bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4445: Novel antibody-dendrimer conjugates efficiently complex plasmid DNA
Authors: Wang Yang , McBride Bill , Goldenberg David M. , Chang Chien-Hsing 
Published: June 2012

Abstract
Introduction: Cationic polymers, such as polylysine, polyethylenimine, or polyamidoamine (PAMAM)-based dendrimers, form complexes with nucleic acids. However, their potential applications in nanomedicne as non-viral vectors for delivering therapeutic genes or siRNAs remain a challenge. One approach to improve selectivity and potency of a dendrimeric nanoparticle may be achieved by conjugation with an antibody that internalizes upon binding to target cells. In this study, we describe the synthesis and initial characterization of a novel immunoconjugate, designated E1-G5/2, which was made by the modular Dock-and-Lock (DNL) method to comprise half of a generation 5 (G5) PAMAM dendrimer (G5/2) site-specifically linked to a stabilized dimer of Fab derived from hRS7, a humanized antibody that is rapidly internalized upon binding to the Trop-2 antigen expressed on various solid cancers. Methods: E1-G5/2 was prepared by combining two self-assembling modules, AD2-G5/2 and hRS7-Fab-DDD2, under mild redox conditions, followed by purification on a Protein L column. To make AD2-G5/2, we derivatized the AD2 peptide with a maleimide group to react with the single thiol generated from reducing a G5 PAMAM with a cystamine core and used reversed-phase HPLC to isolate AD2-G5/2. We produced hRS7-Fab-DDD2 as a fusion protein in myeloma cells. The molecular size, purity and composition of E1-G5/2 were analyzed by size-exclusion HPLC, SDS-PAGE, and Western blotting. The biological functions of E1-G5/2 were assessed by binding to an anti-idiotype antibody against hRS7, a gel retardation assay, and a DNase protection assay. Results: E1-G5/2 was shown by size-exclusion HPLC to consist of a major peak (&gt;90%) flanked by several minor peaks. The three constituents of E1-G5/2 (Fd-DDD2, the light chain, and AD2-G5/2) were detected by reducing SDS-PAGE and confirmed by Western blotting. Anti-idiotype binding analysis revealed E1-G5/2 contains a population of antibody-dendrimer conjugates of different size, all of which are capable of recognizing the anti-idiotype antibody, thus suggesting structural imperfections in the commercial supply of the G5 dendrimer. Gel retardation assay showed E1-G5/2 was able to maximally condense plasmid DNA at a charge ratio of 6:1 (+/-), with the resulting dendriplexes completely protecting the complexed DNA from degradation by DNase I. Conclusion: The DNL method can be used to build dendrimer-based nanoparticles that are targetable with antibodies. Such agents may have improved properties as carriers of drugs, plasmids, or siRNAs for diverse applications in vitro and in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4445. doi:10.1158/1538-7445.AM2011-4445
Abstract 4455: Influence of convective fluid flow on the penetration of anti-cancer drugs through multicell layers
Authors: Phillips Roger M. , Makeen Hafiz , Periasamy Raj , Loadman Paul M. , Jones Pamela F. , Sleeman Brian D. , Smye Stephen W. , Twelves Chris 
Published: June 2012

Abstract
One consequence of elevated interstitial fluid pressures (IFP) within solid tumours is disruption to the normal process of convective fluid flow (CFF) from the vasculature into the interstitium. Loss of convective fluid flow in tumours has a significant effect on reducing drug delivery and is recognised as a major factor that contributes to the drug resistant phenotype of many solid tumours. Experimental models of IFP and CFF have traditionally relied upon in vivo tumour models but here, we describe an in vitro assay which could be used to evaluate strategies designed to manipulate convective fluid flow. The model is based upon a conventional transwell model for assessing drug penetration across multicell layers which has been modified to allow the fluid level in top chamber to be raised above that in the bottom chamber. The difference in hydrostatic pressure across the multicell layer drives convective fluid flow, the rate of which can be varied by increasing or decreasing the height of fluid in the top chamber and/or by using multicell layers of different thicknesses. When CFF was 0.19 ml/min, the penetration of gefitinib, imatinib and doxorubicin across DLD-1 human colon carcinoma multicell layers was significantly enhanced compared to similar experiments where CFF was zero. The enhancement of penetration rates was 75 fold for doxorubicin, 53 fold for gefitinib and 62 fold for imatinib. The magnitude of these effects has potential therapeutic significance and support the proposal that strategies aimed at reducing tumour IFP and increasing CFF may enhance the efficacy of chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4455. doi:10.1158/1538-7445.AM2011-4455
Abstract 4465: Inhibition of tumor growth, lymphangiogenesis, and metastasis by iron chelators, deferoxamine and deferasirox, in breast cancers
Authors: Kang Han Na , Kang Myoung Hee , Km Jung Lim , Kim Jun Suk , Choi Chul Won , Seo Jea Hong , Yoo Young A 
Published: June 2012

