can be reversed by zosuquidar which was confirmed in a rhodamine 123 assay using fluorescence microscopy and FACS analysis. Furthermore, zosuquidar as well its acid-sensitive albumin conjugate re-sensitized cells to doxorubicin as well to an albumin-binding prodrug of doxorubicin, i.e. the 6-maleimidocaproyl hydrazone derivative of doxorubicin, achieving IC50 values in the same order of magnitude as the parental cell lines. Thus a novel formulation of zosuquidar has been developed that may be used to improve the toxicity issues and tumor targeting properties of the original compound.
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 779. doi:1538-7445.AM2012-779
Abstract 784A: Profiling pancreatic cancer metabolism and tumor microenvironment for therapy
Authors: Bose Sminu , Tsukamoto Takashi , Slusher Barbara , Royer Robert E. , Jagt David L. Vander , Le Anne 
Published: August 2012

Abstract
Pancreatic cancers have one of the highest fatality rates among all cancers and their response to therapies is highly variable. We have recently shown that inhibition of lactate dehydrogenase A (LDHA) and glutaminase (GLS) through small drug-like molecules causes pancreatic tumor regression. These studies indicate that targeting the metabolic reprogramming of cancer cells is a promising new approach to pancreatic cancer therapy. In order to translate these metabolic inhibitors to the clinic, our goal is to characterize and enable targeted selection of patients based on predicted metabolic response. Although genetic mutations may ultimately be the prime causes of early stage cancer, they can also lead to changes in cancer metabolism which enable cancer cells to proliferate and survive even under the hypoxic and nutrient-deprived conditions often encountered in the tumor microenvironment. The biochemical changes in cancer cells, which determine their behavior in terms of growth, survival and mobility, represent a functional readout of responses to external agents. We hypothesize that the metabolites of tumors that are sensitive to metabolic inhibitors are measurably different from those of resistant ones. We can therefore propose these metabolites as potential functional predictors of response. The proposed research will also study the metabolic reprogramming of cancer cells in the tumor microenvironment that can affect pancreatic cancer sensitivity to LDHA and GLS inhibition. The proposed experiments will use Metabolomics technology to trace the metabolic prototypes of pancreatic orthotopic xenografts to identify the metabolic signature of FX11 or BPTES-sensitive tumors as compared to resistant ones. For an analysis of the effects due to the tumor hypoxic microenvironment, we will use our innovative tool, the HypoxCR reporter system, which can simultaneously detect hypoxic cells and proliferating cells to define the effects of the pancreatic cancer tumor microenvironment on their sensitivity to metabolic inhibitors. This will be the first evaluation of the hypoxic tumor microenvironment in regards to how it affects the response of subfractions of pancreatic orthotopic xenograft tumor cells to metabolic inhibitors.
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 784A. doi:1538-7445.AM2012-784A