bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C125: Tanespimycin pharmacokinetics: Results of a randomized dose-escalation crossover phase 1 study of two formulations
Authors: Burris Howard A. , Jones Suzanne , Messina Marianne , Berman David 
Published: June 2012

Abstract
Introduction: Tanespimycin is an inhibitor of Hsp90, a chaperone for proteins involved in tumor growth and survival. In vitro, tanespimycin sensitizes tumors to anti-cancer therapies. Tanespimycin has demonstrated clinical activity as monotherapy and in combination with bortezomib in multiple myeloma pts and with trastuzumab in pts with HER2+ breast cancer.
Study Design: In this single-center, open-label dose-escalation study, pts were randomized to receive 1 dose IV of Cremophor-containing tanespimycin or tanespimycin suspension and then crossed over and received 1 dose of the other formulation. One cohort (3–6 pts) received 275 mg/m2 and 1 cohort (6–12 pts) received 340 mg/m2. After crossover, pts continued receiving tanespimycin suspension twice weekly on days 1, 4, 8, and 11 of each 21-d cycle until disease progression. Blood samples were collected on days 1 and 8 at the following times: predose, during infusion, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h postdose. Plasma concentrations of tanespimycin and its metabolite 17-AG were quantified by LC/MS/MS. Investigators graded adverse events (AEs) using the CTCAE v3.0 and tumor responses using RECIST.
Results: A total of 17 pts were enrolled in the study: 5 pts in the 275 mg/m2 cohort; 12 pts in the 340 mg/m2 cohort. Fourteen pts continued treatment following crossover. The mean age was 59.5 y and 76.5% were women. The median time since diagnosis was 41.5 mos and most common primary diagnoses were breast cancer 29%, non-small cell lung cancer 12%, and larynx cancer 6%. The plasma concentration:time curves show biexponential decay with a rapid distribution followed by a slower elimination phase. Profiles for the Cremophor-containing and suspension formulations were similar with Cmax for the 275 mg/m2 dose of 8050 ng/mL and 5235 ng/mL, respectively, and Cmax for the 340 mg/m2 dose of 10,578 ng/mL and 9270 ng/mL, respectively. t1/2 ranged from 3–4 h for tanespimycin and 4–5 h for 17-AG. Tmax for all doses was approximately 1 h for tanespimycin and 1.5–2.6 h for 17-AG. The most common AEs (all grades) in the continuation phase were: vomiting (65%; Gr3/4 0%), diarrhea (53%; Gr3/4 18%), nausea (47%; Gr3/4 0%), fatigue (35%; Gr3/4 9%), and headache (24%; Gr3/4 0%). Of the 11 response evaluable pts, 7 pts had a best response of stable disease (duration ranged from 4.1+ to 35.6 wks).
Conclusion: Tanespimycin suspension was well tolerated in pts with solid tumors. Plasma concentration:time curves were similar for the 2 formulations with biexponential decay showing a rapid distribution followed by a slower elimination. These results support ongoing studies with twice weekly doses of 340 mg/m2 tanespimycin suspension.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C125.
Abstract C127: Factors affecting the pharmacokinetics (PK) and pharmacodynamics (PD) of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors
Authors: Wu Huali , Infante Jeffrey R. , Jones Suzanne F. , Burris Howard A. , Chan Emily , Keedy Vicki L. , Bendell Johanna C. , Zamboni Beth A. , Kodaira Hiroshi , Ikeda Satoshi , Zamboni William C. 
Published: June 2012

Abstract
Background: Irinotecan (CPT-11) is a prodrug of SN-38 that has antitumor activity in a wide range of solid tumors. IHL-305 is a PEGylated-liposomal formulation of CPT-11. The PK of liposomal agents is highly complex due to the variability in the disposition of the inactive-encapsulated drug and the release of active-drug from the liposome. We previously reported that age, body weight, and monocytes affect the PK and PD of PEGylated liposomal agents. Thus, we evaluated the effect of these factors on the PK and PD of IHL-305 as part of a phase I study.
Methods: IHL-305 was administered IV over 1 h at 3.5, 7, 10.5, 14, 28, 33.5, 37, 50, 67, 80, 88, 120, 160, and 210 mg/m2 q 28 d. Serial plasma samples were obtained prior to infusion, at the end of infusion (EOI), and from 1 to 192 h after EOI. Plasma samples were processed to measure sum total (encapsulated + released) CPT-11, released CPT-11, SN-38 and SN-38 glucuronide (SN-38G). The total (lactone + hydroxy acid) forms were measured by HPLC. The area under the plasma concentration versus time curve (AUC) for each form was calculated from 0 to last sampling time and from 0 to ∞. The ratio of total body weight to ideal body weight (TBW/IBW) was calculated.
