bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B24: Detection of O6- and N7-methylguanine adducts by LC/MS in brain tumor tissues obtained from patients treated with temozolomide.
Authors: Sadr Emad Seyed , Catana Dragosh , Tessier Alain , Sadr Mohamad Seyed , Alshami Jad , Sabau Carmen , Del Maestro Rolando 
Published: June 2012

Abstract
The current standard of care for glioblastoma includes surgery, radiotherapy and chemotherapeutic agents such as temozolomide (TMZ), a DNA methylating compound. The cytotoxic effects of TMZ have been linked to guanine methylation at the N7 and O6 positions. These adducts are not currently used as markers of TMZ efficacy.
Using liquid chromatography/mass spectrometry (LC/MS), we have established a sensitive analytical assay to directly detect both N7- and O6-methylguanine adducts from DNA following TMZ treatment. A limit of detection below 1 fmol was observed for O6-methylguanine, while N7-methylguanine was observed below 5 fmol. O6- and N7-methylguanine were successfully detected by LC/MS in tumour and normal brain tissue samples from patients treated with a neoadjuvant TMZ regimen for 14 days (75 mg/m2). Variations in levels of both methylated guanines were detected between patients as well as within different locations of the same tumour sample. This technique provides a direct detection of the damage inflicted by TMZ. This could potentially indicate the efficacy of the drug, allowing for prompt analysis and response. It also holds potential for determining efficacy of treatment dose, schedule and possible concomitant drugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B24.
Abstract B38: Troglitazone enhances breast cancer cell 18F-FDG uptake and intracelluar lactic acid accumulation through PPAR-r independent activation of the MAPK pathway.
Authors: Lee Su Jin , Paik Jin-Young , Cung Quach , Jung Kyung-Ho , Lee Kyung-Han 
Published: June 2012

Abstract
Purpose: There is growing interest in the anti-tumor effects of thiazolidinediones including troglitazone (TGZ). In this study, we assessed how TGZ acts on cancer cell glucose uptake, and further investigated its mechanism and relation to cancer cell survival.
Methods: T47D human breast cancer cells were treated with TGZ and measured for trypan blue and MTT assay-based cell viability, FDG uptake, intra- and extracellular lactic acid levels, and superoxide production. Involvement of signaling pathways for FDG uptake was investigated with specific kinase inhibitors and Western blots.
Results: TGZ caused dose-dependent suppression of T47D cell survival, and glucose deprivation substantially enhanced the killing effect from 15.6% to 84.2% of cells. However, in contrast to energy restriction mimetic agents that reduced FDG uptake, TGZ stimulated a prompt increase of FDG uptake that reached 245.0% of controls by 10 μM at 1 h. This response was poorly replicated by rosiglitazone and was unaffected by GW9662, indicating a PPAR-independent mechanism of action. TGZ rapidly stimulated mitogen-activated protein kinase (MAPK) activity, and inhibition of this pathway with PD98059, as well as inhibition of epidermal growth factor receptor (EGFR) activity with BIBX1382, completely abrogated the ability of TGZ to enhance FDG uptake. The increase in glucose uptake was accompanied by elevated lactic acid accumulation in the cells but not culture media. This indicates that TGZ stimulates glycolytic activity but suppresses lactic acid extrusion, which may contribute to its anti-tumor effects.
Conclusion: TGZ-induced suppression of T47D cell survival is potentiated by restricted glucose availability, but is uniquely accompanied by enhanced FDG uptake that occurs via PPAR-independent MAPK activation. This is associated with an increase in glycolytic metabolism along with suppression of lactic acid extrusion, which may play a role in the anti-tumor effect of TGZ.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B38.
Abstract B4: An important regulatory role of HDM2 in tumor angiogenesis pathway.
Authors: Muthumani Praneetha , Rathinavelu Appu 
Published: June 2012

