bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3514: LT-00673, a highly potent PARP inhibitor, shows antitumor activity against tumor cells with DNA repair deficiencies
Authors: Shen Yuqiao Jerry , Feng Ying , Wang Bing , Chu Daniel , Myers Peter , Post Leonard 
Published: February 2011

Abstract
Poly (ADP-ribose) polymerases (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. Previous studies have indicated that inhibitors of PARP-1 and −2 could enhance the tumor 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. More recently, it was further suggested that other genetic deficiencies, such as PTEN gene mutation and malfunction of DNA mismatch repair, may also sensitize cells to cytotoxicity of PARP inhibitors. We have previously reported a novel PARP inhibitor, called LT-00673, that inhibits PARP-1 with IC50 of 0.58 nM. LT-00673 is also a potent inhibitor of PARP-2, but does not inhibit poly (ADP-ribose) glycohydrolase (PARG). In cell culture studies, LT-00673 potentiates chemotherapeutic agents such as temozolomide and SN-38, and displays potent single-agent cytotoxicity in BRCA-1 and BRCA-2 mutant cells. In xenograft tumor model studies, daily oral dosing of LT-00673 significantly enhances the antitumor effects of cytotoxic therapies in a dose-dependent manner. Furthermore, once daily oral dosing of LT-00673 at 0.33 mg/kg/day results in tumor regression in the MX-1 model (BRCA-1 deficient). In the current study, we further investigated the pharmacokinetic properties of LT-00673 in dogs and rats, and compared antitumor efficacies of different dosing schedules of LT-00673 using xenograft tumor models. We also demonstrated that several PTEN-deficient human cancer cell lines are highly sensitive to LT-00673 as a single agent.
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 3514.
Abstract 3523: C7, C9-dimethylifosfamide analogs evaluation for antitumor activity and toxicity: Detoxification pathways might explain nephrotoxicity
Authors: GIRAUD Bérénice , HEBERT Guillaume , DEROUSSENT Alain , DAUDIGEOS Estelle , MARTELLI Sonia , VASSAL Gilles , PACI Angelo 
Published: February 2011

Abstract
Ifosfamide (IFO) is an anticancer drug, widely used against various types of human solid tumors. This prodrug produced active alkylating isophosphoramide mustard. But its side-chain oxidative metabolism is associated with toxicities in high-dose chemotherapy. As acrolein urotoxicity is limited by coadministration of mesna, chloroacetaldehyde (CAA) is responsible for neurotoxicity and nephrotoxicity. C7, C9 dimethyl-ifosfamide analogs have been synthesized to prevent these side effects. In vitro metabolism and anticancer activity investigations demonstrated that the generated dimethylated mustards were faster alkylating agents (28 fold faster) than isophosphoramide mustard and IC50 values on 9L glioblastoma cells showed higher cytotoxicity of analogs, especially the 7S,9S enantiomer (1). This later was selected for in vivo investigations. As these analogs were still metabolized through the same N-deschloroalkylation pathway, monoochloroacetone (MCA) is produced instead of CAA. In a first step, in vitro/ex vivo experiments were conducted to investigate its toxicity. The toxicity of both metabolites was compared by evaluation of cell viability using canine kidney cell lines (MDCK) and rabbit renal proximal tubules (RRPT). Cell viability experiments showed that similar IC50 values were obtained for CAA and MCA (21 and 23 µM) on MDCK. To determine detoxification pathways, several experiments were conducted on RRPT. Whereas these compounds could react directly with glutathione (GSH), identification of GSH and its conjugates (GSR) was performed by LC/MS after incubation of MDCK and RRPT with 200 µM CAA and MCA. Both enzymatic reduction and GSH conjugation pathways occurred. Conjugates were then quantified by LC-MS/MS over 1-650 µM for GSH and over 1-200 µM for GSR from 20 to 120 min. The results demonstrated a rapid depletion of GSH and few differences in detoxification's kinetics for CAA and MCA. As MCA in vivo generated levels are still unknown, 7S,9S dimethyl-IFO analog is currently under investigation on human tumor cells xenografted in mice in order to confirm its antitumor activity and to evaluate its toxicity.
(1) Storme T, Deroussent A, Mercier L, Prost E, Re M, Munier F, Martens T, Bourget P, Vassal G, Royer J and Paci A. J Pharmacol Exp Ther. 2009, 328(2):598-609.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3523.
Abstract 3524: Plasma pharmacokinetics and metabolism of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice
Authors: Parise Robert A. , Eiseman Julie L. , Egorin Merrill J. , Clausen Dana M. , Covey Joseph M. , Beumer Jan H. 
Published: February 2011

