bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2489: Targeting pro-survival BCL-2 family members increases radiation sensitivity in breast cancer cells
Authors: Wu Hao , Schiff Devora S. , Goyal Sharad , Neboori Hanmanth J.R. , Haffty Bruce G. 
Published: June 2012

Abstract
In previous studies we have shown that BCL-2 expression was associated with an increased risk of local recurrence in patients with early stage breast cancer (Yang Q, Breast Cancer Res Treat, 2009). Additionally, BCL-2-overexpressing lymphoma and prostate cancer cell lines were resistant to radiation-induced apoptosis. The BCL-2 family encompasses two groups: the pro-survival group (BCL-2, BCL-XL, BCL-w, MCL-1, A1) and pro-apoptotic group (BAK, BAX, BAD, BIK, etc.) ABT-737 is a BH3 mimetic compound that targets the pro-survival members excluding MCL-1. Targeting pro-survival BCL-2 family members presents an attractive novel adjuvant therapeutic option. The purpose of this study was to explore an approach to overcoming radiation resistance by targeting pro-survival BCL-2 family proteins in breast cancer cells. First, siRNAs were employed to target BCL-2 in MCF-7 and BT474 breast cancer cells. Apoptosis was determined by detecting cleaved PARP after siRNA and radiation treatment. Cleaved PARP in BCL-2 siRNA treated MCF-7 cells increased compared to non-targeting siRNA treated cells 72 hours after 8Gy of radiation, indicating the targeting BCL-2 alone increased apoptotic cell death. Despite evidence of increased radiation related apoptosis, cell viability showed there was no significant difference between BCL-2 siRNA and non-targeting siRNA treated MCF-7 cells at 2, 4, 6 and 8Gy, p&gt;0.05, indicating that targeting the BCL-2 alone did not enhance radiation sensitivity. However, the combination of radiation (8Gy) and ABT-737 (variable doses) enhanced BAK and cleaved PARP at 24hr, 48hr and 72hr. Further, the cell viability of the combination of radiation (2Gy) and ABT-737 (5µM) significantly decreased 16.5%, p&lt;0.01 and 26.5%, p&lt;0.01, compared with radiation alone or ABT-737 alone treated MCF-7 cells, respectively. Similar results were observed in T47D and MDA-MB231 cells. Finally, after knocking down MCL-1 by siRNA, cell viability went down in 14.5% (p&lt;0.05) in MCL-1 siRNA treated MCF-7 cells compared with non-targeting siRNA treated cells at 5µm of ABT-737. In addition, MCL-1 protein level decreased after treatment of radation alone and the combination of radiation and ABT-737 in MCF-7, MDA-MB 231 and ZR75-1 cells. Together, our results showed that synergistic effect of radiation and ABT-737 on breast cancer cell lines through down-regulating MCL-1 and activating bak-apoptotic pathway. These results support the combination of radiation and pro-survival BCL-2 family inhibitor as a potential novel therapeutic strategy in breast cancer treatment.
Supported by the Breast Cancer Research Foundation
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 2489. doi:10.1158/1538-7445.AM2011-2489
Abstract 2501: PEGylated human recombinant hyaluronidase (PEGPH20) enhances radiotherapy in hyaluronan-rich solid tumors
Authors: Bahn Jesse D. , Skipper James , Garcia Arnie , Jiang Ping , Osgood Ryan , Symons Rebecca , Frost Gregory I. , Shepard H. , Thompson Curtis B. , Li Xiaoming 
Published: June 2012