Results: 39 patients (pts) (13 male) were treated. Median (range) of age and TBW/IBW were 60 years old (yo) (42–75 yo) and 1.16 (0.81–2.7), respectively. There was high inter-patient variability in the PK disposition of sum total CPT-11, released CPT-11, SN-38 and SN-38G. Sum total CPT-11 is associated with linear and non-linear clearance. The ratio of SN-38 to released CPT-11 and SN-38G to SN-38 were similar to those reported after irinotecan. Pts whose age and TBW/IBW were greater than the median of the study had a 1.7- to 2.6-fold higher ratio of released CPT-11 AUC to sum total CPT-11 AUC. In pts &lt; 60 yo and in pts ≥ 60 yo, the ratio of % decrease in monocytes at nadir to % decrease in ANC at nadir were 1.65 ± 1.36 and 1.24 ± 0.68, respectively. There was an inverse relationship between pts age and % decrease in monocytes at nadir with younger pts having a higher % decrease in monocytes. Pts with a higher % decrease in monocytes at nadir have an increased clearance of sum total CPT-11 and increased exposure of released CPT-11 and ratio of released CPT-11 AUC to sum total CPT-11 AUC.
Conclusions: PK and PD of IHL-305 are consistent with a PEGylated-liposomal carrier. IHL-305 has pharmacological advantages compared with irinotecan. The inter-patient variability in the PK and PD of IHL-305 was associated with age, body composition, and monocytes. Sponsored by Yakult Honsha Co., Ltd., Tokyo, Japan
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C127.
Abstract C13: Ascorbate induces cytotoxicity in prostate cancer cells through an autophagy pathway
Authors: Chen Ping , Chalmers Brian , Yang Jun , Li Benyi , Drisko Jeanne A. , Chen Qi 
Published: June 2012

Abstract
Ascorbate (Vitamin C) has been shown to act as a pro-oxidant agent under pharmacological concentrations, and thus can cause cancer cell death in vitro and inhibit tumor growth in animal models, through formation of H2O2. The cell death mechanisms induced by ascorbate need to be further elaborated.
The goal of our study was to determine whether ascorbate is cytotoxic to prostate cancer cells and if so, to determine the mechanism of ascorbate-induced cytotoxicity. We hypothesized that through generation of H2O2, pharmacological concentrations of ascorbate can deplete prostate cancer cell ATP and cause cell death through autophagy pathway. A panel of prostate cancer cell lines PC-3, LNCap, C4-2, LaPC4 and 22RV1 were incubated with millimolar range of ascorbate for two hours. Then ascorbate was washed out and cells were incubated in fresh media for 24 hrs before cell viability was assessed. Cell ATP levels were determined by HPLC. The results showed that 4 out of the 5 tested cell lines have IC50s &lt; 5 mM, while the most resistant cell line LaPC4 has IC50 at 12 mM. Addition of catalase - a H2O2 scavenger to the culture media, completely protected the cells from the death caused by ascorbate, confirming the death is mediated by H2O2. PC-3 cell ATP levels significantly decreased after 2 hrs of incubation with 5 mM ascorbate, and did not recover over the following 24 hrs. To determine if ascorbate induced autophagy, western blot of PC-3 cells for LC3 was performed. The results showed an increase of LC3-II form at 2 hrs of ascorbate treatment, indicating the processing of LC3 protein to its lipidated form. At 24 hrs the LC3-II bands were decreased, which may due to degradation of LC3 proteins at the autophagosomes. We also generated cells (PC3-LC3G) that express a fusion protein of LC-3 and GFP. The GFP-LC3 protein punctation were observed at 4 hrs of ascorbate treatment, indicating a translocation of LC3 to the autophagic membranes. These results suggest that ascorbate induces cytotoxicity in prostate cancer cells through depletion of cell ATP and induction of autophagy. To further confirm this pathway, an autophagy inhibitor 3-MA is under testing, the degradation of GFP-LC3 is also under analysis to determine whether ascorbate increases the autophagic flux. Also, to confirm the role of ATP drop in ascorbate-induced autophagy, 3-aminibenzamide (3AB) and 4-hydroxyquinazoline (4HQ) are being used to prevent the drop in ATP level.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C13.