Abstract
HDM2 is a master regulator and plays an important role in Tumor angiogenesis. To confirm this hypothesis, we used wild type LNCaP and HDM2 transfected LNCaP-MST prostate cancer cells for our study. In the HDM2 transfected cells we observed 96% higher HDM2 protein expression compared to LNCaP cells. In general, HDM2 over expression has been reported to be a potential cause for p53 degradation in many cancer cells. To confirm this negative correlation, p53 level was observed in HDM2 transfected cells. Compared to the wild type cells, only 10% of the p53 level was found in the HDM2 transfected LNCaP-MST cells. This confirms our speculation that, HDM2 mediated degradation of p53 may occur in LNCaP-MST cells. Following HDM2 transfection, the VEGF level was also increased by 180% in LNCaP-MST cells compared to LNCaP cells. Since, previous studies have indicated that HIF-1α has a major role in inducing VEGF transcription, we determined the level of HIF-1α in both cells. In LNCaP-MST cells, nearly 90% higher HIF-1α protein level was observed, this might be due to the inhibition of both prolyl hydroxylase and factor inhibiting HIF (FIH) activity by HDM2, which are essential to hydroxylate HIF-1α in critical position. Once, hydroxylated, HIF-1α can no longer bind to p300 and induce VEGF transcription. In addition, an increase in the activated form of STAT3 (p-STAT3) causing elevated VEGF transcription has been previously reported in many cancer cells. Accordingly, the p-STAT3 protein expressions observed in HDM2 transfected LNCaP-MST cells were 15 folds higher compared to the non-transfected wild type LNCaP cells. A negative regulatory role of p53 in controlling the levels of active STAT3 has also been previously reported in prostate cancer cell lines. Hence, it is suggested that HDM2 might be inducing the expression of active STAT3 by degrading p53 protein in LNCaP-MST cells. Overall, our results demonstrate that HDM2 has an important role in regulating the VEGF transcription via modulating HIF-1α and STAT3 protein expressions.
We thank the Royal Dames of Fort Lauderdale, Inc. for their support.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B4.
Abstract B43: Effects of anticancer drugs on cancer cells under hypoxic conditions.
Authors: Laitinen Sara , Fryknas Marten , Larsson Rolf , Gullbo Joachim 
Published: June 2012

Abstract
Introduction. Environment inside even a small tumor is characterized by total or partial oxygen deprivation, hypoxia. It has been shown that radiotherapy and some traditional chemotherapies are often less effective in hypoxia, and therefore it is important to investigate how different drugs act in different microenvironments. In this study we perform a screening of the effects of 15 clinically used chemotherapeutic drugs on five different cell lines in conditions of normoxia, hypoxia and anoxia.
Material and method. A panel of 15 commercially available drugs: 5-fluorouracil, acriflavine, cisplatin, digitoxin, digoxin, docetaxel, doxorubicin, etoposide, irinotecan, melphalan, mitomycin c, rapamycin, sorafenib, thalidomide and tirapazamine, was tested on the cancer cell lines A2780 (ovarian), ACHN (renal), MCF-7 (breast), H69 (SCLC) and U-937 (lymphoma). Parallel aliquots of the cells were grown at different oxygen pressures and after 72 hours of drug exposure fluorometric microculture cytotoxicity assay was performed.
Result and discussion. As shown in table 1 sorafenib, irinotecan and docetaxel were in general more effective in an oxygenated environment, while cisplatin, mitomycin c and tirapazamine were more effective in a low oxygen environment. Surprisingly, hypoxia in H69, MCF-7 and U-937 cells mostly rendered higher drug sensitivity. In contrast ACHN appeared more sensitive to hypoxia, giving slower proliferating cells, and consequently, was more resistant to most drugs in hypoxia.
Conclusion. A panel of standard cytotoxic agents was tested against five different human cancer cell lines cultivated at normoxic, hypoxic and anoxic conditions. Results show that impaired chemosensitivity is not universal, in contrast different cell lines behave different and some drugs appear even less effective in normoxia.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B43.
Abstract B46: Effective therapeutic response of MDA-MB-231 cell line to rapamycin.
Authors: Ferreira Livia C. , Lopes Juliana R. , Jardim Bruna V. , Leonel Camila , Gelaleti Gabriela B. , Caldas Heloisa C. , Abbud Mario F. , Zuccari Debora A.P.C. 
Published: June 2012

