bluuebunny/crossref_metadata_2025_split huggingface dataset:
UGT1A7 and UGT1A9 Polymorphisms Predict Response and Toxicity in Colorectal Cancer Patients Treated with Capecitabine/Irinotecan
Authors: Carlini Leslie E. , Meropol Neal J. , Bever John , Andria Michael L. , Hill Todd , Gold Philip , Rogatko Andre , Wang Hao , Blanchard Rebecca L. 
Published: June 2022

Abstract
Purpose: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11).
Experimental Design: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m2) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m2, twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies.
Results: The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 −118 (dT)9/9 genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response.
Conclusions: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)9/9 genotype may be particularly likely to exhibit greater antitumor response with little toxicity.
Visualization of Endogenous p53-Mediated Transcription In vivo Using Sodium Iodide Symporter
Authors: Kim Kwang Il , Chung June-Key , Kang Joo Hyun , Lee Yong Jin , Shin Jae Hoon , Oh Hyun Jeong , Jeong Jae Min , Lee Dong Soo , Lee Myung Chul 
Published: June 2022

Abstract
Purpose: To develop a gamma camera imaging method for the determination of endogenous gene expression, we evaluated the expression of endogenous p53 gene using human sodium iodide symporter (hNIS) gene as reporter.
Experimental Design: We constructed cis-p53RE-hNIS reporter vector placed under control of an artificial enhancer (p53RE). Moreover, we transfected it into human hepatoma cell line SK-Hep1 by liposome. Geneticin was used for the selection of stable transfectant (SK-Hep1p53NIS). To evaluate the function of hNIS, the inhibition study was examined with 1 mmol/L potassium perchlorate. After treatment of Adriamycin with serial dose for 24 hours, we measured the uptake of 125I and did Western blot analysis to evaluate expression of p53 protein. Tumor xenografts were produced in nude mice by s.c. injection of SK-Hep1p53NIS cells. After 7 days, scintigraphic images of nude mice before and after Adriamycin treatment were obtained using [99mTc]-pertechnetate.
Results: In the SK-Hep1p53NIS cells, Adriamycin-treated cells accumulated up to three times higher than did nontreated cells. Potassium perchlorate inhibited completely the uptake of 125I. As Adriamycin dose increased, radioiodide uptake was significantly correlated with activated p53 as well as total p53 protein level. When Adriamycin (2 mg/kg) was treated in the same mice, a significantly higher uptake of [99mTc]-pertechnetate was observed in SK-Hep1p53NIS xenografts compared with nontreated xenografts (P &lt; 0.05, unpaired t test).
Conclusions: These results suggest that p53 expression level can be monitored by NIS gene expression using cis-p53RE-hNIS system in vitro and in vivo.
Different Effect of Paclitaxel on Primary Tumor Mass, Tumor Cell Contents, and Metastases for Four Experimental Human Prostate Tumors Expressing Luciferase
Authors: El Hilali Nadia , Rubio Nuria , Blanco Jerónimo 
Published: June 2022