Abstract
Introduction: BEN is an alkylating agent in early clinical trials based on its in vitro and in vivo activity against renal cell carcinoma. We have previously reported that BEN is rapidly metabolized into its carboxylic acid (BA) and that BEN and BA undergo chemical conversion in vitro. In support of current clinical trials, we characterized the pharmacokinetics of BEN, BA, and their products in mice.
Materials & Methods: Female CD2F1 mice were dosed with 20 mg/kg BEN i.v. Twelve blood samples were obtained between 0 and 24 hrs and urine was collected at 0-6 hrs and 6-24 hrs. Formic acid was added to all samples (5%, v/v) and the sample processing was performed on ice to stop ex vivo chemical conversions. Plasma and urine concentrations of BEN, and its metabolites and conversion products were quantitated with LC-MS/MS. Plasma and urine pharmacokinetic parameters were calculated non-compartmentally.
Results: BEN was rapidly converted to at least 13 different metabolites or products. The half-life (T1/2) of BEN was approximately 60 min. Half-lives of metabolites were all &gt;2 h. The analytes that could be quantitated in urine represented approximately 30% of the dose administered.AnalyteCmax (µg/ml)Tmax (min)T½ (min)AUC0-inf (mg/mL*min)Vd/F (L/kg)Cl/F (mL/min/kg)% Dose 0-24 h urineBEN4.355922.974.50.96.6BA26.1531315.72.80.18.5BA-(OH)20.71107323.988.10.815.5BEN-(Cl)20.001151080.2471264481.1NDBA-(Cl)20.027580.58938534NDBEN-(OH)20.6565416.811732.9NDBA-Cl-OH 513 BA-Cl 528 BA-OH 529 BA-Gluc 1031 BA-(OH)2-Gluc 1531 BA-Cl-OH-Gluc 3049 BA-Cl-Gluc 15107 BA-OH-Gluc 1036
ND, not detectable; NQ, not quantifiable.
Conclusions: BEN is rapidly metabolized to BA and chemically converted to many subsequent products, some of which are glucuronidated. Several metabolites and conversion products contain chloroethyl or methanesulphonate moieties, which would allow them to alkylate cellular targets and exhibit anti-neoplastic properties or cause toxicity. The enzymes responsible for the metabolism of BEN and BA need to be identified.
Support: N01-CM07106, N01-CM52202, P30-CA47904 from the NCI.
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 3524.
Abstract 3534: Proposed pathway of disposition of ON 01910. Na, a novel clinical trial stage anti-cancer agent: Implicaton of Mrp2 in biliary excretion in the isolated perfused rat liver system
Authors: Taft David , Chun Amy , Ren Chen , Maniar Manoj 
Published: February 2011

