bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3619: Inhibition of FLT3 autophosphorylation and downstream signaling both in vitro and in vivo by AC220, a second generation potent and selective FLT3 inhibitor
Authors: Gunawardane Ruwanthi , Rooks Allison , Dao Alan , Brigham Daniel , Ricono Jill , Zarrinkar Patrick , Bhagwat Shripad , Belli Barbara , Wierenga Wendell , Armstrong Robert 
Published: February 2011

Abstract
Fms-like tyrosine kinase 3 (FLT3) is thought to be a major driver in the pathogenesis of acute myeloid leukemia (AML). FLT3-activating mutations are found in ∼ 30% of AML patients and are associated with poor outcome in this patient population. AC220 is a small molecule kinase inhibitor with potent and selective FLT3 inhibitory activity. Here we characterize the effect of AC220 on FLT3 autophosphorylation, activation of downstream signaling pathways (STAT5, ERK and AKT), cell cycle distribution, and apoptosis endpoints in multiple leukemia cell lines expressing either wild type FLT3 (FLT3-WT, SEM-K2 cells (FLT3-WT overexpression) and RS4;11 cells (FLT3-WT)) and/or ITD-mutated FLT3 (FLT3-ITD, MV4-11 (FLT3-ITD), MOLM-14 (FLT3-ITD/FLT3-WT)). Across each of these parameters we also compare the effects of AC220 to those of other known FLT3 inhibitors including, sorafenib, sunitinib, lestaurtinib, and midostaurin. AC220 inhibited FLT3 autophosphorylation in both FLT3-WT and FLT3-ITD cells with roughly equal potency, while other FLT3 inhibitors showed differential pFLT3 inhibition across several cell lines. Although AC220-mediated inhibition of FLT3 autophosphorylation was observed in all cell lines, subsequent cell death was only detected in the cell lines with activated FLT3. This contrasts with other FLT3 inhibitors, where potent inhibition of cell proliferation in the non-FLT3 activated RS4;11 cells was observed, highlighting the lack of FLT3 selectivity of these compounds. Consistent with FLT3 inhibition, AC220 also inhibited constitutively activated STAT5, ERK and AKT in these cell lines, suggesting that one or more of these pathways play a role in FLT3-mediated cell growth and survival. Furthermore, the inhibition of these downstream markers correlated with the inhibition of FLT3 across each of the FLT3 inhibitors tested. Lastly, in an MV4-11 murine xenograft model, AC220 administration resulted in the reduction of phosphorylated FLT3 and downstream signaling molecules concomitant with tumor reduction. Together, these data suggest that selective FLT3 inhibition is sufficient to inhibit the growth and induce cell death of FLT3-driven leukemia cells. AC220 is currently being evaluated in a phase II clinical trials in relapsed or refractory AML patients.
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 3619.