Abstract
The accumulation of the glycosaminoglycan hyaluronan (HA) in the extracellular matrix (ECM) of solid tumors contributes to increased tumor interstitial fluid pressure IFP), localized edema and reduced intratumoral blood flow. We recently reported that sustained enzymatic depletion of tumor HA with a pegylated recombinant human hyaluronidase PH20 (PEGPH20) decreases tumor IFP and water content, while significantly increasing vascular perfusion within HA-rich prostate PC3 tumors (Thompson et al, 2010). As localized tissue hypoxia reduces the effectiveness of radiation therapy (Baumgartner et al, 1998), we hypothesized that PEGPH20 treatment would reduce tumor hypoxia, thereby radio-sensitizing tumor cells. To evaluate whether PEGPH20 sensitizes HA-rich tumors, radiotherapy resistant human prostate PC3 cells (2×106) were inoculated into the right tibia periosteum of nude mice (NCR nu/nu) and tumor growth monitored with a high resolution 3D ultrasound. When the tumors reached ∼800 mm3 (n ≥ 8/group), mice were staged into 4 treatment groups: (1) vehicle control; (2) mono-radiotherapy at 2.5 Gy, q3d; (3) PEGPH20 monotherapy, 4.5 mg/kg, i.v. q3d; or (4) PEGPH20 plus radiotherapy. To increase intra-tumoral blood flow, PEGPH20 was administrated 3 hours prior to radiation therapy. Histological evaluation of a subset of mice confirmed that HA was completely degraded 3 hours post- PEGPH20 treatment. At study Day 15, tumor growth inhibition (TGI) with radiation alone or PEGPH20 alone was 99.2% (p=0.009) and 71.4% (p=0.08), respectively, relative to vehicle treated animals. PEGPH20 plus radiotherapy inhibited tumor growth by 140.6% (p=0.0002), relative to vehicle treated animals. The mean tumor size of the PEGPH20 plus radiotherapy group was reduced to ∼550 mm3, with 3-out-of-8 partial regressors (i.e. tumor size decrease to 50% or less of tumor staging size). These findings suggest that PEGPH20-mediated HA removal, and subsequent increase in tumoral blood flow, may increase the efficacy of radiation therapy in hyaluronan-rich tumors.
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 2501. doi:10.1158/1538-7445.AM2011-2501
Abstract 2511: Glycogen synthase kinase 3 beta inhibitors protect hippocampal neurons from radiation-induced apoptosis by regulating MDM2/p53 pathway
Authors: Thotala Dinesh Kumar , Hallahan Dennis E. , Yazlovitskaya Eugenia M. 
Published: June 2012

Abstract
Exposure of the brain to ionizing radiation can cause neurocognitive deficiencies. The pathophysiology of these neurological changes is complex and includes radiation-induced apoptosis in the subgranular zone of the hippocampus. We have recently found that inhibition of glycogen synthase kinase 3β (GSK-3β) resulted in significant protection from radiation-induced apoptosis in hippocampal neurons. The Molecular mechanisms of this cytoprotection include abrogation of radiation-induced accumulation of p53. Here we show that pretreatment of irradiated HT-22 neurons with small molecule inhibitors of GSK-3β SB216763 or SB415286, or with GSK-3β-specific shRNA resulted in accumulation of the p53-specific E3 ubiquitin ligase MDM2. Knockdown of MDM2 using specific shRNA or chemical inhibition of MDM2 prevented the protective changes triggered by GSK-3β inhibition in irradiated HT-22 and restored radiation cytotoxicity. We found that this could be due to regulation of apoptosis by subcellular localization and interaction of GSK-3β, p53 and MDM2. These data suggest that the mechanisms of radioprotection by GSK-3β inhibitors in hippocampal neurons involve regulation of MDM2-dependent p53 accumulation and interactions between GSK-3β, MDM2 and p53.
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 2511. doi:10.1158/1538-7445.AM2011-2511
Abstract 2519: A class of biometallo-organic compounds that target human topoisomerase IIa
Authors: Fagenson Alexander M. , Akerman Matthew P. , Munro Orde , Muller Mark T. 
Published: June 2012

Abstract
Topoisomerase IIa (topo II) is a nuclear enzyme that changes the topological state of DNA by breaking and rejoining the phosphodiester backbone of DNA. It is an important target for anticancer therapy and a number of agents are known to influence its action in vivo. These agents operate by either disrupting the cleavage-resealing cycle (interfacial poisons) or by simply blocking catalytic action of topo II (catalytic inhibitors). A new class of metallo-drugs is described that is unique in acting by both mechanisms. These are a series of fully characterized crystalline d8 coordination compounds with tetradentate ligands that we have evaluated for their targeting potential with topo II. These compounds are quite toxic to cells in culture with inhibitory values in low micromolar range. Mechanistic in vitro data with purified enzyme reveal these compounds to act as both catalytic inhibitors and as interfacial poisons over the same range of drug concentration. For example, CC50 values (drug concentrations yield 50% maximum DNA cleavage) were 3.47 µM for the prototype metallo-agent (compared to 5.47 µM for etoposide). Acting as catalytic inhibitors, the IC50 value was 3.17 µM. In sum, these compounds exhibit dual mechanisms in vitro, by stabilizing the covalent cleavage complex as well as blocking catalytic function. Analysis of endogenous topo II activity in HeLa cells confirms that the compounds target endogenous topo II by stabilizing the covalent cleavage complex and therefore acting as a poison in a cellular context. Endogenous topo I was not affected by the drug showing that these novel metallo-agents are type II specific. The dual mechanism of targeting of topo II suggests significant anti-tumor potential, and further studies are being conducted to evaluate clinical potential.
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 2519. doi:10.1158/1538-7445.AM2011-2519
Abstract 2522: Therapeutic synergism of cabazitaxel in combination with cisplatin in tumor-bearing mice
Authors: Vrignaud Patricia 
Published: June 2012