Abstract
Introduction: ON 01910. Na is a novel targeted anti-cancer agent under clinical investigation in Phase I and Phase II trials. Preclinical studies indicate that the compound preferentially distributes to the liver but is not extensively metabolized in vivo The purpose of this study was to evaluate the disposition of ON 01910. Na employing the isolated perfused rat liver (IPRL) model. The specific goals were to 1) Assess the dose-linearity of ON 01910. Na disposition; 2) Probe the role of the Mrp2 transporter on ON 01910. Na biliary excretion; and 3) Establish the effect of concurrent dosing with oxaliplatin and doxorubicin on ON 01910. Na hepatobiliary disposition. Methods: Perfusion experiments (n=3/group) were performed at 4 doses (0.8, 4, 8, 20 mg), targeting a range of perfusate levels between 10 and 250 ug/ml. ON 01910. Na (10 ug/ml) disposition was then studied in the presence of doxorubicin (2.5 ug/ml) and oxaliplatin (2 ug/ml). IPRL experiments were also conducted using livers from Mrp2 deficient rats. ON 01910. Na was assayed in perfusate and bile samples by HPLC. Results: ON 01910. Na parameter estimates are provided in the table below. The compound displayed nonlinear excretion in the IPRL, and ON 01910. Na disposition was altered in mrp2-deficient rats. The effect of co-administered chemotherapeutic agents is being investigated. Conclusions: ON 01910. Na showed extensive biliary excretion in the IPRL, and IPRL findings correlated with in vivo data in rats. ON 01910. Na biliary transport appears to be mediated in part by Mrp2.ON 01910. Na Disposition in the IPRLaPARAMETERON 01910. Na (µg/ml) 10.050.0100250t1/2 (hr)0.460 (0.0340)0.327 (0.0674)0.585 (0.0810)1.26 (0.318)Cmax (µg/ml)11.3 (1.75)56.1 (7.12)106 (11.2)257 (658)AUC (0-∞) (µg*min/ml)290 (87.1)1480 (73.0)4010 (963)21100 (2580)Cl (ml/min)2.91 (0.753)2.71 (0.134)2.08 (0.557)0.959 (0.125)% Drug Excreted in Bile57.2 (5.04)59.2 (7.40)68.4 (0.870)45.6 (2.66)aData presented as mean (standard deviation)
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 3534.
Abstract 3537: P-glycoprotein expression level is responsible for alterations in plasma membrane microfluidity as probed by fluorescence correlation spectroscopy
Authors: Winckler Pascale , Jaffiol Rodolphe , Morjani Hamid , Deturche Regis , Royer Pascal , Jeannesson Pierre 
Published: February 2011

Abstract
Expression of P-glycoprotein (P-gp), the multidrug resistance (MDR) 1 gene product, leads to MDR in tumors. By using the fluorescent membrane probe DiA and Fluoresence Correlation Spectroscopy (FCS) to explore the plasma membrane microfluidity, we have previousely shown a showed a decrease in plasma membrane microfluidity in LR73R cells (the Chinese hamster ovarian LR73R cells transfected with MDR1 cDNA) (1).
In the present study, and in order to study the relationship between membrane microfluidity and the level of P-gp expression, a strategy using flow cytometry and calcein-AM functional fluorescence-activated cell sorting permitted us to select two cell populations from LR73R cells expressing distinct levels of P-gp (P4 “lower calcein-AM uptake” and P5 “higher calcein-AM uptake”). Data obtained on the cytotoxic effects of doxorubicin (DOX) showed clearly that P4 cells were 10-fold resistant to DOX than P5 cells. A direct correlation between the sensitivity of the cells to DOX and the calcein-AM uptake was observed. In addition, intranuclear DOX measurements using microspectrofluorometry showed a decrease in nuclear accumulation of DOX in P4 cells when compared to P5 cells. This was in agreement with the functional calcein-AM uptake assay.
By using the fluorescent membrane probe DiA FCS analysis, we explored the membrane microfluidity in P4 and P5 cells. We show that P5 cells presented an increase in membrane fluidity when compared to P4 cells. LR73 cells presented the highest microfluidity when compared to P4 and P5 cells. This was in agreement with the previous published data (1) and demonstrate also that the microfluidity of the plasma membrane is strongly related to the level of Pgp expression.
(1) Boutin C, Roche Y, Millot C, Deturche R, Royer P, Manfait M, Plain JM, Jeannesson P, Millot JM, Jaffiol R. High heterogeneity of plasma membrane microfluidity in multidrug-resistant cancer cells. J Biomed Opt. 2009 14(3): 034030.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3537.
Abstract 3544: Assessment of chemo-response in cells derived from patients with malignant ascites
Authors: Peedicayil Abraham , Rattan Ramandeep , He Xiaoping , Kalli Kimberly R. , Cliby William A. , Chien Jeremy , Shridhar Vijayalakshmi 
Published: February 2011