Abstract 3625: Exogenous short-term activation of c-Met and EGFR sensitizes them to kinase inhibitors
Authors: Zhang Ying , Farenholtz Kaitlyn , Yang Yanzhi , Guessous Fadila , Kofman Alexander V. , Christensen James , Abounader Roger 
Published: February 2011

Abstract
Activation of the c-Met and EGFR receptor tyrosine kinases induces brain tumor malignancy and is associated with poor clinical outcome of brain tumor patients. Consequently, c-Met and EGFR are promising targets for the therapy of brain tumors and clinically applicable inhibitors of these receptors have been developed by biotechnology and pharmaceutical companies. We tested the effects of a specific and potent c-Met kinase inhibitor (PF-2341066) on glioma cells and glioma stem cells. Surprisingly, we found that the inhibitor induced significantly greater cell death when c-Met was shortly pre-activated with its ligand hepatocyte growth factor (HGF). Glioblastoma cells (U87, U373), primary glioblastoma cells (GBM10) and glioblastoma stem cells (1228, 0308) were pre-treated with 20 ng/ml HGF for 2h, 4h, 6h, 8h, 16h or 24h prior to treatment with PF-2341066 (100 nM for established and primary cells and 300 nM for cancer stem cells) for 24 hr. The cells were subsequently assessed for apoptosis using annexin-V flow cytometry. The results showed that the inhibitor induced significantly greater (34-79%) absolute cell death in pre-activated cells than in non-activated cells. The optimal time of pre-activation that achieved greatest sensitization of the receptor to kinase inhibitor-induced cell death was 2-4 hours. Using a similar experimental approach, we also tested the effects of EGFR pre-activation on EGFR inhibitor erlotinib-induced cell death in glioma cells. Glioma cells were pre-treated with EGF (100ng/ml) for 3h, 6h, 16h or 24h prior to treatment with erlotinib (2.5 µM) for 24 hrs and assessment of cell death by annexin V flow cytometry. EGFR pre-activation led to significantly greater (138 %) erlotinib-induced cell death than without pre-activation. Based on the above findings, we hypothesize that short-term exogenous activation of c-Met, EGFR and possibly also other receptor tyrosine kinases can trigger fast oncogene addiction that sensitizes tumor cells to death induced by receptor tyrosine kinase inhibitors. We are currently testing this hypothesis using in vivo glioblastoma animal models. Verification of this new hypothesis would imply that quick short-term activation of tyrosine kinase receptors by bolus delivery of receptor tyrosine kinase ligands would sensitize tumors to kinase inhibitors and therefore improve the efficacy of these inhibitors in cancer therapy.
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 3625.
Abstract 3636: The complex mechanism of resistance of human neuroblastoma cells to chemotherapeutic drugs
Authors: Clark Sandra H. , Lautz Timothy B. , Zheng Xin , Holub Janette L. , Qui Yi-Yong , Chu Fei , Madonna Mary Beth 
Published: February 2011

Abstract
It has become evident that the biological processes which allow malignant cells to survive in the presence of cytotoxic drugs are extraordinarily complex, and recent findings indicate that a multitude of cellular defense mechanisms may be involved in the development of drug resistance. In order to dissect the dynamic changes in gene expression during the process of acquiring drug resistance, four human neuroblastoma cell lines (IMR 32, BE(2)-C, SK-N-SH and SH-SY5Y) were used to generate drug-resistant cell lines using clinically appropriate chemotherapeutic agents (Doxorubicin and Busulfan). Additionally, in order to understand the physiological role of histone deacetylase (HDACs) in the development of drug resistance in human neuroblastoma and to determine if this development can be delayed or totally suppressed by the HDACs inhibition, the cells were separated into those that were pretreated with a histone deacetylase (HDAC) inhibitor: suberoylanilide hydroxamic acid (SAHA), and those that were not pretreated. Cells were deemed drug-resistant when the cells were able to grow efficiently in drug concentrations of two log concentrations higher than the IC50 level. Neuroblastoma cells were collected at each log phase increase of cytotoxic agent to compare changes in P-glycoprotein and midkine expression; cross-resistance between chemotherapeutic agents, and presence of survival proteins in each group. The creation of these resistant human neuroblastoma cell lines and the determination of the transcriptional changes occurring as the cells become resistant may have important implications for clinical treatment of human neuroblastoma.
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 3636.
Abstract 3639: Cell death mechanisms associated with the carbamoylating activity of the anticancer prodrug Laromustine
Authors: Paine Adam N. , Praggastis V. Alexandra , Dale Lindsay E. , Tepper Jared L. , Reichelderfer Bridget , Rice Kevin P. 