Abstract C134: Survivin suppressant YM155: A pharmacokinetic comparison between U.S. and Japanese populations
Authors: Cao Ying J. , Aoyama Yumiko , Kakihara Toru , Katashima Masataka , Sawamoto Taiji , Roy Michael , Wang Jimmy , Abeyratne Anura , Nakahara Takahito , Steinberg Joyce , Keating Anne 
Published: June 2012

Abstract
Survivin is a member of IAPs. YM155 is a compound that suppresses survivin, and has been shown to exhibit anti-tumor activity in preclinical and clinical studies. The current analysis is designed to compare the pharmacokinetics (PK) of YM155 between US and Japanese patient populations using data obtained from two phase 1 trials, one done in Japan and the other in the US. Patients with a confirmed solid tumor or NHL (US only) that were refractory to standard therapy or for which no standard therapy was available participated in these trials. YM155 was administered as a continuous IV infusion for 168 hours, every 21 days. During the first two treatment cycles, serial blood and urine samples were collected for up to 48 hours after the discontinuation of YM155 infusion on Day 7. Forty-one subjects in the US trial (including 5 subjects with NHL) and 33 subjects in the Japanese trial had adequate samples for PK evaluation. The maximum tolerated dose (MTD) was 4.8 mg/m2/day and 8.0 mg/m2/day in the US and Japanese populations, respectively. In both populations, median YM155 concentration appeared to reach steady-state 12–24 hours after the start of the YM155 infusion. After discontinuation of the YM155 infusion, plasma YM155 concentration declined rapidly in a biphasic pattern with mean terminal half-life between 6 and 29 hours. The geometric mean ratio [90 % confidence interval(CI)] of steady-state YM155 concentration (Css) and area under observed YM155 concentration-time curve extrapolated to infinity (AUCinf) between cycle 2 and cycle 1 was 1.09 (0.99 –1.29) and 1.02 (0.90–1.16) in the US, and 0.98 (0.80 – 1.21) and 1.00 (0.97–1.03) in the Japanese populations, respectively, suggesting that there was no time-dependence in YM155 exposure. The slope of regression of natural logarithm transformed Css and AUCinf on natural logarithm transformed dose (mean and 95% CI) was 0.66 (0.31–1.00) and 0.65 (0.29–1.00) in the US and 1.00 (0.86–1.14) and 0.99 (0.85–1.12) in the Japanese populations, respectively. At the US MTD dose of 4.8 mg/m2/day, Css (mean ± SD) during cycle 1 was 7.6 ± 2.6 ng/mL (n=24) in the US and 8.7 ± 1.4 ng/mL (n=6) in the Japanese populations. The geometric mean ratios (90 % CI) of AUCinf, Css, and clearance between Japanese and US populations were 1.06 (0.93 – 1.22), 1.14 (1.00 – 1.31) and 0.80 (0.70 – 0.92), respectively. In conclusion, data currently available suggests that PK of YM155 is time-independent in both the US and Japanese patient populations; there appear to be no differences between U.S. and Japanese patients in terms of blood plasma YM155 concentration and its time course, although high variability was observed.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C134.
Abstract C141: In vitro and in vivo characterization of two novel β-catenin RNA antagonists, EZN-3889 and 3892
Authors: Zhang Yixian , Sapra Puja , Kim Steven , Shi Victoria , Qu Zhengxing , Castaneda Stephen , Wang Maoliang , Zhu Peifang , Filpula David , Greenberger Lee M. , Horak Ivan D. 
Published: June 2012

Abstract
Background: β-Catenin is an important signaling molecule in the Wnt pathway that plays a key role in tumorgenesis. In the absence of Wnt signaling, the cytoplasmic level of β-catenin is kept low due to rapid proteasomal-mediated degradation of GSK3β phosphorylated β-catenin. Activation of Wnt signaling leads to the inactivation of GSK3β, resulting in stabilization and accumulation of β-catenin in the cytoplasm. Consequently, β-catenin translocates into the nucleus, where it binds with members of the T-cell factor (Tcf)/lymphocyte enhancer-binding factor family of transcription factors and activates the expression of many target genes important for cancer development. Most colon cancers have activating mutations in the APC tumor suppressor or in β-catenin itself. Furthermore, activating β-catenin mutations have been found in a variety of other tumors such as melanomas, hepatocellular carcinomas, skin, breast, and prostate cancer, whereas β-catenin is not activated in most normal tissues. Therefore, inhibition of β-catenin is likely to have therapeutic effects in many cancers. We report here the identification of two β-catenin LNA-based mRNA-antagonists, EZN-3889 and EZN-3892.
Material and Methods: In vitro, the ability of the compounds to inhibit mRNA, cell growth, and reporter gene were evaluated by qRT-PCR, MTS, and luciferase assays respectively, in multiple cell lines. In vivo, β-catenin mRNA down-modulation in liver and human tumors, which were grown on the flank of nude mice, was evaluated after intravenous administration of the compounds.
