bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiosensitization of Squamous Cell Carcinoma by the Alkylphospholipid Perifosine in Cell Culture and Xenografts
Authors: Vink Stefan R. , Lagerwerf Saskia , Mesman Elly , Schellens Jan H.M. , Begg Adrian C. , van Blitterswijk Wim J. , Verheij Marcel 
Published: March 2006

Abstract
Purpose: Combined modality treatment has improved outcome in various solid tumors. Besides classic anticancer drugs, a new generation of biological response modifiers has emerged that increases the efficacy of radiation. Here, we have investigated whether perifosine, an orally applicable, membrane-targeted alkylphospholipid, enhances the antitumor effect of radiation in vitro and in vivo.
Experimental Design: Several long-term and short-term in vitro assays (clonogenic survival, sulforhodamine B cytotoxicity, apoptosis, and cell cycle analysis) were used to assess the cytotoxic effect of perifosine in combination with radiation. In vivo, the response of human KB squamous cell carcinoma xenografts was measured after treatment with perifosine, irradiation, and the combination. Radiolabeled perifosine was used to determine drug disposition in tumor and normal tissues. At various intervals after treatment, tumor specimens were collected to document histopathologic changes.
Results: In vitro, perifosine reduced clonogenic survival, enhanced apoptosis, and increased cell cycle arrest after radiation. In vivo, radiation and perifosine alone induced a dose-dependent tumor growth delay. When combining multiple perifosine administrations with single or split doses of radiation, complete and sustained tumor regression was observed. Histopathologic analysis of tumor specimens revealed a prominent apoptotic response after combined treatment with radiation and perifosine. Radiation-enhanced tumor response was observed at clinically relevant plasma perifosine concentrations and accumulating drug disposition of &gt;100 μg/g in tumor tissue.
Conclusions: Perifosine enhances radiation-induced cytotoxicity, as evidenced by reduced clonogenic survival and increased apoptosis induction in vitro and by complete tumor regression in vivo. These data provide strong support for further development of this combination in clinical studies.
An Evaluation of Tumor Oxygenation and Gene Expression in Patients with Early Stage Non–Small Cell Lung Cancers
Authors: Le Quynh-Thu , Chen Eunice , Salim Ali , Cao Hongbin , Kong Christina S. , Whyte Richard , Donington Jessica , Cannon Walter , Wakelee Heather , Tibshirani Robert , Mitchell John D. , Richardson Donna , O'Byrne Ken J. , Koong Albert C. , Giaccia Amato J. 
Published: March 2006

Abstract
Background: To directly assess tumor oxygenation in resectable non–small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes.
Methods: Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes.
Results: The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001).
Conclusions: Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors.
The cyclooxygenase-2 (PTGS2) 8473T&gt;C polymorphism is associated with breast cancer risk.
Authors: Langsenlehner Uwe , Yazdani-Biuki Babak , Eder Tanja , Renner Wilfried , Wascher Thomas C , Paulweber Bernhard , Weitzer Werner , Samonigg Hellmut , Krippl Peter 
Published: March 2006

Abstract
Cyclooxygenase-2 (COX-2) is involved in carcinogenesis, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. The gene for COX-2, designated as PTGS2, carries a common polymorphism at position 8473 in the 3'-untranslated region (PTGS2 8473T&gt;C), which has been associated with susceptibility to malignant disease. To investigate the role of this polymorphism for breast cancer, we determined the prevalence of PTGS2 genotypes in 500 women with breast cancer and 500 sex- and age-matched healthy control subjects. Homozygous carriers of the 8473-CC genotype were more frequent among patients (12.4%) than among controls (6.6%; P = 0.002). The odds ratio for carriers of this genotype for breast cancer was 2.1 (95% confidence interval, 1.3-3.3). Among patients, estrogen receptor positivity was less frequent among carriers of a CC genotype (63.9%) than among carriers of a TT or TC genotype (76.9%; P = 0.028). Tumor size, histologic grade, presence of primary lymph node metastases, progesterone receptor positivity, or age at diagnosis were not associated with PTGS2 genotypes. We conclude that the homozygous PTGS2 8473-CC genotype may be associated with breast cancer risk.
Variant diphtheria toxin-interleukin-3 fusion proteins with increased receptor affinity have enhanced cytotoxicity against acute myeloid leukemia progenitors.
Authors: Hogge Donna E , Yalcintepe Leman , Wong Siaw-Hui , Gerhard Brigitte , Frankel Arthur E 
Published: March 2006

Abstract
A fusion protein linking a truncated form of diphtheria toxin (DT(388)) to human interleukin-3 (DT(388)IL3) kills malignant progenitors from some patients with acute myeloid leukemia (AML) while sparing normal progenitors. This study evaluated two variants of DT(388)IL3 with increased affinity for the IL-3 receptor (IL-3R) for their cytotoxicity to AML progenitors and determined the ability of quantitative reverse transcription-PCR assessment of expression of the IL-3R subunits to predict the effectiveness of wild-type DT(388)IL3 and its variants. Both the IL-3 deletion variant (Delta125-133) and the amino acid substitution variant (K116W) showed enhanced toxicity against AML colony-forming cells (AML-CFC; but not normal CFC) compared with wild-type DT(388)IL3 with the K116W variant achieving &gt;90% AML-CFC kill with 17 of 23 patient samples. This variant was also more effective against AML cells engrafting in nonobese diabetic severe combined immunodeficient mice. There was a significant correlation between the expression of the alpha and, particularly, the common beta subunit of the IL-3R on AML blasts detected by quantitative reverse transcription-PCR and AML-CFC kill. Thus, the combined use of IL-3R expression to select patients most likely to respond to DT(388)IL3 and the improved cytotoxicity of the K116W DT(388)IL3 variant against leukemic progenitors may enhance the clinical usefulness of these fusion proteins.
PDLIM4 repression by hypermethylation as a potential biomarker for prostate cancer.
Authors: Vanaja Donkena Krishna , Ballman Karla V , Morlan Bruce W , Cheville John C , Neumann Roxann M , Lieber Michael M , Tindall Donald J , Young Charles Y F 
Published: March 2006