Abstract
Objectives. To assess chemo-response of patient derived ovarian cancer cells to first line chemotherapeutic agents as well as targeted therapies.
Methods. Ascites was obtained at laparotomy from 14 patients with epithelial ovarian cancer. Short term cultures were established in 11 of these and the cells characterized by morphology and immuno-staining to cytokeratin AE1/AE3 and E-cadherin. MTT assays were done on the 11 samples after 48 hours of exposure to Cisplatin, Paclitaxel, Vandetanib and Flavopiridol.
Results. Three samples did not grow well and ultimately showed senescence or were over-run by fibroblasts. In the remaining 11 samples, morphology showed the cells to be arranged in a cobble-stone or rosette pattern. Most of the cells stained positive for cytokeratin AE1/AE3 and E-cadherin. The majority of samples (8/11, 73%) were sensitive to either Cisplatin or Paclitaxel. Of the three resistant samples, one was sensitive to Vandetanib, one to Flavopiridol and one was resistant to all four drugs. Two patients did not receive chemotherapy due to morbidity or mortality. Among those who were treated, 4 (50%) had complete response and are currently free of disease.
Conclusions. Short term cultures may be a good method of studying chemo-response of tumor cells ex-vivo.
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 3544.
Abstract 3552: Mirk kinase mediates cisplatin resistance in ovarian cancers
Authors: Hu Jing , Friedman Eileen A. 
Published: February 2011

Abstract
Epithelial carcinoma of the ovary is the fifth most frequent cause of cancer death in women, and the second most frequent gynecological malignancy. Cisplatin based regimens are the standard of care, but efficacy is limited by drug resistance. Cisplatin treatment increased intracellular levels of toxic reactive oxygen species (ROS) in each of four ovarian cancer cell lines in a dose-dependent manner, while concomitantly reducing cell numbers, which suggested that further increasing ROS levels might increase cisplatin toxicity. The serine/threonine kinase Mirk/dyrk1B is known to increase the expression of a cohort of antioxidant genes in various cells. Targeting Mirk expression by RNA interference also increased ROS levels in these ovarian cancer cell lines while decreasing levels of ferroxidase (ceruloplamin) which prevents the generation of hydroxyl radicals. A combination of Mirk depletion and cisplatin treatment enabled low levels of drug to increase ROS to toxic levels in both SKOV3 cells and TOV21G cells. Increased tumor cell death by the combination treatment was confirmed by loss of viable cells capable of dye exclusion, a decrease in cell number, and an increase in pro-apoptotic proteins. Mirk has a second function in ovarian cancer cells, to maintain cells in quiescent state where they are less vulnerable to chemotherapeutic drugs and radiation. The majority of ovarian cancer cells in human tumors are not cycling as shown by lack of Ki67 expression. Some of these cells may be in a reversible quiescent state where they can contribute to cancer spread under favorable growth conditions. Depletion of Mirk in SKOV3 cells enabled them to escape quiescence. Studies using cisplatin revealed a Mirk-dependent G0/G1 checkpoint in SKOV3 and other p53 mutant ovarian cancer cells. The Mirk gene is on the 19q13 amplicon which is found in about one-third of all ovarian cancers. The Mirk gene was amplified in the OVCAR3 cell line where it mediated both quiescence and increased expression of antioxidant genes which decreased cellular ROS levels. Mirk protein was expressed in 21 of 28 resected human ovarian cancers as shown by immunohistochemical analysis, and was detected in each of 7 ovarian cancer cell lines, where it was an active kinase. Mirk is not an essential gene for either murine embryogenesis or the viability of human diploid fibroblasts. Targeting Mirk in ovarian cancers may sensitize these tumors to lower levels of cisplatin, both by increasing ROS levels and by releasing tumor cells from quiescence.
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 3552.
Abstract 3563: Novel anticancer agents modulate multiple signal transduction pathways for cancer therapy
Authors: Jong Ling , Chao Wan-ru , Shi Yihui , Green Carol , Sambucetti Lidia , Collins Nathan 
Published: February 2011