Results: These molecules were potent down-modulators of β-catenin (IC50 = 0.1 to 3 nM) as well as protein (&gt; 80% at 20 nM) of multiple cell lines, when transfected into tumor cells. Growth inhibition appeared to correlate with the status of either APC mutation or activating β-catenin mutations, suggesting that β-catenin is the driver of cancer cells. Interestingly, we found that these two antagonists specifically down modulated β-catenin mRNA and protein effectively in multiple cell lines with a long-lasting effect in the absence of any tranfection reagent. In mice, both molecules significantly down modulated β-catenin mRNA in the liver.
Conclusions: β-catenin antagonists potently and specifically inhibited β-catenin mRNA expression both in vitro and in vivo after intravenous injection. Further studies will examine the antitumor efficacy of the compounds. hese novel agents specifically inhibit a transcription factor that has been difficult to target with conventional agents.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C141.
Abstract C147: siRNA targeting TS and TK as an anticancer therapy
Authors: Di Cresce Christine , Figueredo Rene , Koropatnick James 
Published: June 2012

Abstract
Thymidylate synthase (TS) is the only de novo source of thymidylate (dTMP) for DNA synthesis, repair and proliferation. Cytosolic thymidine kinase 1 (TK1) and mitochondrial thymidine kinase 2 (TK2) represent “scavenger” pathways for alternative production of essential dTMP by phosphorylation of intracellular thymidine (Thd). Both TS and TKs are upregulated in multiple human tumors, supporting a role for both in malignancy. Drugs targeting TS-protein are a mainstay in cancer treatment but toxicity to normal tissues and tumor cell drug resistance limit their effectiveness. We hypothesize that, when TS-protein is inhibited, the capacity of TKs to generate dTMP may modulate resistance to anti-TS drugs.
Antisense molecules, including oligonucleotides (ODNs) and siRNAs, can selectively target specific mRNAs (including TS and TK mRNAs) encoding proteins mediating drug resistance. We have previously reported that antisense ODNs targeting TS inhibit human tumor cell growth in vitro and in immunocompromised host mice, and antisense TS ODNs and siRNAs enhance the growth inhibitory effects of TS-targeting drugs. Antisense TS, therefore, is an attractive candidate for development as an anticancer drug, both alone and in combination with drugs targeting TS protein (raltitrexed, pemetrexed, 5FUdR, and others). The ability of antisense TS drugs to inhibit tumor cell growth and response to other TS-targeting drugs does not correlate with the degree of antisense downregulation of TS mRNA, suggesting that factors other than TS attenuate antitumor effects.
We used siRNAs targeting TK1 or TK2 to knock down TK expression in attempt to reduce human tumor cell growth when targeting TKs alone, in combination with siRNAs targeting TS, and in combination with TS siRNA and the anti-TS protein drug 5FUdR. We report that TK and TS levels are highly variable among a panel including human cervical (HeLa) and breast carcinoma (MCF7), colorectal cancer (HT-29) and human mesothelioma cell lines. Furthermore, 24 hrs post-transfection, siRNAs targeting TK1 or TK2 reduce targeted TK-mRNA by greater than 85% at concentration of 5 nM in human cervical carcinoma (HeLa) and human breast carcinoma (MCF7) cells. At 96 hrs post-transfection, siRNA targeting TK1 or TK2 do not independently reduce human tumor cell growth in vitro. Furthermore, simultaneous siRNA targeting of TS and TK effectively, independently, and non-antagonistically reduce both TS and TK mRNA. Antisense targeting TK1 or TK2 alone, unlike siRNA targeting TS alone, does not enhance the capacity of 5FUdR to inhibit human tumor cell growth in vitro. We suggest, however, that combined antisense targeting of TS and TK1/TK2 (particularly under conditions where extracellular thymidine levels are high) will be more effective than either used alone to reduce tumor cell growth and sensitize them to the effects of antitumor TS-targeting chemotherapeutics.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C147.
Abstract C150: SOX9 modulates Wnt/beta-catenin singal in cancer cells by regulating TCF4 and LRP6 expression
Authors: Wang Hong-yun , Richardson Andrea , Balk Steven P. , Yuan Xin 
Published: June 2012

Abstract
Introduction: Cancers frequently exploit developmental genes/pathways to sustain their uncontrolled growth or invasion. SOX9, an important developmental transcription factor is one of the signature genes of the basal-like breast cancers. SOX9 over-expression has been demonstrated in various cancers and is associated with a poor prognosis. In prostate cancer, SOX9 supports tumor proliferation, angiogenesis and local invasion in xenografts. The role of SOX9 as a biomarker and molecular mechanisms of its biological functions were further explored in this study.