Published: February 2011

Abstract
The preclinical anticancer prodrug Laromustine (VNP40101M; Cloretazine) yields 2-chloroethylating and methyl carbamoylating activities upon activation in cells. While the induction of DNA damage from its chloroethylating activity is widely considered to be the primary cause of its therapeutic cytotoxicity, Laromustine's carbamoylating activity has proven critical to the drug's mechanistic profile. Methyl isocyanate, the carbamoylating species derived from Laromustine in situ, can enhance the effectiveness of DNA damaging agents, including the cogenerated chloroethylating agent. This consequence is thought to be a result of a diminishment of cellular DNA damage response. However, carbamoylating agents themselves cause acute cell death in cultured mammalian neoplastic cells, principally via apoptosis. Several overlapping cell death pathways can be induced upon exposure to Laromustine's carbamoylating activity. Using Laromustine and its analogs, the chloroethylating-only 90CE and the carbamoylating-only 101MDCE, we identified molecular markers of apoptosis via Western blot analysis and flow cytometry. Poly(ADP-ribose) polymerase (PARP) is often proteolyzed by caspase-3 in the course of an apoptotic death. We report here that Laromustine, with its carbamoylating activity, induced PARP cleavage similarly to the cytotoxic agent etoposide in HL-60 human leukemia cells. In addition, flow cytometry analyses using FITC-annexin V / propidium iodide staining revealed that the carbamoylating activity of Laromustine is responsible for substantial apoptosis in HL-60 cells at clinically relevant doses within three hours of drug treatment. However, the DNA damaging, 2-chloroethylating activity did not induce appreciable apoptosis in similar experiments. Levels of poly(ADP-ribosyl)ation and expression levels of the Bax and Bcl-2 proteins are also being investigated. Given its effects on DNA repair systems and its provocation of apoptosis, methyl isocyanate continues to demonstrate its utility to the cytotoxic action of Laromustine.
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 3639.
Abstract 3640: Increased anti-tumor effects of sequential docetaxel followed by 5-FU treatment against human oral cancer cells
Authors: Tamatani Tetsuya , Ferdous Tarannum , Uchida Daisuke , Nagai Hirokazu , Miyamoto Youji 
Published: February 2011

Abstract
[Background] Docetaxel (TXT), a novel member of the taxoid family, and 5-fluorouracil (5-FU) are key drugs against oral cancer chemotherapy. The promising clinical activity of TXT and 5-FU has promoted considerable interest in combining these drugs. Although the combination treatment has been reported to improve the response rates, sequential treatment with TXT and 5-FU was unknown.
[Purpose] The aim of this study was to evaluate the anti-tumor effects of sequential treatment with TXT and 5-FU against oral squamous cell carcinoma cells.
[Methods and Results] Two human oral squamous cell carcinoma cell lines, B88 and CAL27 cells were used in this study. The effects of sequential treatment on the inhibition of tumor growth with TXT and 5-FU were investigated by 3-(4, 5-dimethylthiaol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometric analysis, and the xenograft on nude mice. In vivo study, B88 or CAL cells (5×106) were subcutaneously inoculated into the backs of nude mice. When the tumor reached 0.5 cm in diameter, tumor-bearing nude mice received either the intraperitoneal administration of TXT (10 mg/kg) alone, 5-FU (15 mg/kg) alone, TXT followed by 5-FU or 5-FU followed by TXT treatment. TXT followed by 5-FU treatment more effectively inhibited the tumor growth in vitro and in vivo, and induced apoptosis than 5-FU followed by TXT treatment. To elucidate the mechanisms underlying growth inhibitory effect of TXT followed by 5-FU, we examined the expression of 5-FU metabolic enzymes, thymidylate synthase (TS), dehydropyrimidine dehydrogenase (DPD), and ortate phosphorybosyl transferase (OPRT) by real-time PCR and western blot analysis. Down-regulation of TS and DPD expression, and up-regulation of OPRT expression were induced by TXT treatment compared with 5-FU, suggesting that they enhanced the efficacy of 5-FU.
[Conclusions]These findings demonstrated that sequential treatment with TXT followed by 5-FU can be effective for the patients with oral squamous cell carcinoma.
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 3640.
Abstract 3660: Bicarbonate attenuates irinotecan-induced cytotoxicity by altering intracellular pH in HT29 cells
Authors: Miyazaki Teruo , Saitoh Erika , Nagai Yoshiaki , Ikegami Tadashi , Matsuzaki Yasushi , Kobayashi Kunihiko , Bouscarel Bernard E. 