Abstract
The assessment of alternative therapeutics agents can develop more effective treatments in breast cancer, resulting in molecular-targeted drugs, developed from the knowledge of molecules involved in specific pathways that provide growth and progression of cancer. A large number of studies have suggested that immunosuppressive agents can act as powerful anti-cancer drugs. Rapamycin, a potent immunosupressor used routinely in transplant patients, also has antiproliferative, antifungal and antimicrobial activity. Recent studies show that rapamycin can alter the function of blood vessels by promoting thrombosis in tumor vessels and thus prevents the formation of tumor vasculature. In addition, experiments have focused on the antiangiogenic effects, antiproliferative and antimetastatic target protein inhibitors of rapamycin (mTOR), affecting the expression of genes involved in metabolism and protein synthesis. Thus, believing in the inhibitory effect of rapamycin in tumor progression in diferent tumor types, this study evaluated its antitumor activity in mammary tumoral cell line. Samples of breast cancer cell line, MDA-MB-231 (estrogen receptor negative) were cultured in medium DMEM with high glucose concentration (Cultilab), and incubated at 37° C in 5% CO2. All culture medium used was enriched with 20% BSA, 1% penicillin/streptomycin and 1% L-glutamine. It was established five groups, four of them received different concentrations of rapamycin (group I - 1nM, group II - 10nM, group III - 50nM and group IV - 100nM) and one group was classified as control group (control - group V). After the interval of 72 hours of application of rapamycin, cells were stained with Trypan Blue (cell vitality). The growth curve was performed by counting cells in a Neubauer chamber, in order to evaluate the effects of drug. After 72 hours, the group V contained 200 cells. In the treated groups I and II, there was a small decrease in cell number, reaching 180 and 150 cells, respectively. In group III, there was a reduction in cell number reached 118 cells and in group IV was observed 50% reduction in the number of cells compared to group V. These results prove that rapamycin is effective in controlling cell proliferation and causes a decrease in the number of cells. In addition, the action of rapamycin may be dose dependent, as increasing the dose applied in the same cell concentration there was a decrease in the amount of cells. This fact suggests that rapamycin can be a possible alternative to the establishment of therapeutic strategies for breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B46.
Abstract B52: A phase I-IIA, dose-escalating study of intravenous melphalan-flufenamide (J1) in adult patients with advanced solid tumors (I), advanced ovarian cancer, or non-small cell lung cancer (IIA).
Authors: Gullbo Joachim , Berglund Ake , Ullen Anders , Larsson Rolf , Lewensohn Rolf , Nygren Peter , Spira Jack 
Published: June 2012

