bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer Immunotherapy Based on Killing of Salmonella-Infected Tumor Cells
Authors: Avogadri Francesca , Martinoli Chiara , Petrovska Liljana , Chiodoni Claudia , Transidico Pietro , Bronte Vincenzo , Longhi Renato , Colombo Mario P. , Dougan Gordon , Rescigno Maria 
Published: September 2005

Abstract
A major obstacle for the development of effective immunotherapy is the ability of tumors to escape the immune system. The possibility to kill tumor cells because they are recognized as infected rather than as malignant could help overcome immune escape mechanisms. Here we report a conceptually new approach of cancer immunotherapy based on in vivo infection of tumors and killing of infected tumor cells. Attenuated but still invasive, Salmonella typhimurium can be successfully exploited to invade melanoma cells that can present antigenic determinants of bacterial origin and become targets for anti-Salmonella–specific T cells. However, to fully appreciate the anticancer therapeutic properties of S. typhimurium, tumor-bearing mice need to be vaccinated against S. typhimurium before intratumoral Salmonella injection. Tumor infection when coupled to anti-Salmonella vaccination leads to 50% to 100% tumor-free mice with a better outcome on larger tumors. Invasive Salmonella also exert an indirect toxic effect on tumor cells through the recruitment of inflammatory cells and the cross-presentation of tumor antigens, which allow induction of tumor-specific immune response. This is effective in retarding the growth of untreated established distant tumors and in protecting the mice from subsequent tumor challenges.
The Seco-Taxane IDN5390 Is Able to Target Class III β-Tubulin and to Overcome Paclitaxel Resistance
Authors: Ferlini Cristiano , Raspaglio Giuseppina , Mozzetti Simona , Cicchillitti Lucia , Filippetti Flavia , Gallo Daniela , Fattorusso Caterina , Campiani Giuseppe , Scambia Giovanni 
Published: September 2005

Abstract
A prominent mechanism of drug resistance to taxanes is the overexpression of class III β-tubulin. The seco-taxane IDN5390 was chosen for its selective activity in paclitaxel-resistant cells with an overexpression of class III β-tubulin. Moreover, the combined treatment paclitaxel/IDN5390 yielded a strong synergism, which was also evident in cell-free tubulin polymerization assays. In the presence of an anti-class III β-tubulin as a blocking antibody, tubulin polymerization induced by paclitaxel and IDN5390 was enhanced and not affected, respectively, whereas synergism was abolished, thereby indicating that IDN5390 activity is not modulated by class III β-tubulin levels. Such properties can be explained by taking into consideration the composition of class III β-tubulin paclitaxel binding site; in fact, Ser277 interacting with paclitaxel C group in class I is replaced by an Arginine in class III. IDN5390 that has an open and flexible C ring and an acidic α-unsaturated enol-keton moiety better fits with class III β-tubulin than paclitaxel at the binding site. Taking altogether, these findings indicate that the concomitant treatment IDN5390/paclitaxel is able to successfully target class I and III β-tubulin and the combined use of two taxanes with diverse spectrum activity against tubulin isotypes could represent a novel approach to overcome paclitaxel resistance.
Efforts to Control the Errant Products of a Targeted In vivo Generator
Authors: Singh Jaggi Jaspreet , Kappel Barry J. , McDevitt Michael R. , Sgouros George , Flombaum Carlos D. , Cabassa Catalina , Scheinberg David A. 
Published: September 2005

Abstract
Alpha-particle immunotherapy by targeted α-emitters or α-emitting isotope generators is a novel form of extraordinarily potent cancer therapy. A major impediment to the clinical use of targeted actinium-225 (225Ac) in vivo generators may be the radiotoxicity of the systemically released daughter radionuclides. The daughters, especially bismuth-213 (213Bi), tend to accumulate in the kidneys. We tested the efficacy of various pharmacologic agents and the effect of tumor burden in altering the pharmacokinetics of the 225Ac daughters to modify their renal uptake. Pharmacologic treatments in animals were started before i.v. administration of the HuM195-225Ac generator. 225Ac, francium-221 (221Fr), and 213Bi biodistributions were calculated in each animal at different time points after 225Ac generator injection. Oral metal chelation with 2,3-dimercapto-1-propanesulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA) caused a significant reduction (P &lt; 0.0001) in the renal 213Bi uptake; however, DMPS was more effective than DMSA (P &lt; 0.001). The results with DMPS were also confirmed in a monkey model. The renal 213Bi and 221Fr activities were significantly reduced by furosemide and chlorothiazide treatment (P &lt; 0.0001). The effect on renal 213Bi activity was further enhanced by the combination of DMPS with either chlorothiazide or furosemide (P &lt; 0.0001). Competitive antagonism by bismuth subnitrate moderately reduced the renal uptake of 213Bi. The presence of a higher target-tumor burden significantly prevented the renal 213Bi accumulation (P = 0.003), which was further reduced by DMPS treatment (P &lt; 0.0001). Metal chelation, diuresis with furosemide or chlorothiazide, and competitive metal blockade may be used as adjuvant therapies to modify the renal accumulation of 225Ac daughters.
Sun Exposure, Vitamin D Receptor Gene Polymorphisms, and Risk of Advanced Prostate Cancer
Authors: John Esther M. , Schwartz Gary G. , Koo Jocelyn , Van Den Berg David , Ingles Sue A. 
Published: September 2005