Abstract
Cancer is remarkably heterogeneous and is associated with wide variations in biological behavior. Except for some rare cancers whose growth may depend on a single factor, no single signaling pathway drives the oncogenic behavior of all tumors. In fact, most single-target agents that have undergone development in recent years have lacked the exquisite level of effectiveness. Multitarget drugs and the network approach may thus constitute a useful means for discovering novel drugs; such drugs emerge from the sum of the interactions that, together, are the principal determinants of the system-scale behavior of the cell. A multitarget agent is not necessarily more toxic than single-target agents. These multitarget drugs have presumed low-affinity interactions with several of their targets, and do not necessarily shut down a pathway completely or activate it excessively; thus they may have lower side effects.
We has developed a novel class of dietary indole analogs with oral anticancer activity against a variety of cancer in animal models, including prostate, breast, lung and ovarian tumors. Western blot analysis shows that SR13654, SRI advanced lead, is able to induce apoptosis by caspase activation and poly(ADP-ribose) polymerase (PARP) cleavages. Using the Boyden chamber assay, we showed that SR13654 significantly inhibits PC-3 cells’ invasion at low concentration, and its anti-invasive activity is not due to cell killing or simple cell growth inhibition. In vitro and in vivo mechanistic studies show that SR13654 inhibits Src activation, down-regulates survivn expression, enhances EGFR degradation. SR13654 also produced a decrease in cyclin D1 and B1, and an increase in p21 levels in cancer cells. Screening a full panel of 285 kinases shows that SR13654 is not a kinase inhibitor. More in-depth mechanistic studies are undergoing. Preclinical safety studies indicate that this class of compounds holds great promise for extended therapeutic use to maximize disease control without compromising quality of life.
SR13654 has relatively poor water solubility, which could limit its use in intravenous dosing. We have developed the second generation of water-soluble analogs, such as SR13677, which has significantly improved water solubility and is at least 5-fold more potent than SR13654 against various cancer cell lines. With support from the 2009 DOD/Prostate Cancer Research Program (PCRP) “Laboratory-Clinical Transition” Award, we will advance the optimized candidate through preclinical development and future IND filing.
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 3563.
Abstract 3569: Photodynamic activity of the glucoconjugated silicon(IV) phthalocyanine SiPcGlu
Authors: FONG Wing-Ping , Cheang Wai-San , Lo Pui-Chi , Ng Dennis K.P. 
Published: February 2011

Abstract
Photodynamic therapy involves the use of a non-toxic photosensitizer which exhibits killing effect upon activation by light. It has been used successfully in treating age-related macular degeneration, actinic keratosis and various cancers like lung, bladder and esophageal cancers. The success of photodynamic therapy depends on the properties of the photosensitizer and there is a continuous search for better photosensitizers with desirable photophysical and biochemical effects. In the last few years, we have synthesized a series of silicon(IV) phthalocyanines with different axial substituents and demonstrated their photocytotoxic effects in the in vitro heptocellular carcinoma HepG2 cells. Among them the glucoconjugated silicon(IV) phthalocyanine SiPcGlu is most promising with IC50 value down to nanomolar range in the cell culture system. In the present investigation, the in vivo effect of SiPcGlu was studied in the HepG2 tumor-bearing nude mice model. The biodistribution of SiPcGlu was followed to evaluate its tumor-selectivity and the tumor volume was measured after photodynamic therapy. The level of intrinsic toxicity induced was also investigated by examining the level of plasma enzyme markers. The distribution and clearance results showed that the concentration of SiPcGlu in the tumor was relatively higher at 24 hr post-injection when compared with all the other tissues examined. One percent of initial dose per gram tissue could be found in the tumor while the corresponding values for the other tissues ranged from 0.8% (lung) to 2.5% (skin). Thus, a drug-light interval of 24 hr was selected in the photodynamic therapy experiment. A laser light dose of 30 J/cm2 (bandwidth 675 ± 3 nm) was spotted onto the tumor 24 hr after intravenous injection of the drug (one μmol per kg body weight). Significant tumor regression was observed for the experimental group of mice. Fifteen days after photodynamic treatment, the volume of the tumor was less than 20% of the initial volume while mice in the two control groups, viz. dark control in which the mice received drug but no irradiation and the light control group in which the mice received irradiation but no drug, did not show any tumor regression. The photodynamic treatment did not cause any apparent toxicity to the animals as the plasma levels of the three enzyme markers, alanine transaminase, aspartate transaminase and creatine kinase, were similar in all the three groups of mice. To conclude, the present results suggest that SiPcGlu is a good candidate for further evaluation on its anti-tumor potential. (This project is supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, Project No. CUHK 4569/05M.)
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 3569.