Methods: Immunohistochmical analysis of SOX9 protein expression was performed on a tissue microarray of 129 breast cancer samples. Gene profiles of the breast cancer samples were examined by ANOVA analysis to identify genes that are expressed at significantly higher level among SOX9-high protein expressing samples. SOX9 regulated genes were validated by their corresponding changes in expression levels to SOX9 silencing in cancer cell lines. The effect of SOX9 silencing on cancer progression was examined in the MCF10A DCIS.com xenografts.
Results: SOX9 protein expression was highly represented in the basal-like breast cancers and was associated with poor tumor grades. Among the genes correlated with higher SOX9 expression were two major components of the canonical Wnt/ -catenin signal pathway, ie TCF4 and LRP6. These genes were up- or down-regulated in various cancer cell lines in response to SOX9 overexpression or silencing. More importantly, the Wnt3a induced -catenin activity was significantly reduced when SOX9 protein was specifically down-regulated. SOX9 down-regulation in MCF10A DCIS xenografts lead to a squamous differentiation and a block in the progression from DCIS to invasive carcinoma.
Conclusion: This study identified a novel function of SOX9 in modulating Wnt/β-catenin signaling by regulating TCF4 and LRP6 expression. SOX9 enhanced Wnt/β-catenin activity in the absence of APC or β-catenin mutations may play an important role in determining tumor subtype, maintaining tumor stem cells or supporting tumor growth or progression.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C150.
Abstract C153: Both TRAIL receptor DR5 isoforms are required for the induction of cell death in human colon carcinoma
Authors: Jani Tanvi S. , DeVecchio Jennifer , Peters Kristi , Houghton Janet 
Published: June 2012

Abstract
Colorectal cancer continues to be the third most common malignancy in the United States. This disease remains resistant to treatment, with only 25–30% of patients disease-free long term; for the rest, median su rvival is only 18–22 months. We previously demonstrated synergistic interaction between FUra/LV combined with IFN- (which potentiates FUra/LV-induced DNA damage and requires the death receptor Fas) in human colon carcinoma cell lines and xenografts. FUra/LV/IFN- also demonstrated responses in heavily pretreated and previously untreated patients in Phase I trial and is currently completing Phase II evaluation in Stage IV colorectal cancer. Further, lexatumumab, an agonistic TRAIL-R2 (DR5) monoclonal antibody, is highly synergistic with FUra/LV/IFN- in xenograft models, dependent on TRAIL receptor activation. Lexatumumab demonstrated the broadest spectrum in vitro activity in a panel of 6 human colon carcinoma cell lines when compared to the activity of the recombinant ligand, TRAIL (targeting DR4 and DR5).
To further understand the mechanism of lexatumumab-induced cell death via DR5, DR5 expression, was determined in human colon carcinoma cell lines (Western, RT-PCR) and primary colon tumors (RT-PCR). The short isoform of the receptor (DR5S) was expressed at a higher level than the long isoform (DR5L). To determine the specific function of each isoform in regulating death signaling, a BJAB-derived cell line lacking DR5 expression (DR5−/−) was employed. DR5 −/− cells were resistant to lexatumumab-induced apoptosis, even when each DR5 isoform was expressed individually, despite the fact that the individual isoforms could still bind ligand (lexatumumab). Analysis of receptor complex formation indicated that DR5, FADD, and caspase-8 were recruited; however, caspase-8 was not processed. Apoptotic signaling was restored when both DR5 isoforms were re-expressed in DR5−/− cells. Lexatumumab sensitivity of HCT8 cells was eliminated by stable shRNA knockdown of both DR5 isoforms, as was the recruitment of FADD and caspase-8 to the receptor complex. In contrast, following 1 hr lexatumumab treatment in wild type HCT8 cells, both DR5 isoforms were recruited to the receptor complex; cell death correlated with recruitment of FADD, cleavage of caspase-8, cleavage of RIP, and reduced expression of c-FLIPS and c-FLIPL. TRAF2 and c-IAP2, but not TRAF1 or c-IAP1, were also recruited; however, the significance of these signaling molecules in the cell death response is currently unknown.
Overall, data indicate that both DR5S and DR5L are required for lexatumumab-induced cell death via the DR5 receptor. Although the significance of this is currently unknown, factors that regulate lexatumumab-induced cell death vs survival at the level of receptor complexes are currently being elucidated.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C153.