Abstract
Substantial experimental evidence indicates that the hormonal form of vitamin D promotes the differentiation and inhibits the proliferation, invasiveness, and metastasis of human prostatic cancer cells. Results from epidemiologic studies of vitamin D status and/or vitamin D receptor (VDR) polymorphisms and prostate cancer risk have been mixed. We conducted a population-based, case-control study of advanced prostate cancer among men ages 40 to 79 years from the San Francisco Bay area. Interview data on lifetime sun exposure and other risk factors were collected for 905 non-Hispanic White men (450 cases and 455 controls). Using a reflectometer, we measured constitutive skin pigmentation on the upper underarm (a sun-protected site) and facultative pigmentation on the forehead (a sun-exposed site) and calculated a sun exposure index from these measurements. Biospecimens were collected for 426 cases and 440 controls. Genotyping was done for VDR polymorphisms in the 5′ regulatory region (Cdx-2), exon 2 (FokI), and the 3′ region (TaqI and BglI). Reduced risk of advanced prostate cancer was associated with high sun exposure determined by reflectometry [odds ratio (OR), 0.51; 95% confidence interval (95% CI), 0.33-0.80] and high occupational outdoor activity (OR, 0.73; 95% CI, 0.48-1.11). Significant risk reductions with the high-activity alleles FokI FF or Ff, TaqI tt, and BglI BB genotypes and a nonsignificant reduction with Cdx-2 AG or AA genotype were observed in the presence of high sun exposure, with ORs ranging from 0.46 to 0.67. Our findings support the hypothesis that sun exposure and VDR polymorphisms together play important roles in the etiology of prostate cancer.
Farnesyltransferase Inhibitor SCH66336 Induces Rapid Phosphorylation of Eukaryotic Translation Elongation Factor 2 in Head and Neck Squamous Cell Carcinoma Cells
Authors: Ren Hening , Tai Shyh-Kuan , Khuri Fadlo , Chu Zuming , Mao Li 
Published: September 2005

Abstract
Farnesyltransferase inhibitors (FTI) are a class of therapeutic agents designed to target tumors with mutations of the ras oncogene. However, the biological effect of FTIs is often independent of ras mutation status, which suggests the existence of additional mechanisms. In this study, we investigated the molecular effects of SCH66336, an FTI, in head and neck squamous cell carcinoma cells using proteomic approaches. We showed that SCH66336 induced phosphorylation (inactivation) of eukaryotic translation elongation factor 2 (eEF2), an important molecule for protein synthesis, as early as 3 hours after SCH66336 administration. Protein synthesis was subsequently reduced in the cells. Paradoxically, activation of eEF2 kinase (eEF2K), the only known kinase that regulates eEF2, was observed only at 12 hours after SCH66336 treatment. Consistent with this observation, the inhibition of phosphorylated-MEK and phosphorylated-p70S6K, the two key signaling molecules responsible for activation of eEF2K, also occurred at least 12 hours after SCH66336 administration. Our data suggest that inhibition of protein synthesis through inactivation of eEF2 is a novel mechanism of SCH66336-mediated growth inhibition and that this effect is independent of ras-MEK/p70S6K-eEF2K signaling cascades.
Cleavable ErbB4 Isoform in Estrogen Receptor–Regulated Growth of Breast Cancer Cells
Authors: Junttila Teemu T. , Sundvall Maria , Lundin Mikael , Lundin Johan , Tanner Minna , Härkönen Pirkko , Joensuu Heikki , Isola Jorma , Elenius Klaus 
Published: September 2005