Abstract
Introduction: Melphalan-flufenamide (previously designated J1) is an enzyme-activated (aminopeptidase N, APN) prodrug of melphalan. The mechanism of enzyme activation results in the selective intracellular trapping of melphalan in tumor cells. Treatment with melphalan-flufenamide results in a 10–20 fold higher intracellular concentration of melphalan in tumor cells than treatment with equal doses of melphalan, and has demonstrated enhanced cytotoxic activity in numerous in-vitro and in-vivo assays. Consistent with these observations, exposure to melphalan-flufenamide results in greater reductions in the rate of DNA synthesis and greater pro-apoptotic effects than direct treatment with the same doses of melphalan.
Experimental: In the dose-escalating phase I part of this study patients with end-stage solid tumor malignancies were admitted. After definition of Recommended Phase Two Dose (RPTD) the trial shifted to a phase IIA trial and only patients with selected diagnoses could be included.
Results: The dose limiting toxicity was bone marrow suppression, mainly reversible thrombocytopenia. This was particularly evident in heavily pretreated patients, and RPTD was set to an intravenous infusion of 50 mg (fixed dose) every third week. No cumulative toxicity was observed. In the phase IIA part of the study forty patients were included, twenty of which had ovarian cancer, and thirteen NSCLC. The ovarian cancer patients had received 3–8 previous lines of chemotherapy (mean 3.9, and 90 % had received both taxane and platinum drugs), the NSCLC patients 2–4 lines (mean 2.5, 100 % had received platinum drugs). Twenty-four patients could be radiologically evaluated after 3 cycles of melphalan-flufenamide. Out of twelve evaluable ovarian carcinoma patients two had PD, nine had SD and one had PR according to RECIST criteria. Two patients with SD had a CA125 response of −50 and −70 % respectively. Two patients with SD had clinical progression (ascites effusion) shortly after first evaluation. Eleven patients with NSCLC were evaluated; three had PD and eight SD, according to RECIST. Thus, in NSCLC disease stabilization was best response, one patient received nine cycles of melphalan-flufenamide, and progressed after seven months of therapy.
Summary: The APN-activated prodrug melphalan-flufenamide can safely be given to cancer patients. Dose is limited by hematological toxicity. The study suggests clinical activity (biochemical and radiological) in ovarian cancer, even after failure to several lines of chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B52.
Abstract B60: Phenothiazines inhibits repair of chemotherapy-induced DNA double-strand break in tumor but not in normal fibroblasts by modulating chromatin configuration.
Authors: Zong Dali , Haag Petra , Yakymovych Ihor , Lundholm Lovisa , Lewensohn Rolf , Viktorsson Kristina 
Published: June 2012

Abstract
Acquisition of drug resistance mechanisms by tumor cells poses severe limitations on the efficacy of conventional chemotherapy. Since most clinically useful chemotherapeutic agents cause DNA damage, suppression of tumor DNA repair capacity is expected to enhance tumor eradication. Based on earlier observations that phenothiazine compounds confer chemosensitization in lung cancer cells, we investigated whether these compounds could modulate DNA repair and the molecular details of their mechanisms of action. Colony formation and MTT assays were used to demonstrate phenothiazine-mediated chemosensitization. Immunoblotting, immunofluorescence and FACS studies were used to probe the effects of phenothiazines on DNA repair. Modulation of chromatin structure was achieved by increasing or decreasing the salt content in the culture media. In silico predictions of drug action based on gene signatures was performed by Connectivity Mapping. Our data revealed that phenothiazine co-treatment along with DNA damaging agents (e.g., bleomycin, cisplatin) resulted in sustained activation of, DNA-PK and FancD2, both of which are involved in DSB repair, even many hours after the removal of the DNA damaging agent. This effect was observed in a variety of human tumor cell lines, including those derived from lung-, breast- and ovarian cancer. Notably, repair of DNA damage by non-transformed fibroblasts and epithelial cells was not antagonized by phenothiazines, revealing a potential selectivity for tumor cells. Modulation of DSB repair by phenothiazines was sensitive to osmolality of the culture media. In addition, gene signature induced by phenothiazine treatment showed similarities to gene signatures induced by HDAC inhibitors. Taken together, phenothiazines may represent a novel of class of chemosensitizers which disrupt DSB repair by altering chromatin configuration.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B60.
Abstract B63: Targeting cancer cells with a glucose-conjugated DNA repair inhibitor.
Authors: Tomaszowski Karl-Heinz , Schirrmacher Ralf , Schirrmacher Esther , Kaina Bernd 
Published: June 2012