Abstract
Cabazitaxel (Jevtana), a semi-synthetic taxane derived from 10-deacetyl baccatin III, is as efficient as docetaxel in promoting tubulin assembly in vitro and stabilizing microtubules against cold-induced depolymerization. Cabazitaxel was selected for clinical development based on better antiproliferative activity than docetaxel against chemotherapy resistant tumor-cell lines (Bissery M.C. et al, AACR 2000) and a broad spectrum of in vivo antitumor activity (Vrignaud P. et al, AACR 2000), not only in docetaxel-sensitive tumor models, such as the human gastric N87 xenograft, but also in tumors models in which docetaxel was either poorly active or inactive. As an example, cabazitaxel was highly active in mice bearing UISO-BCA1 tumors, a human mammary xenograft expressing Her-2, which is poorly sensitive to ixabepilone and not sensitive to docetaxel. In addition, cabazitaxel penetrates the blood brain barrier (Cisternino S. et al, British J. Pharm. 2003) and has marked antitumor activity in nude mice bearing intracranial glioblastomas (Dykes D.J. et al, AACR 2000). Cabazitaxel was recently approved by the FDA for patients with metastatic hormone-refractory prostate cancer previously treated with docetaxel-based therapy.
In order to explore other therapeutic indications, the cabazitaxel-cisplatin combination was evaluated in C51 tumor-bearing mice. A 5-arm dose-response study was performed with cabazitaxel and cisplatin administered IV on days 5 and 12 after tumor implantation as single agents and in combination using 3 different sequences of administration: simultaneous in group A and sequentially separated by a 24h interval in groups B (cabazitaxel first) and C (cisplatin first). At their highest nontoxic doses (HNTD), both single agents were found active with tumor growth delays (T-C) of 15.2 days for cabazitaxel at 20 mg/kg/inj and 22.1 days for cisplatin at 4.3 mg/kg/inj. The 3 combination arms showed greater antitumor activity at their respective HNTD with T-C of 38.4 days in group A, 37.8 days in B, and 36.2 days in C. Of interest, 2 (A) and 3 (B & C) dose levels were found more active than the single agents in the combination arms.
In conclusion, a therapeutic synergism was achieved when cabazitaxel was combined with cisplatin in C51 tumor-bearing mice. These data are supporting the ongoing Phase I clinical study of cabazitaxel-cisplatin combination in solid tumors.
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 2522. doi:10.1158/1538-7445.AM2011-2522
Abstract 2528: Therapeutic targeting of a novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate to human solid tumors based on selective uptake by PCFT
Authors: Desmoulin Sita Kugel , Wang Lei , Tait Larry , Polin Lisa , Hou Zhanjun , Cherian Christina , Gangjee Aleem , Matherly Larry H. 
Published: June 2012