Abstract
ErbB1 and ErbB2 receptors are well-characterized targets for anticancer drugs, but the clinical relevance of the related ErbB4 receptor is unknown. Here, we have assessed the clinical significance of the proteolytically cleavable ErbB4 isoforms in breast cancer patients and investigated their functions in vitro. The expression of transcripts encoding the cleavable ErbB4 isoforms associated with estrogen receptor-α (ER) expression (P &lt; 0.001) and a high histologic grade of differentiation (P ≤ 0.002) in real-time reverse transcription-PCR analysis of 62 breast cancer samples. Despite high ErbB4 mRNA expression levels in a subset of samples, ErbB4 gene amplification was not observed. High ErbB4 protein expression levels, as assessed by immunohistochemistry, associated with a favorable outcome in ER-positive cases from a series of 458 breast cancer patients (P = 0.01), whereas no association between ErbB4 expression and survival was found among women with ER-negative cancer (P = 0.86). However, nuclear ErbB4 immunoreactivity was associated with poor survival as compared with women whose cancer had membranous ErbB4 staining (P = 0.04). In vitro, overexpression of a cleavable ErbB4 isoform in ER-positive breast cancer cells resulted in translocation of a proteolytically released intracellular ErbB4 receptor fragment into the nucleus, as well as, enhanced proliferation, anchorage-independent growth, and estrogen response element–mediated transcriptional activity. These results suggest that the association of ErbB4 expression with clinical outcome is dependent on the subcellular localization of ErbB4 and that a proteinase-cleavable ErbB4 isoform promotes growth of ER-positive breast cancer and enhances ER-mediated gene transcription.
In vitro Procoagulant Activity Induced in Endothelial Cells by Chemotherapy and Antiangiogenic Drug Combinations: Modulation by Lower-Dose Chemotherapy
Authors: Ma Li , Francia Giulio , Viloria-Petit Alicia , Hicklin Daniel J. , du Manoir Jeanne , Rak Janusz , Kerbel Robert S. 
Published: September 2005

Abstract
One of the emerging problems concerning the use of antiangiogenic drugs, when used in combination with certain chemotherapy regimens, is enhanced rates and severity of adverse clotting events. For as yet unknown reasons, certain drugs and particular combinations can induce an elevated incidence of thromboembolic events in treated cancer patients [e.g., SU5416, a vascular endothelial cell growth factor receptor-2 (VEGFR-2) antagonist, when combined with gemcitabine and cisplatin (CDDP)]. Such results highlight the need to develop assays capturing the essence of enhanced clot formation under such combination treatment and which may have predictive potential as well. Here, we report the possibility of such an assay (i.e., the ratio of tissue factor over tissue factor pathway inhibitor expression or activity in cultured human endothelial cells calculated as a coagulation index). A marked increase in coagulation index was observed after exposure to SU5416 and the CDDP/gemcitabine chemotherapy combination in contrast to either of these treatments used alone. Substitution of SU5416 with any one of ZD6474, SU6668, IMC-1121, a monoclonal antibody to VEGFR-2, or an antibody to VEGF (bevacizumab) did not cause a marked increase in the coagulation index, nor did the combination of SU5416 with 5-fluorouracil and leucovorin. Finally, we noted that reducing the concentrations of gemcitabine and CDDP (i.e., use of “metronomic dosing” in vitro) significantly attenuated the coagulation index increase induced by these drugs, suggesting that use of low-dose chemotherapy regimens might be an approach to consider for reducing the incidence of adverse clotting events associated with chemotherapy alone or in conjunction with antiangiogenic drug combination therapies.
Tumor-Stromal Interaction through the Estrogen-Signaling Pathway in Human Breast Cancer
Authors: Yamaguchi Yuri , Takei Hiroyuki , Suemasu Kimito , Kobayashi Yasuhito , Kurosumi Masafumi , Harada Nobuhiro , Hayashi Shin-ichi 
Published: September 2005