Abstract
Iron participates in a range of reactions that are necessary for cell viability and cell proliferation and it has been reported that iron depletion by chelator inhibits the proliferation of various cancer cells. Among the different kind of iron chelators, deferoxamine is the most widely studied molecule as an anti-tumor agent. Deferasirox is a new rationally-designed oral iron chelator and there are few reports regarding in vitro and in vivo effect on myeloid leukemia cells.This study was undertaken to evaluate the in vitro and in vivo effects of DFX (deferoxamine) and DFS (Deferasirox) on anti-cancer activities in breast cancer cells and to define molecular mechanisms underlying these effects. We found that DFX or DFS displayed significant anti-proliferative activity in a dose-and time-dependent manner in MDA-MB-231 and MDA-MB-435 cells. DFX or DFS treatment led to the enhanced percentages of apoptotic cell, which was mediated through the mitochondrial death pathway that requires up-regulation of Bad phosphorylation, PUMA, and caspase-3 /-9 activities. In addition, DFX or DFS treatment significantly attenuated the motility and invasiveness of metastatic breast cancer cells, which is attributed to the decrease in EMT process and lymphangiogenesis. Importantly, the in vivo study revealed that DFX or DFS retarded tumor growth and suppressed the metastatic capacity to lymph nodes by down-regulating lymphangiogenesis in the orthotropic breast tumor model. These data demonstrate that DFX or DFS induces anti-cancer activity of breast cancer cells by both inducing apoptosis and suppressing metastasis in vitro and in vivo. Hence, DFX and DFS could provide another strategy for treating breast cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4465. doi:10.1158/1538-7445.AM2011-4465
Abstract 4516: SC-2001, a SHP-1 enhancer, induces apoptosis in hepatocellular carcinoma through SHP-1 dependent STAT3 inactivation
Authors: Chen Kuen-Feng , Su Jung-Chen , Chen Wei-Lin , Liu Chun-Yu , Cheng Ann-Lii , Chen Pei-Jer , Shiau Chung-Wai 
Published: June 2012

Abstract
The activation of signal transducers and activators of transcription 3 (STAT3) signaling cascade plays a role in regulating cell survival, proliferation, and angiogenesis in various types of cancer, including hepatocellular carcinoma (HCC). Agents that can suppress STAT3 pathway have potentials for the treatment of HCC. Here, we investigated the effects of SC-2001 ((Z)-2-((3-methoxy-2H-pyrrol-2-ylidene)methyl)-1H-pyrrole), a compound from bacterium on HCC. We found that SC-2001 down-regulated the phosphorylation of STAT3 (Tyr 705) and subsequently inhibited transcriptional activities of STAT3. Downstream molecules, driven by STAT3 were repressed by SC-2001. In addition, ectopic expression of STAT3 in HCC cells abolished the prominent apoptotic death in cells treated with SC-2001, indicating that STAT3 is indispensable in mediating drugs’ effects. Importantly, SC-2001 enhanced the expression of SHP1, a negative regulator of STAT3. Knockdown of SHP-1 by small interference RNA, but neither SHP-2, nor PTP-1B, reduced apoptotic effects of SC-2001, indicating SHP-1 played a key role in mediating SC2001-induced cell death. In conclusion, our results suggest that SC-2001 induced apoptosis in HCC, and this effect is mediated through a through SHP-1-dependent STAT3 inactivation.Further clinical investigations of SC-2001 may be warranted. Supported by NSC98-2314-B-002-067-MY3, NSC98-3112-B-002-037, and NSC-99-2314-B-002-017-MY2
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4516. doi:10.1158/1538-7445.AM2011-4516
Abstract 4530: Pralatrexate-induced apoptosis in multiple myeloma cells correlates with RFC-1 and DHFR expression
Authors: Mangone Michael , Marchi Enrica , Scotto Luigi , O'Connor Owen A. , Cho Hearn J. 
Published: June 2012