Abstract
Purpose: Primary tumor growth is usually assesed by measuring tumor mass or volume, under the assumption that such variables correlate with the contents of tumor cells. However, tumors are complex interacting mixtures of tumor cells and host components. The different sensitivity of such components to cytostatic agents should be taken into consideration when evaluating the effectiveness of antineoplastic agents. We evaluate the effect of the antineoplastic agent paclitaxel on primary tumors expressing luciferase and their metastases using a sensitive luminescence-based procedure to directly asses the number tumor cells, in comparison with traditionally used tumor mass measurement.
Experimental Design: Nude mice bearing human prostate tumors expressing the luciferase gene, LNCaP.Sluc, DU 145.Sluc, and PC-3.Sluc, i.m. inoculated, and PC-3M.Sluc, orthotopically inoculated, were subjected to a 10-day treatment with either 10 mg/kg/d paclitaxel or saline solution. At the end of the treatment period, primary tumors as well as metastasis target organs were harvested, weighed, and homogenized. The presence of tumor cells in the tissue homogenates was evaluated using a luminometer, following the addition of luciferin. Tumor cell equivalent is defined as the amount of light produced by a single tumor cell in culture.
Results: Paclitaxel had a different effect on the primary tumor mass and the contents of tumor cells for each tumor type. Whereas LNCaP.Sluc, PC-3.Sluc, and PC-3M.Sluc primary tumor masses were significantly reduced by the action of paclitaxel, their contents in tumor cell equivalents were not significantly affected. In contrast, paclitaxel only reduced significantly the number of tumor cell equivalents in DU 145 primary tumors. In the lymph nodes, paclitaxel reduced the number of DU 145.Sluc metastases significantly, by a factor of 103, but had no significant effect on the rest of tumor cells. However, in lungs and muscle, paclitaxel treatment reduced significantly the number of metastatic PC-3.Sluc and PC-3M.Sluc tumor cell equivalents. In the bones, no tumor cell type was significantly affected by paclitaxel.
Conclusions: Some components of tumor stroma seem to be more sensitive to antineoplastic agents than the tumor cells themselves and may also contribute to modulate the response to therapy. Our results caution against the use of a single general variable, such as tumor mass, to evaluate the effectiveness of antineoplastic agents and emphasize the effect of the tumor cell environment in their sensitivity to treatment.
Therapy of Hematogenous Melanoma Brain Metastases with Endostatin
Authors: Kirsch Matthias , Weigel Patrick , Pinzer Thomas , Carroll Rona S. , Black Peter McL. , Schackert Hans-Konrad , Schackert Gabriele 
Published: June 2022

Abstract
Purpose: Cerebral metastases represent the most common type of brain tumors. This study investigated the effects of endogenous endostatin on hematogenous cerebral melanoma metastases.
Experimental Design: Murine K1735 melanoma cells were transfected with the mouse endostatin cDNA. Experimental tumors were induced either by s.c. injection, intracerebral implantation, or via injection into the internal carotid artery to simulate hematogenous metastatic spread. The effects of endostatin expression on tumor incidence, growth pattern, and vascularity were analyzed.
Results: In vitro secretion of endostatin by 2.5 × 105 cells within 24 hours was 0.12 ± 0.03 ng, 4.35 ± 0.4, and 1.18 ± 0.7 ng/mL for wild type and two endostatin-transfected K1735 clones termed K1735-endo/2 and K1735-endo/8, respectively. Tumor inhibition in vivo correlated with endogenous endostatin production. Within 25 days, growth of s.c. K1735-endo/2 tumors was &lt;20% compared with wild-type controls. Following intracerebral implantation the average survival time of mice was 27.8 ± 2.6 versus 13.3 ± 3.7 days in the K1735-endo/2 versus the wild-type group, respectively. Intracarotid injection of 1 × 105 wild-type cells killed the mice within 24 ± 1.8 days. In contrast, endostatin expression prevented macroscopic metastatic tumor growth in 11 of 12 mice, although viable microscopic tumor pockets were detectable in all animals.
Conclusion: Endostatin inhibits tumor progression of multiple cerebral metastases in vivo. Hematogenous micrometastases are more efficiently suppressed than tumors resulting from high focal cell numbers which may be due to a higher angiogenic signaling exerted by massive cell deposits. Endostatin may prevent solid tumor growth more effectively by inhibition of early angiogenesis.
Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor-2 and Epidermal Growth Factor Receptor Small Molecule Tyrosine Kinase Inhibitor, in Combination with SC-236, a Cyclooxygenase-2 Inhibitor
Authors: Tuccillo Concetta , Romano Marco , Troiani Teresa , Martinelli Erika , Morgillo Floriana , De Vita Ferdinando , Bianco Roberto , Fontanini Gabriella , Bianco Raffaele A. , Tortora Giampaolo , Ciardiello Fortunato 
Published: June 2022