Abstract
Alkylating agents are important chemotherapeutic drugs used for the treatment of several types of cancers, including brain tumors, melanoma and lymphoma. These chemotherapeutic agents have a strong affinity towards oxygen atoms in DNA giving rise to the important genotoxic DNA lesions O6-methylguanine and O6-chloroethylguanine, which are responsible for the cytotoxic effects of several alkylating anticancer drugs (e.g. temozolomide and lomustine). The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is considered as an important player of drug resistance because it removes these DNA adducts from the DNA. The MGMT protein restores guanine in the DNA by a suicide repair reaction leading to irreversible inactivation and degradation of the protein. Therefore depletion of MGMT renders cells more susceptible to treatment with alkylating anticancer drugs. There has been numerous attempts to inactivate MGMT with different inhibitors like O6-benzylguanine (O6-BG) or O6-(4-bromothenyl) guanine (O6-BTG, lomeguatrib) in glioblastoma and malignant melanoma cells. These strategies however have failed thus far, mainly due to the severe side effects associated with the systemic sensitization of the patients to chemotherapeutic agents. The application of targeting strategies for MGMT inhibitors therefore should improve chemotherapy by selective inhibition of MGMT in the tumor. In our previous work we have shown that O6-BG and O6-BTG bound to glucose is efficient in inhibiting MGMT on enzyme level and in the cell, causing sensitization to DNA alkylating N-nitrosoureas (Kaina et. al., 2004; 2010). Here we show, using a quantitative MGMT assay, that intracellular uptake of O6-benzylguanine-C8-glucose (O6-BG-Glu) occurs by a transporter-dependent mechanism and not through passive diffusion. We observed differences in the transport kinetics between several cell lines. Most cancer cell lines are able to take up the inhibitor, whereas normal cells only show marginal uptake of the glucose-conjugated inhibitor. The uptake is probably not depended on the glucose transporter GLUT since blocking of GLUT does not abolishes MGMT inhibition. Uptake of the glucose conjugated inhibitors in cancer cells leads to an increased DNA damage response, induction of apoptosis and significant decrease in surviving fraction after treatment with alkylating anticancer drugs, pointing to the usefulness of the glucose-mediated MGMT inhibitor targeting strategy. References: Kaina et al., J. Pharmacol. Expt. Therap., 311, 585–593 (2004); Kaina et al., Cell. Mol. Life Sci., 67, 3663–3681 (2010)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B63.
Abstract B64: Structure and preclinical characterization of BMN 673, a potent and orally active PARP inhibitor as an anticancer agent.
Authors: Shen Yuqiao , Feng Ying , Wang Bing , Myers Peter , Chu Daniel , Post Leonard E. 
Published: June 2012

Abstract
In this presentation we will present the chemical structure, biological activity and pharmacokinetic (PK) properties of BMN 673, a potent inhibitor of poly (ADP-ribose) polymerases (PARP)-1 and -2. PARP-1 and -2 are key nuclear enzymes that are activated by DNA damage and play a critical role in the base excision DNA repair (BER) pathway. Inhibitors of PARP-1 and -2 could enhance the cytotoxicity of DNA damaging agents by preventing cancer cells from repairing DNA damage. In addition, PARP inhibitors have been shown to selectively kill cancer cells that are deficient in BRCA-1 or BRCA-2 function. A previously unexplored chemical scaffold was discovered with good PARP inhibitory activity. Optimization of this scaffold produced BMN 673, the most potent PARP inhibitor reported to date. BMN 673 selectively kills cancer cells with BRCA-1 or BRCA-2 mutations. In xenograft tumor model studies, oral dosing of BMN 673 results in complete regression of the BRCA-deficient tumors. In addition to BRCA-1/2 mutations, we examined the correlation of other DNA repair defects with the tumor cells' sensitivity to BMN 673 treatment. We show that tumor cells with PTEN mutation are highly sensitive to BMN 673 treatment in vitro. Xenograft tumor models that harbor PTEN deficiency responded to oral BMN 673 treatment with significant tumor growth delay. Deficiencies in ATM and other homologous recombination (HR) DNA repair genes, as well as unidentified genetic deficiencies, result in sensitivity to cell killing by BMN 673 in head-and-neck cancer, myeloma, and mantle cell lymphoma. These results suggest that BMN 673 may be a valid treatment option for cancers with these genetic defects. In animal PK/PD studies, BMN 673 displays good oral bioavailability and PK properties, and demonstrates significant in vivo PARP inhibition in xenograft tumors and other tissues. BMN 673 is currently in phase 1 clinical trials in patients with solid tumors or hematological malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B64.