Abstract
The proton-coupled folate transporter (PCFT) is a proton-folate symporter with an acidic pH optimum, such that PCFT may provide a mechanism for targeting cytotoxic antifolates to tumors, based on their acidic microenvironments (pH 6.2-6.8). PCFT transcripts and protein are high in human solid tumor tissues and cell lines (especially hepatic and ovarian tumors) and limited in most human normal tissues. We identified a novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate (AG71) that is a selective transport substrate for PCFT over the ubiquitously expressed reduced folate carrier (RFC) and a potent inhibitor of the de novo purine nucleotide biosynthetic enzyme glycinamide ribonucleotide (GAR) formyl transferase (GARFTase). Both AG71 and the clinically relevant antifolate pemetrexed (Pmx) were potently inhibitory toward proliferation of a HeLa subline (R1-11-PCFT4) that lacked RFC expression and was engineered to ectopically express physiologically relevant PCFT levels. Unlike Pmx, AG71 did not inhibit proliferation of R1-11-RFC6 cells which express physiologically relevant RFC levels but no PCFT. In colony-forming assays at pH 6.8, AG71 inhibited colony formation of R1-11-PCFT4 cells in a dose- and time-dependent manner, comparable to Pmx. We measured uptake of [3H]AG71 in R1-11-PCFT4 cells and found that transport was optimal at pH 5.5 but still significant at pH 6.8. At pH 6.8, AG71 was metabolized by folylpoly-γ-glutamate synthase to AG71 polyglutamates, as detected by HPLC. GARFTase was validated as a major intracellular target with an in situ GARFTase activity assay at pH 6.8 involving [14C]glycine incorporation into [14C]formyl GAR. In HepG2 human hepatocellular carcinoma cells, PCFT levels were elevated and [3H]AG71 was transported at pH 6.8, whereupon it was extensively metabolized to polyglutamates. By proliferation assays, AG71 was potently inhibitory (IC50 of 227.5 nM) toward HepG2 cells. To test in vivo efficacy of AG71, SCID mice were implanted with subcutaneous HepG2 tumors and treated with AG71 (180 mg/kg × 3d). Compound AG71 was highly active against HepG2 tumors. In conclusion, we have established the expression patterns and pH-specific transport for PCFT in human solid tumor cells and demonstrated that the novel PCFT-targeted antifolate AG71 can be internalized into tumor cells by PCFT leading to significant growth delay of HepG2 xenografts. Our findings offer exciting new therapeutic possibilities for selectively targeting chemotherapy to tumors with novel antifolates based on their acidic microenvironments.
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 2528. doi:10.1158/1538-7445.AM2011-2528
Abstract 2534: Novel and stable water-soluble N-mustards with potent therapeutic efficacy against human tumor xenografts in nude mice
Authors: Su Tsann-Long , Kakadiya Rajesh , Dong Huajin , Chen Yi-Ren , Lee Pei-Chih , Chou Ting-Chao , Hsiao Pei-Wen , Lee Te-Chang , Marvania Bhavin 
Published: June 2012

Abstract
The bioavailability of drugs is one of the important factors to determine whether a drug can be successfully developed for clinical application. Consequently, the physicochemical properties, including solubility, permeability, stability pKa, and lipophilicity/hydrophilicity balance, are key factors that influence the bioavailability of drugs. Compounds with poor solubility usually have a higher risk of difficulties to overcome during the period of new drug discovery and development because these properties may affect antitumor evaluations in animal models as well as pharmacokinetic and pharmacodynamic properties of the compound. In the present studies, we have synthesized a series of novel water-soluble N-mustard-benzene conjugates bearing a urea linker were synthesized. The benzene moiety contains a variety of hydrophilic side chains. These side chains are linked to the meta- or para-position of the urea linker via a carboxamide or an ether linkage. Compounds having a carboxamide hydrophilic side-chain can be converted into water-soluble hydrochloride or mesylate. The preliminary antitumor studies revealed that these conjugates exhibited potent cytotoxicity in vitro and antitumor therapeutic efficacy against human tumor xenografts in vivo. Furthermore, these derivatives have little or no cross-resistance to either Taxol or Vinblastine. Among these conjugates, compound WS-1707, which bearing a N,N-dimethylaminoethylcarboxamide hydrochloride water-soluble side-chain possessed potent therapeutic efficacy in nude mice bearing human breast carcinoma MX-1 (Remarkably, complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft (complete tumor remission), prostate adenocarcinoma PC-3 xenograft (&gt;99% suppression), and human colon cancer HCT-116 xenograft (&gt;95% suppression) at the maximal tolerable dose 30 mg/kg, Q2D×5, intravenous injection. We also compared the therapeutic potency of WS-1707 with Carbopltin, and Doxetaxol in nude mice bearing prostate cancer HL2 xenograft (orthotopic implantation). It reveals that WS-1707 is as potent as Doxetaxol (&gt;82% tumor suppression), but significantly more potent than Carboplatin. Study on the mechanism of action that this agent is able to induce DNA cross-linking through alkaline agarose gel shift assay. Early pharmacokinetic study shows that this conjugates has acceptable profile in rats with a half-life of 0.56 h. These results suggest that this agent is a promising candidate for preclinical studies.
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 2534. doi:10.1158/1538-7445.AM2011-2534
Abstract 2556: Indole-3-carbinol (I3C) and gemcitabine as potential combinatorial therapy in pancreatic cancer
Authors: Lyn-Cook Beverly , Mohammed Sulma , Word Beverly , Hammons George 
Published: June 2012