Abstract
Purpose: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor (VEGF) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. Enhanced cyclooxygenase-2 (COX-2) expression has been linked to cancer cell proliferation, EGFR activation, VEGF secretion, and tumor-induced angiogenesis. ZD6474 is an orally available, small molecule, dual VEGF receptor-2 (VEGFR-2) and EGFR tyrosine kinase inhibitor. We investigated the activity of ZD6474 in combination with SC-236, a selective COX-2 inhibitor, to determine the antitumor activity of the simultaneous blockade of EGFR, COX-2, and VEGF functions.
Experimental Design: The antitumor activity in vitro and in vivo of ZD6474 and/or SC-236 was tested in human cancer cell lines with a functional EGFR autocrine pathway.
Results: The combination of ZD6474 and SC-236 determined supra-additive growth inhibition in all cancer cell lines tested. In nude mice bearing established human colon (GEO) or lung adenocarcinoma (A549) cancer xenografts and treated with ZD6474 and/or SC-236 for 3 weeks, a reversible tumor growth inhibition was seen with each agent, whereas a more prolonged growth inhibition that lasted for 3 to 5 weeks following the end of treatment resulted from the combination of the two agents. A long-term, 10-week treatment with ZD6474 plus SC-236 resulted in sustained tumor growth inhibition in all mice with tumor eradication in 3 of 10 GEO tumor–bearing mice and in 4 of 10 A549 tumor–bearing mice.
Conclusions: This study provides a rationale for evaluating the simultaneous blockade of EGFR, COX-2, and VEGF signaling as cancer therapy in a clinical setting.
Targeting of Nuclear Factor κB Pathways by Dehydroxymethylepoxyquinomicin, a Novel Inhibitor of Breast Carcinomas: Antitumor and Antiangiogenic Potential In vivo
Authors: Matsumoto Gaku , Namekawa Jun-ichi , Muta Mariko , Nakamura Tadahiko , Bando Hiroko , Tohyama Kazumi , Toi Masakazu , Umezawa Kazuo 
Published: June 2022

Abstract
We previously designed and synthesized the new nuclear factor κB (NF-κB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of the antibiotic epoxyquinomicin C. We looked into the effect of DHMEQ on cellular phenotypes and tumor growth in mice injected with human breast carcinoma cell line MDA-MB-231 or MCF-7. In estrogen-independent breast adenocarcinoma cell line MDA-MB-231, NF-κB is constitutively activated. The addition of DHMEQ (10 μg/mL) completely inhibited the activated NF-κB for at least 8 hours. On the other hand, NF-κB is not activated in estrogen-dependent MCF-7 cells. In this cell line, DHMEQ completely inhibited the tumor necrosis factor-α-induced activation of NF-κB. DHMEQ did not inhibit the degradation of IκB but inhibited the nuclear translocation of NF-κB by both p65/p50 and RelB/p52 pathways. MDA-MB-231 cells secrete interleukin (IL)-6 and IL-8 without stimulation, and DHMEQ decreased the secretion levels of both cytokines. When MDA-MB-231 or MCF-7 cells were stimulated by tumor necrosis factor-α, the inhibitory effects of DHMEQ were still maintained. I.p. administration of DHMEQ (thrice a week) significantly inhibited the tumor growth of MDA-MB-231 (12 mg/kg) or MCF-7 (4 mg/kg) in severe combined immunodeficiency mice. No toxicity was observed during the experiment, including the loss of body weight. An immunohistological study on resected MCF-7 tumors showed that DHMEQ inhibited angiogenesis and promoted apoptosis. Furthermore, in Adriamycin-resistant MCF-7 cells highly expressing multidrug resistance gene-1, DHMEQ also exhibited the above capability, including down-regulation of IL-8. Thus, DHMEQ might be a potent drug for the treatment of various breast carcinomas by inhibiting the NF-κB activity.
Loss of Reduced Folate Carrier Function and Folate Depletion Result in Enhanced Pemetrexed Inhibition of Purine Synthesis
Authors: Zhao Rongbao , Zhang Shubing , Hanscom Marie , Chattopadhyay Shrikanta , Goldman I. David 
Published: June 2022