Abstract
In postmenopausal breast cancers, locally produced estrogen by adipose stromal cells causes the progression of tumor growth. Although aromatase, a key enzyme of estrogen synthesis, is highly expressed in the adipose stromal cells, and aromatase inhibitors show greater efficacy in postmenopausal breast cancers, the mechanism of increasing aromatase activity in the stromal cells remains unclear. To analyze the estrogen signals and to detect the estrogen receptor (ER)–activating ability of adipose stromal cells for individual human breast cancers, we developed a new reporter cell system. To visualize the activation of ER, we first established a stable transformant, named E10, of human breast cancer MCF-7 cells by transfection with the estrogen-responsive element-green fluorescent protein (GFP) gene. E10 cells specifically express GFP when ER is activated by estrogen or by coculture with adipose stromal cells isolated from breast tumor tissues in the presence of testosterone, a substrate for aromatase. Treatment of adipose stromal cells with dexamethasone, a stimulator of aromatase gene expression, resulted in an increase in the expression of GFP in E10 cells in the coculture. Using this system, we characterized the adipose stromal cells of 67 human breast cancers and found that GFP expression levels vary among the cases, suggesting that the ability of adipose stromal cells to activate ERs is unique for individual breast cancers. High induction levels of GFP were observed more frequently in postmenopausal cases than in premenopausal cases, whereas they did not significantly correlate with the ER expression status. Aromatase inhibitors inhibited the induction of GFP expression in the coculture, but the sensitivities to the drugs varied among the individual cases. Aromatase gene expression levels in adipose stromal cells did not always correlate with their ability to induce GFP. These results suggest that this system to detect total ER activation based on the interaction with adipose stromal cells is a useful tool for analyzing local estrogen signals and for tumor-stromal interactions.
Genome-Wide Association Study in Esophageal Cancer Using GeneChip Mapping 10K Array
Authors: Hu Nan , Wang Chaoyu , Hu Ying , Yang Howard H. , Giffen Carol , Tang Ze-Zhong , Han Xiao-Yu , Goldstein Alisa M. , Emmert-Buck Michael R. , Buetow Kenneth H. , Taylor Philip R. , Lee Maxwell P. 
Published: September 2005

Abstract
Whole genome association studies of complex human diseases represent a new paradigm in the postgenomic era. In this study, we report application of the Affymetrix, Inc. (Santa Clara, CA) high-density single nucleotide polymorphism (SNP) array containing 11,555 SNPs in a pilot case-control study of esophageal squamous cell carcinoma (ESCC) that included the analysis of germ line samples from 50 ESCC patients and 50 matched controls. The average genotyping call rate for the 100 samples analyzed was 96%. Using the generalized linear model (GLM) with adjustment for potential confounders and multiple comparisons, we identified 37 SNPs associated with disease, assuming a recessive mode of transmission; similarly, 48 SNPs were identified assuming a dominant mode and 53 SNPs in a continuous mode. When the 37 SNPs identified from the GLM recessive mode were used in a principal components analysis, the first principal component correctly predicted 46 of 50 cases and 47 of 50 controls. Among all the SNPs selected from GLMs for the three modes of transmission, 39 could be mapped to 1 of 33 genes. Many of these genes are involved in various cancers, including GASC1, shown previously to be amplified in ESCCs, and EPHB1 and PIK3C3. In conclusion, we have shown the feasibility of the Affymetrix 10K SNP array in genome-wide association studies of common cancers and identified new candidate loci to study in ESCC.
Emodin Down-Regulates Androgen Receptor and Inhibits Prostate Cancer Cell Growth
Authors: Cha Tai-Lung , Qiu Lin , Chen Chun-Te , Wen Yong , Hung Mien-Chie 
Published: September 2005

Abstract
Hormone-refractory relapse is an inevitable and lethal event for advanced prostate cancer patients after hormone deprivation. A growing body of evidence indicates that hormone deprivation may promote this aggressive prostate cancer phenotype. Notably, androgen receptor (AR) not only mediates the effect of androgen on the tumor initiation but also plays the major role in the relapse transition. This provides a strong rationale for searching new effective agents targeting the down-regulation of AR to treat or prevent advanced prostate cancer progression. Here, we show that emodin, a natural compound, can directly target AR to suppress prostate cancer cell growth in vitro and prolong the survival of C3(1)/SV40 transgenic mice in vivo. Emodin treatment resulted in repressing androgen-dependent transactivation of AR by inhibiting AR nuclear translocation. Emodin decreased the association of AR and heat shock protein 90 and increased the association of AR and MDM2, which in turn induces AR degradation through proteasome-mediated pathway in a ligand-independent manner. Our work indicates a new mechanism for the emodin-mediated anticancer effect and justifies further investigation of emodin as a therapeutic and preventive agent for prostate cancer.
Activated Marrow-Infiltrating Lymphocytes Effectively Target Plasma Cells and Their Clonogenic Precursors
Authors: Noonan Kimberly , Matsui William , Serafini Paolo , Carbley Rebecca , Tan Gladys , Khalili Jahan , Bonyhadi Mark , Levitsky Hyam , Whartenby Katie , Borrello Ivan 
Published: September 2005