Published: February 2011

Abstract
[Background/Aim] The therapeutic efficacy of irinotecan (CPT-11) is often limited by the induction of severe late-onset diarrhea. CPT-11 and its active metabolite (SN-38) have a labile α-hydroxy-lactone ring that undergoes pH-dependent reversible hydrolysis, and the toxicity is more potent in the lactone (LA) form at acidic pH compared to that in the carboxylate (CA) form in physiological and higher pH. We have previously demonstrated that sodium bicarbonate (Bicarb) reduced the intestinal toxicity of CPT-11/SN-38 in in vivo, in a mouse model, and in a cultured intestinal cancer (HT29) cell line. The hypothesis was that protective action of Bicarb might be due, at least in part, to reduced CPT-11/SN-38-induced intracellular (pHi) acidification.
[Method] HT29 cells were exposed to ∼1µM SN-38 LA or CA form for 2h and further incubated in fresh medium at two different extracellular pH (6.2 and 7.4) adjusted by HCl with 44 mM Bicarb for an additional 96h. In addition, the HT29 cells exposed to SN-38 LA were also incubated at 5-set points of extracellular pH at 6.8, 7.0, 7.4, 7.8, 8.2 adjusted by either increasing concentrations of Bicarb (5, 10, 20, 44, 100mM, respectively) or HCl/NaOH in combination with Trice, Tris, and NaH2PO4 to maintain extracellualr pH during culture. The cell proliferation and apoptosis were examined by MTT assay and Flow Cytometry, respectively. The pHi following SN-38 exposure was also analyzed using Snarf-1 with two concentrations (10 and 30mM) of Bicarb.
[Result] The cell proliferation was significantly decreased on exposure to SN-38 LA form compared to the CA form, while there was no difference in the lower cell growth on exposure to LA form between pH 6.2 and 7.4. In the SN-38 exposed cells, the cell proliferation and apoptosis were significantly higher and lower, respectively, dependent on the concentration of Bicarb. However, the decreased cell viabilities were not influenced by extracellular pH without Bicarb. The SN-38 LA exposure induced a significant decrease of pHi, and the incubation with 30mM Bicarb significantly prevented from the acidification of pHi compared to that in 10mM Bicarb.
[Conclusion] The present study showed that cell cytotoxicity of SN-38 was independent of extracellular pH but dependent on pHi that converts the SN-38 form, while the acidification of pHi was reduced by Bicarb. The novel protective mechanism of Bicarb action against intestinal cell injury by CPT-11/SN-38 would be beneficial for anti-cancer therapy.
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 3660.
Abstract 3666: Follicle-stimulating hormone inhibits apoptosis and autophagy in ovarian cancer cells by activating survivin and Rab25
Authors: Liu Yingtao , Huang Yan , Jin Hongyan , Cheng Kwai Wa , Lu Yiling , Yu Yinhua , Feng Youji 
Published: February 2011

Abstract
Follicle-stimulating hormone (FSH) has been demonstrated to increase the risk of ovarian malignancy, but the mechanisms remains unclear. Our previous results showed that FSH increases the expression of VEGF through activation of survivin, which is mediated by the activation of the PI3K/AKT signaling pathway. We reported, herein, that FSH promoted ovarian cancer cells proliferation and prevented apoptosis in vitro and in vivo. FSH up-regulated the expression of survivin and down-regulated the expression of programmed cell death 6 (PDCD6) and death receptor 5 (DR5), two molecules required for apoptosis induction. Further, we have defined that the decreased expression of DR5, but not PDCD6, was mediated by survivin. We have established animal xenografts tissue arrays, the tumors from the groups with FSH treatment had higher expression of survivin and lower expression of DR5 comparing with the tumors from untreated groups, further confirming the interaction of FSH-survivin-DR5. In addition, we have demonstrated that FSH does not only inhibit apoptosis, but also inhibit autophagy. FSH inhibits autophagy by activating mTOR pathway in ovarian cancer cells under different stress conditions, including serum starvation. By Reverse