Abstract
Pemetrexed is a novel antifolate with polyglutamate derivatives that are potent inhibitors of thymidylate synthase (TS) and to a lesser extent glycinamide ribonucleotide formyltransferase (GARFT). Conditions that might modulate relative suppression of these sites were assessed by the pattern of hypoxanthine and thymidine protection. When grown with 25 nmol/L racemic 5-formyltetrahydrofolate, thymidine alone fully protected wild-type HeLa cells to at least 1 μmol/L pemetrexed, but protection of a reduced folate carrier (RFC)-null subline required both thymidine and hypoxanthine above a concentration of 30 nmol/L pemetrexed. As medium 5-formyltetrahydrofolate was decreased, protection by thymidine alone decreased, and was further diminished when HeLa cells were grown in dialyzed serum. There was little protection by thymidine of RFC-null HeLa cells under the latter conditions. Thymidine alone was not protective, and hypoxanthine alone produced only a small (2-fold) increase in IC50, in a HeLa-derived line 8-fold resistant to pemetrexed due to a modest increase in TS. Finally, in MCF-7 breast cancer cells there was greater protection with thymidine alone than in HeLa cells when cells were grown in medium containing a low concentration of 5-formyltetrahydrofolate. These observations indicate that as intracellular folates decrease in HeLa cells, due to decreased extracellular reduced folate, or loss of RFC function, pemetrexed inhibition of GARFT increases. These data support the concept that the contribution to pemetrexed activity by inhibition of GARFT, particularly at low folate levels, is a contributing factor to drug activity but relative inhibition of TS and GARFT may vary among human tumors and cell lines.
Potentiation of a Dendritic Cell Vaccine for Murine Renal Cell Carcinoma by CpG Oligonucleotides
Authors: Chagnon Fanny , Tanguay Simon , Ozdal Ozdem Levent , Guan Meng , Ozen Zeynep Z. , Ripeau Jean-Sébastien , Chevrette Mario , Elhilali Mostafa M. , Thompson-Snipes Lu Ann 
Published: June 2022

AbstractPurpose: An ideal vaccine therapy for tumors should activate both effector and memory immune responses against tumor-specific antigens. Here we investigated the effect of CpG oligodeoxynucleotides (CpG-ODN) for their ability to potentiate the activity of tumor antigen–pulsed bone marrow–derived dendritic cells (DC) in a vaccine model for the treatment of murine renal cell carcinoma (RENCA).Experimental Design: First we evaluated the effects of a murine renal cell carcinoma (RENCA) on immune cell activity in a mouse model using in vitro assays for T-cell proliferation and natural killer cell activation. To overcome the immune suppression of the tumor, we s.c. injected groups of 10 mice with dendritic cells and tumor cells. We compared the effect of different conditioning regimens of the DCs with RENCA antigen and/or CpG-ODNs before injection by measuring tumor size twice a week.Results: Tumor growth was shown to negatively affect spleen cell and T-cell proliferation, IFN-γ production, natural killer cell activity, and NF-κB activation in T cells. In this model, we have shown that RENCA-pulsed CpG-ODN-treated DCs were able not only to significantly reduce tumor growth but also to prevent tumor implantation in 60% of mice. Tumor-free mice were resistant to tumor challenge and the immunity conferred by the vaccine was transferable and tumor specific.Conclusions: This data show that RENCA down-modulates the immune response, and DC vaccine therapy, in conjunction with CpG-ODN, can restore tumor-specific immunity.
Transcriptional Profiling Identifies Gene Expression Changes Associated with IFN-α Tolerance in Hepatitis C–Related Hepatocellular Carcinoma Cells
Authors: Wong Nathalie , Chan Kathy Y-Y. , Macgregor Pascale F. , Lai Paul B-S. , Squire Jeremy A. , Beheshti Ben , Albert Monique , Leung Thomas W-T. 
Published: June 2022

Abstract
Purpose: Treatment with IFN-α therapy has been shown to exhibit antitumor effects on patients with hepatocellular carcinoma (HCC). However, individual responses remained unpredictable because of the frequent presence of intrinsic or acquired IFN-α resistance. Hence, delineation of molecular targets implicated in the resistant pathway holds value in refining the therapeutic benefits of IFN-α.
Experimental Design: The current study analyzed the effect of IFN-α in human HCC cells. Three hepatitis C virus (HCV)–related, five hepatitis B virus (HBV)–related and two non-B non-C–related cell lines were subjected to IFN-α treatment and the cytotoxic effect on cell viability was measured. Further analysis by cDNA microarray and quantitative reverse transcription-PCR were conducted to examine the gene expression changes that mediated the IFN-α resistance observed.
Results: According to the IC50 values determined, HCV-related cell lines indicated distinct resistance (IC50, 389-1468 units/mL) compared with the HBV-related (IC50, 11-77 units/mL) and non-B non-C–related cell lines (IC50, 24-108 units/mL). Unsupervised hierarchical clustering on array data indicated three HCV-related cell lines to cluster independently from the sensitive cell lines, suggesting discrete features in association with IFN-α tolerance. Moreover, Significance Analysis of Microarrays analysis indicated the differential expression of 149 expressed sequence tags that represented 51 up-regulated and 98 down-regulated genes in the resistant cell lines. Comparing the temporal pattern of gene expression between 6- and 24-hour treatments, candidate genes that were considerably induced with time were further highlighted in the tolerant HCV-related cell lines. These candidates were verified by quantitative reverse transcription-PCR, which confirmed the down-regulation of UBA2, ZNF185, and FOXF1 and up-regulation of UBE4B in the drug-tolerant cells.
Conclusions: Our present study showed that the insensitivity to IFN-α therapy in HCC cells is associated with drug-inducible transcriptional alterations. Furthermore, our investigation highlighted potential candidate genes in conferring an anti-apoptotic effect toward IFN-α treatment.
Dual Inhibition of RET and FGFR4 Restrains Medullary Thyroid Cancer Cell Growth
Authors: Ezzat Shereen , Huang Ping , Dackiw Alan , Asa Sylvia L. 
Published: June 2022