Abstract
Pralatrexate (PDX, 10-propargyl 10-deazaaminopterin) is a novel anti-folate agent that is approved for use in relapsed peripheral T cell lymphoma (PTCL). It is distinguished from the parent drug methotrexate (MTX) by having significantly greater affinity for the reduced folate carrier (RFC)-1, the principle transporter that internalize anti-folates, as well as broader efficacy, which strongly suggests that PDX has mechanisms of action beyond inhibition of nucleotide synthesis. Given the activity of PDX in aggressive lymphoid malignancies such as PTCL, we examined the activity of this agent in preclinical models of multiple myeloma (MM), a plasma cell malignancy that is currently incurable. We examined the cytotoxic activity of anti-folates in vitro against a panel of human multiple myeloma cell lines (HMCL) and showed that PDX induced dose-dependent apoptotic cell death in a subset of these. In sensitive cell lines (MM.1s and ARH-77) PDX demonstrated significantly greater potency at 48 hours compared to MTX (LD50 PDX = 2-3 nM vs. LD50 MTX = 25-30 nM). PDX also induced apoptosis in a polyclonal population of primary myeloma cells isolated from a patient specimen, whereas MTX had no effect on viability in these cells. PDX-induced apoptosis in sensitive HMCL was characterized by cleavage and activation of caspase-3 and -9, accompanied by the loss of the anti-apoptotic Bcl-2 family protein Mcl-1. Quantitative RT-PCR analysis of a panel of folate metabolism genes, including RFC-1, folyl polyglutamate synthetase (FPGS), gamma-glutamyl hydrolase (GGH), thymidylate synthase (TS), and dihydrofolate reductase (DHFR) revealed that RFC-1 expression was significantly higher in sensitive HMCL compared to resistant. Dose-dependent up-regulation of DHFR protein expression was observed by western blot in PDX-resistant cell lines, but not in PDX-sensitive ones. Incubation of HMCL with the proteasome inhibitor bortezomib or the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), both of which demonstrate activity in MM, did not affect expression of RFC-1 in PDX-resistant HMCL and did not synergize with PDX to induce apoptosis in vitro. These results demonstrate that PDX induces apoptosis in sensitive HMCL, and that RFC-1 expression and DHFR up-regulation are functional biomarkers for susceptibility to this anti-folate. These data support further exploration of PDX therapy in MM, including combination therapy with agents that can increase expression of RFC-1 and/or block up-regulation of DHFR.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4530. doi:10.1158/1538-7445.AM2011-4530
Abstract 4559: Herceptin trimers linked by EDC could boost direct tumor cell death and overcome resistance to trastuzumab treatment via programmed tumor cell necrosis
Authors: Hu Jiemiao , Liu Xinli , Huang Qianrong , Zhang Boyu , Hughes Dennis PM , Chandra Joya , Xia Xueqing , Li Shulin 
Published: June 2012