AbstractA major limitation of adoptive immunotherapy is the availability of T cells specific for both terminally differentiated tumor cells and their clonogenic precursors. We show here that marrow-infiltrating lymphocytes (MILs) recognize myeloma cells after activation with anti-CD3/CD28 beads with higher frequency than activated peripheral blood lymphocytes from the same patients. Furthermore, activated MILs target both the terminally differentiated CD138+ plasma cells and the myeloma precursor as shown by profound inhibition in a tumor clonogenic assay. The presence of antigen in the marrow microenvironment seems to be important for the maintenance of tumor specificity. Taken together, these results highlight the intrinsic tumor specificity of MILs and describe a novel approach for the generation of tumor-specific T-cell populations suitable for adoptive immunotherapy of multiple myeloma.
Oncolytic Herpes Simplex Virus Vector Therapy of Breast Cancer in C3(1)/SV40 T-antigen Transgenic Mice
Authors: Liu Renbin , Varghese Susan , Rabkin Samuel D. 
Published: September 2005

AbstractOncolytic herpes simplex virus vectors are a promising strategy for cancer therapy, as direct cytotoxic agents, inducers of antitumor immune responses, and as expressers of anticancer genes. Progress is dependent upon representative preclinical models to evaluate therapy. In this study, two families of oncolytic herpes simplex virus vectors (G207 and NV1020 series) that have been in clinical trials were examined for the treatment of breast cancer, using the C3(1)/T-Ag transgenic mouse model. Female mice spontaneously develop mammary carcinomas, and the C3(1)/T-Ag–derived tumor cell line M6c forms implantable tumors. Both in vitro and in vivo, G47Δ, derived from G207 by deletion of ICP47 and the US11 promoter, was more efficacious than G207. Whereas NV1023, derived from NV1020 by deletion of ICP47 and insertion of LacZ, was as cytotoxic to M6c cells in vitro as G47Δ, it did not inhibit the growth of s.c. M6c tumors but did extend the survival of intracerebral tumor bearing mice. In contrast, NV1042, NV1023 expressing interleukin 12, inhibited s.c. M6c tumor growth to a similar extent as G47Δ, but was less effective than NV1023 in intracerebral tumors. In the spontaneously arising mammary tumor model, when only the first arising tumor per mouse was treated, G47Δ inhibited the growth of a subset of tumors, and when all tumors were treated, G47Δ significantly delayed tumor progression. When the first mammary tumor was treated and the remaining mammary glands removed, NV1042 was more efficacious than G47Δ at inhibiting the growth and progression of injected tumors.
Inhibitors of the Arachidonic Acid Pathway and Peroxisome Proliferator–Activated Receptor Ligands Have Superadditive Effects on Lung Cancer Growth Inhibition
Authors: Avis Ingalill , Martínez Alfredo , Tauler Jordi , Zudaire Enrique , Mayburd Anatoly , Abu-Ghazaleh Raed , Ondrey Frank , Mulshine James L. 
Published: September 2005

Abstract
Arachidonic acid (AA) metabolizing enzymes and peroxisome proliferator–activated receptors (PPARs) have been shown to regulate the growth of epithelial cells. We have previously reported that exposure to the 5-lipoxygenase activating protein–directed inhibitor MK886 but not the cyclooxygenase inhibitor, indomethacin, reduced growth, increased apoptosis, and up-regulated PPARα and γ expression in breast cancer cell lines. In the present study, we explore approaches to maximizing the proapoptotic effects of PPARγ on lung cancer cell lines. Non–small-cell cancer cell line A549 revealed dose-dependent PPARγ reporter activity after treatment with MK886. The addition of indomethacin in combination with MK886 further increases reporter activity. We also show increased growth inhibition and up-regulation of apoptosis after exposure to MK886 alone, or in combination with indomethacin and the PPAR ligand, 15-deoxy-Δ12,14-prostaglandin J2 compared with single drug exposures on the adenocarcinoma cell line A549 and small-cell cancer cell lines H345, N417, and H510. Real-time PCR analyses showed increased PPAR mRNA and retinoid X receptor (RXR)α mRNA expression after exposure to MK886 and indomethacin in a time-dependent fashion. The results suggest that the principal proapoptotic effect of these drugs may be mediated through the known antiproliferative effects of the PPARγ-RXR interaction. We therefore explored a three-drug approach to attempt to maximize this effect. The combination of low-dose MK886, ciglitazone, and 13-cis-retinoic acid interacted at least in a superadditive fashion to inhibit the growth of lung cancer cell lines A549 and H1299, suggesting that targeting PPARγ and AA action is a promising approach to lung cancer growth with a favorable therapeutic index.