Abstract
Pancreatic cancer has a poor prognosis, mainly due to lack of effective therapies. The use of non-toxic dietary agents in combination with standard treatment is showing promise in several highly deadly cancers. This study demonstrated the ability of dietary agent, indole-3-carbinol (I3C), to lower the LD50 of gemcitabine (Gemzar) and significantly decrease the growth of both male (MiaPaca2) and female (SU86.86) pancreatic cancer cells. In the male cell line (MiaPaca2) I3C enhanced the anti-proliferative effect at lower doses, decreasing gemcitabine IC50 from 30nM alone to 3nM in combination, a ten-fold decrease in the amount of gemcitabine needed to kill a significant number of cancer cells. Sex difference in response to gemcitabine was also demonstrated. Pancreatic cancer cells from the female cell line (SU86.86) were highly resistant to gemcitabine alone and growth was not affected even at doses as high as 500 μM compared to another powerful anti-cancer drug, doxorubicin (IC50=2.47 µM). However, I3C in combination with gemcitabine exerted powerful anti-cancer effects. The IC50 with 200 µM I3C was 0.388 µM and 1.13 µM with 100 µM I3C, which were lower than that of doxorubicin. Gemcitabine is the current FDA approved single agent for first-line treatment for patients with stage II, III and metastatic adenocarcinoma of the pancreas. This study demonstrated the potential of I3C, a possible non-toxic hypomethylating agent, combined with the anti-cancer agent, gemcitabine, to be a powerful strategy for treating pancreatic cancer.
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 2556. doi:10.1158/1538-7445.AM2011-2556
Abstract 2582: P2X7 receptor is functional in myeloma cell lines and myeloma patient cells and can be modulated by P2X7 receptor antagonists: Implications for myeloma therapy
Authors: Donovan Kathleen A. , Moon-Tasson Laurie , Hromockyj Alexander E. , Meyer Debra M. , Lust John A. 
Published: June 2012

Abstract
Inflammation is a driving factor in the pathogenesis of many cancers including multiple myeloma. Myeloma is a plasma cell tumor whose early stages are characterized by cytokine dependent growth, predominantly driven by IL-6. We have demonstrated that IL-1β is a key inducer of IL-6 expressed by bone marrow stromal cells in a paracrine fashion. The P2X7 receptor (P2X7R) is an ATP-gated ion channel expressed by cells of the hematopoetic lineage that has been shown to play a critical role in IL-1β processing and secretion. We investigated the role this receptor may play in the IL-1/IL-6 cytokine pathway in multiple myeloma. A panel of multiple myeloma cell lines was evaluated by RT-PCR for the expression of P2X7R mRNA. Levels of expression in ANBL-6, MM1S, U266, RPMI-8226 and KAS-6/1 were comparable to U937, a previously characterized P2X7R positive cell line. A newly derived plasmacytoma cell line, PCYT3, showed very low levels of message expression. The ability of ATP to trigger the processing and release of IL-1β by activation of the P2X7 channel was studied using KAS-Pro, a myeloma cell line stably transfected with a pro- IL-1β gene. IL-1β, measured by ELISA, was released in a dose dependent fashion in response to increasing amounts of ATP ranging from 1mM to 5mM. Three P2X7R specific antagonists were tested for their effect on ATP stimulated IL- 1β release from KAS-Pro; all 3 compounds demonstrated inhibition in a dose dependent manner with varying degrees of potency correlating with P2X7R inhibition. In addition fresh patient samples (15 multiple myelomas/ 4 smoldering myelomas/8 MGUS) were evaluated for inhibition of IL-1β release by the P2X7R antagonists through direct measurement of IL-1β by ELISA as well as by an indirect measurement of IL-1β induced IL-6 production by normal bone marrow stromal cells. Greater than 90% inhibition of IL-1β release was demonstrated in all MM & SMM patients positive for IL-1β expression. IL-1β was not detected in any of the MGUS patients and therefore no affect of the inhibitors was observed. These results confirm the activity of functional P2X7 receptors on myeloma cell lines and in fresh patient samples and suggest a role for the use of P2X7 receptor antagonists in the therapy of myeloma.
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 2582. doi:10.1158/1538-7445.AM2011-2582