Abstract
The human epidermal growth factor receptor 2 (Her2) is overexpressed in multiple types of tumors, including breast tumors and osteosarcoma. Tumor-targeted antibody therapy is one of the safest therapeutics available, but it is often ineffective in treating primary and acquired antibody-resistant tumor cells via indirect tumor cell death and inducing direct tumor cell death. This study reveals that Herceptin conjugates, if generated via the crosslinker EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodimide hydrochloride), is capable of causing Her2 positive tumor cell death. Using an HPLC system, two peaks with estimated molecular weights of antibody dimers and trimers were isolated. The Herceptin dimer and trimer separated by HPLC, especially the trimer, induces significant levels of necrotic tumor cell death. Unlike SMCC conjugated Herceptin, this study indicates that the EDC-conjugated Herceptin overcomes the acquired resistance. The Herceptin trimer is more effective than the dimer in enhancing Herceptin-resistant tumor cell death. Surprisingly different from the known cell death mechanism often resulting from antibody treatment, the Herceptin trimer causes effective and direct tumor cell death via a novel cell death mechanism: programmed cell necrosis. Inhibition of RIP, a critical regulator of programmed necrotic cell death, reversed the Herceptin trimer-induced cell death. In summary, the Herceptin conjugate especially trimer linked by EDC could overcome Her2 positive breast cancer or osteosarcoma cells as well as the resistant cell lines via program cell necrosis cell death. This conjugate has great potential for overcoming the tumor cell resistance to the Herceptin treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4559. doi:10.1158/1538-7445.AM2011-4559
Abstract 4560: Anti-tumor activity of a fully human anti-CD27 monoclonal antibody in a transgenic mouse model
Authors: Thomas Lawrence J. , He Li-Zhen , Forsberg Eric M. , Vitale Laura , Boyer James M. , Jones Kristen L. , Weidlick Jeffrey , Glennie Martin J. , Keler Tibor , Marsh Henry C. 
Published: June 2012

Abstract
The costimulatory molecule CD27 is a member of the TNF receptor superfamily, and is constitutively expressed on the majority of mature T cells, memory B cells, and a portion of NK cells. The interaction of CD27 with its ligand CD70 plays an important role in the activation, proliferation, survival, and maturation of effector capacity and memory in T cells; in clonal B cell expansion and germinal center formation; and in NK cell cytolytic activity. Previous published work demonstrated that agonistic anti-mouse CD27 mAbs, given without a DC maturation signal, have potent anti-tumor activity through boosting of T cell immunity. To explore the therapeutic potential of this target, a panel of fully human antibodies recognizing human CD27 was generated using human Ig transgenic mice immunized with recombinant CD27. These anti-CD27 mAbs showed specific and high affinity binding to recombinant CD27 and CD27-expressing lymphoma cells. Human CD27-transgenic (hCD27-Tg) mice were generated to evaluate the anti-CD27 mAbs in vivo. The CD27-Tg mouse line was back-crossed onto a Balb/c background in order to assess anti-tumor activity using the BCL1 B-lymphoma line. Approximately 107 BCL1 cells were delivered i.v. to backcrossed animals on day 0. Doses of 150 to 600 ug of our lead anti-CD27 mAb (clone 1F5) were delivered to mice i.p. on days 3, 5, 7, 9 and 11. In multiple experiments, tumor growth in mice treated with the anti-CD27 mAb 1F5 was substantially delayed compared to that of control-treated mice. Further, many anti-CD27 treated animals did not show evidence of tumor growth several weeks past the point where all control animals had been euthanized. These data confirm that anti-human CD27 mAbs can mediate similar anti-tumor effects as the anti-mouse CD27 agonist antibodies. The 1F5 antibody was also demonstrated to cross-react with CD27 from cynomolgus monkeys, and in a small pilot study was well tolerated and without evidence of significant lymphocyte activation. Taken together the data support the therapeutic potential of this anti-CD27 mAb to enhance immune responses in cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4560. doi:10.1158/1538-7445.AM2011-4560
Abstract 4573: Inhibition of tumor growth by human IgM-isotype monoclonal antibody to ganglioside GD2
Authors: Krauthauser Candice , Nicolaides Nicholas , Lin JianMin 
Published: June 2012