Abstract
Medullary thyroid cancer is frequently an aggressive form of carcinoma for which there are currently no effective forms of systemic therapy. These carcinomas arise as a result of activating mutations in the RET proto-oncogene transmembrane tyrosine kinase receptor. We, therefore, examined the potential efficacy of the tyrosine kinase inhibitor STI571 on the growth of human TT medullary cancer cells in vitro and in xenografted severe combined immunodeficiency mice. Treatment with STI571 resulted in inhibition of RET phosphorylation, cell proliferation, tumor growth and invasiveness. Based on the profile of expression of fibroblast growth factor receptors (FGFR), we examined the effects of FGFR tyrosine kinase inhibition using the small molecule FGFR inhibitor PD173074. This inhibitor resulted in abrogation of fibroblast growth factor-1-mediated FGFR4 phosphorylation in TT cells, an effect that was accompanied by significant arrest of cell proliferation and tumor growth in vivo. Moreover, the combination of STI571 and PD173074 resulted in greater suppression of cell proliferation in vitro and tumor control in vivo than that achieved with either agent alone. These data highlight RET and FGFR4 as therapeutic targets and suggest a potential role for the combined use of tyrosine kinase inhibitors in the management of inoperable medullary thyroid cancers.
Recombinant Adeno-Associated Virus 2-Mediated Antiangiogenic Prevention in a Mouse Model of Intraperitoneal Ovarian Cancer
Authors: Isayeva Tatyana , Ren Changchun , Ponnazhagan Selvarangan 
Published: June 2022

Abstract
Purpose: In the present study, we sought to determine the potential of sustained transgene expression by a single i.m. administration of recombinant adeno-associated virus 2 (rAAV) encoding angiostatin and endostatin in inhibiting i.p. ovarian cancer growth and dissemination in a preclinical mouse model.
Experimental Design: Cohorts of female athymic nude mice received either no virus or 1.2 × 1011 particles of rAAV encoding green fluorescence protein or endostatin plus angiostatin, i.m. Three weeks later, the mice were i.p. injected with 106 human epithelial ovarian cancer cell line SKOV3.ip1. As a measure of effectiveness of the therapy, tumor weight, abdominal distension, ascites volume and vascular endothelial growth factor level, and tumor weight were determined. Immunohistochemistry was done to determine tumor cell apoptosis and endothelial cell proliferation following the therapy. Tumor-free survival was recorded as the end point.
Results: Results indicated a significant tumor-free survival (P &lt; 0.003) following therapy with rAAV encoding endostatin and angiostatin compared with untreated or rAAV-green fluorescence protein–treated mice. Ascites volume in rAAV endostatin and angiostatin–treated mice was significantly lower than naive mice and contained less hemorrhage and tumor conglomerates. The level of vascular endothelial growth factor in the ascites of antiangiogenic vector treated mice was also significantly less compared with the untreated mice. Immunohistochemical analyses indicated increased tumor cell apoptosis and decreased blood vasculature following rAAV endostatin and angiostatin treatment.
Conclusion: The results indicate that antiangiogenic genetic prevention from stable systemic levels of angiostatin and endostatin by i.m. administration of rAAV can be used for the treatment of i.p. ovarian cancer growth and dissemination.