Phase Protein Arrays (RPPA) analysis and western blot confirmation, we found that FSH stimulation increases the level of Rab25 in multiple ovarian cancer cells in a dose dependent manner. Rab25, a small GTPase, is found to be associated with the progression of ovarian tumor. Rab25, belongs to Rab11 supfamily, was shown to involve in endosomal recycling. To study the role of FSH-Rab25 interaction in regulating autophagy, we knocked down Rab25 expression in ES-2, Hey and SKOv3 ovarian cancer cell lines by siRNA, and examined the effects of FSH on autophagy. Rab25 knockdown increased the starvation induced autophagy through the inhibition of pAkt, while FSH administration could partly reverse the effects of Rab25 knockdown, due to the increase of Rab25 expression stimulated by FSH. Our findings indicated that Rab25 is one of the molecules regulated by FSH in ovarian cancer cells that has a novel role as a regulator in autophagy. Taken together, we have demonstrated that FSH promotes ovarian cancer development through regulating expression of survivin, Rab25, PDCD6 and DR5, which in turn regulates cell proliferation, apoptosis as well as autophagy. Further understanding the molecular mechanisms of FSH in the process of ovarian carcinogenesis and development will ultimately help developing an effective cancer prevention method, and find a novel targeted therapy for ovarian cancer.
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 3666.
Abstract 3671: First-line treatment of patients with disseminated poorly differentiated neuroendocrine carcinomas with carboplatin, etoposide, and vincristine
Authors: Andresen Marie T. , Knigge Ulrich , Hansen Carsten Palnæs , Hasselby Jane Preuss , Langer Seppo W. 
Published: February 2011

Abstract
Background:
The poorly differentiated neuroendocrine carcinomas (PDEC) represent a highly malignant tumor with an immense tendency to metastasize and a poor prognosis, with a median survival of approximately 6 months without treatment. Treatment based on platin and etoposide is widely recommended as palliative chemotherapy and corresponds to the treatment of extensive stage small cell lung cancer. The recommendation is based on relatively few, older studies, which did not use the 2000 WHO tumor classification, and no controlled, randomised studies have been published.
Method:
Successive chemonaïve patients with disseminated PDEC (small cell carcinomas excluded) allocated for treatment from May 2007 to June 2008 were identified. Patients received carboplatin AUC 5 IV day 1 + etoposide 100 mg/m2 PO day 1-3, and vincristine 1.3 mg/m2 (maximum 2.0 mg) IV day 1. Treatment was repeated every 3 weeks until progression or intolerable toxicity up to a maximum of 6 courses.
Results:
Twenty-two patients diagnosed with PDEC according to the 2000 WHO tumor classification were eligible for analysis, 11 females and 11 males. The median age was 61 years (range 35-80). Performance status: 0/1/2 = 9/11/2. All patients had disseminated disease. Immunohistochemical analyses of synaptophysin were positive in 21/22 (95.4%), and chromogranin A positive in 17/21 (80.9%). In one patient (4.5%) both analyses were negative; in 17/21 (80.9%) both were positive. The Ki-67 proliferation index ranged from 20% to 100%; the index reaching 50% or higher in 17 patients (77.2%). Octreotide scintigraphy was negative in 10 of 12 scanned patients (83,3%). Three patients (13.6%) achieved complete response (CR), 11 (50%) partial response (PR), 4 (18.2%) no change (NC), and 4 (18.2%) progressive disease (PD). The overall response rate (CR+PR) was 63.6%, and the disease control rate (CR+PR+NC) 81.8%. The median progression free survival time was 7.4 months. The median overall survival time was 10.5 months, and the 1-year survival 48%.
Conclusion: In conclusion, treatment with carboplatin, etoposide, and vincristin in previously untreated patients with disseminated PDEC results in a noticeable survival benefit compared to untreated historical controls. The prognosis is however still poor.
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 3671.