Abstract
Monoclonal antibody, MORAb-028, a human IgM derived from patients with melanoma, specifically binds to tumor cell surface ganglioside-GD2 with high specificity, and kills GD2-expressing target cells via complement-mediated cytotoxicity (CDC). This CDC-mediated anti-tumor activity of MORAb-028 has been confirmed in vitro using various GD2-expressing tumor cells in presence of rat sera.
In the present study, intraperitoneal (i.p) and intratumoral (i.t.) treatment models in nude rats were developed to investigate in vivo anti-tumor activity of MORAb-028. These compartmental models provide an in vivo system to monitor IgM anti-tumor activity that has not been possible in previous studies due to the rodent poly-Ig-Receptor (PIgR) that is able to sequester systemically administered hIgM in the liver thereby lowering serum IgM steady-state levels that in turn lowers distribution of IgM to targeted tumors.
In the present study, murine EL4-luc2 cells that express high levels of GD2 were engineered to express a luciferase-reporter-gene enabling in vivo bioluminescent detection for monitoring tumor status. These cells were used in two different models to test the ability of MORAb-028 to impact tumor growth.
An i.p. model was developed whereby tumor cells were injected directly into the peritoneal cavity of nude rats followed immediately by a single i.p. dose of MORAb-028 at 3mg/kg, a dose that has showed activity in vitro. Tumor progression was monitored by bioluminescence using IVIS living imaging system. On day 24 post treatment, a significant reduction in tumor progression was observed in the MORAb-028-treated animals in comparison to the control. Only minimal tumor growth (∼3 to 5 mm3) was observed in MORAb-028-treated animals in contrast to control animals, in which tumor occupied the entire peritoneal cavity.
In a second model EL-4-luc cells were implanted subcutaneously and antibody was directly administered to palpable tumors. Here, a single intratumoral injection of MORAb-028 was administered into established (300-400 mm3) tumors. Results showed that MORAb-028 treatment significantly inhibited tumor growth and eradicated nearly the entire tumor in ∼30% of the animals. Six days post treatment the tumor volume in MORAb-028-treated animals was ∼250 mm3, whereas the tumor volume was &gt;1500mm3 in control animals. Animals with eradicated tumors showed no sign of recurrence at day 30 when the study was terminated.
These data indicate that MORAb-028 is a potent agent to treat GD2-positive tumors in rat models. These results also suggest that this antibody may be useful in clinical applications for the treatment of GD2-positive human cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4573. doi:10.1158/1538-7445.AM2011-4573
Abstract 4588: Tumor distribution of anti-neuropilin-1 is affected by antibody dose level in a tumor xenograft mouse model
Authors: Bumbaca Daniela , Boswell Charles A. , Mundo Eduardo E. , Xin Yan , Xiang Hong , Port Ruediger E. , Schweiger Michelle G. , Stainton Shannon L. , Bagri Anil , Theil Frank P. , Fielder Paul J. , Khawli Leslie A. , Shen Ben Q. 
Published: June 2012

Abstract
Neuropilin-1 (NRP1) is a VEGF165 and semaphorin receptor widely expressed by vascular endothelial cells in normal tissues and on some tumor cells. Blocking NRP1 with human IgG1 against its b domain has been shown to inhibit tumor growth in several preclinical models. The objective of this study was to assess tumor distribution of anti-NRP1 at different dose levels with the aim of supporting the clinical development of this antibody. Nude mice bearing HM7 tumors were administered [111In]-DOTA labeled anti-NRP1 in the presence of increasing amounts of unlabeled anti-NRP1 via single IV injection. Following dosing, blood and tumors were collected at pre-selected time points. Tumor distribution was evaluated by measuring the radioactivity levels in the tumor and blood samples using a gamma counter. The mice that received only the radiolabeled antibody had relatively low plasma and tumor radioactivity levels at all time points. The plasma and tumor radioactivity levels for all other dose groups were higher than those of the group that received only radiolabeled antibody due to the saturation of the normal tissue sink previously identified. Comparing the tumor to blood radioactivity ratios demonstrated that the different dose groups maintained maximum exposure in the tumor for variable lengths of time, depending on the dose level. At 24 hours post-dose, all doses greater than the radiolabeled antibody alone were able to maintain maximum exposure. Conversely, at 48 hours post-dose, doses ≥ 10 mg/kg were able to maintain that level, while at 120 hours post-dose, only doses ≥ 20 mg/kg were able to maintain maximum exposure. Taken together, this suggests that tumor distribution is both dose and time dependent. This approach has been used to aid the clinical dose selection for anti-NRP1 and may be a valuable tool for the clinical development of other targeted therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4588. doi:10.1158/1538-7445.AM2011-4588