Abstract
PURPOSE: We analyzed the expression of genes to identify reliable molecular markers in the diagnosis and progression of prostate cancer. EXPERIMENTAL DESIGN: Gene expression profiling was done using HG-U133 set microarrays in 32 prostate cancer and 8 benign tissues of patients with cancer. Expression levels of 11 genes were selected for quantitative real-time PCR evaluation in 52 prostate cancer and 20 benign tissues. Further, to assess transcriptional inactivation, we analyzed the promoter methylation of genes by quantitative methylation-specific PCR in 62 tumor and 36 benign tissues. RESULTS: Our results showed a significant down-regulation in the mRNA expression levels of PRIMA1, TU3A, PDLIM4, FLJ14084, SVIL, SORBS1, C21orf63, and KIAA1210 and up-regulation of FABP5, SOX4, and MLP in prostate cancer tissues by TaqMan real-time PCR. Quantitative methylation-specific PCR of PDLIM4, SVIL, PRIMA1, GSTP1, and PTGS2 detected prostate carcinoma with a sensitivity of 94.7%, 75.4%, 47.4%, 89.5%, and 87.7%, and a specificity of 90.5%, 75%, 54.2%, 95.8%, and 90.2%, respectively. Using this panel of methylation markers in combination, we were able to distinguish between prostate cancer and adjacent benign tissues with sensitivities and specificities of about 90% to 100%. Our data provide evidence of transcriptional repression of the putative tumor suppressor gene PDLIM4 by hypermethylation. CONCLUSIONS: Our analysis revealed differential expression of eight down-regulated and three up-regulated genes, implicating their role in prostate cancer development and progression. We further showed that the hypermethylation of PDLIM4 gene could be used as a sensitive molecular tool in detection of prostate tumorigenesis.
Phase I Trial of Intrathecal Spartaject Busulfan in Children with Neoplastic Meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004)
Authors: Gururangan Sridharan , Petros William P. , Poussaint Tina Young , Hancock Michael L. , Phillips Peter C. , Friedman Henry S. , Bomgaars Lisa , Blaney Susan M. , Kun Larry E. , Boyett James M. 
Published: March 2006

Abstract
Purpose: A phase I trial of intrathecal Spartaject Busulfan (SuperGen, Inc., San Ramon, CA) was conducted in children with neoplastic meningitis following recurrent primary brain tumors to describe toxicities, estimate the maximum tolerated dose (MTD), and document evidence of responses to this agent.
Experimental Design: The continuous reassessment method was used to assign cohorts of patients to doses of intrathecal Spartaject Busulfan via an Ommaya reservoir and/or lumbar puncture twice weekly for 2 weeks followed by an assessment of toxicity and response. Patients with stable disease or an objective response continued to receive intrathecal Spartaject Busulfan plus systemic chemotherapy at regular intervals. Cerebrospinal fluid and blood were obtained for pharmacokinetic studies in patients with Ommaya reservoirs after the first dose of intrathecal Spartaject Busulfan. Seven evaluable patients were assigned to the starting dose of 5 mg, two patients to 7.5 mg, three patients to 10 mg, seven patients to 13 mg, and four patients to 17 mg.
Results: Between September 2000 and May 2003, 28 patients were enrolled in this study. Twenty-three patients (median age, 8.8 years; range, 2.5-19.5 years) were evaluable for estimating the MTD, and dose-limiting toxicities were observed in three and included grade 3 vomiting (n = 1 at 5 mg), grade 3 headache (n = 1 at 17 mg), and grade 3 arachnoiditis (n = 1 at 17 mg). Pharmacokinetic data showed that post-infusion concentrations of busulfan ranged from 50 to 150 μg/mL and declined to &lt;1 μg/mL within 5 hours.
Conclusions: Intrathecal Spartaject Busulfan was well tolerated in children with neoplastic meningitis from brain tumors, and the recommended dose for future phase II studies is 13 mg.
Recombinant Human Mullerian Inhibiting Substance Inhibits Long-term Growth of MIS Type II Receptor–Directed Transgenic Mouse Ovarian Cancers In vivo
Authors: Pieretti-Vanmarcke Rafael , Donahoe Patricia K. , Szotek Paul , Manganaro Thomas , Lorenzen Mary K. , Lorenzen James , Connolly Denise C. , Halpern Elkan F. , MacLaughlin David T. 
Published: March 2006

Abstract
Purpose: Mullerian inhibiting substance (MIS) is a glycoprotein hormone that causes Mullerian duct regression in male embryos. In short-term experiments, recombinant human MIS (rhMIS) inhibits xenotransplanted human ovarian cancer cell lines that are thought to be of Mullerian origin. Because this highly lethal cancer has a high recurrence rate after conventional chemotherapy, new treatments are warranted. We examined whether rhMIS as a novel, nontoxic, naturally occurring growth inhibitor can be an effective anticancer drug in long-term studies in vivo against allograft tumors that recapitulate human ovarian carcinoma.
Experimental Design: Mouse ovarian carcinoma (MOVCAR) cell lines expressing the early region of the SV40 virus, including the large and small T-antigen genes under transcriptional control of a portion of the murine MIS receptor type II (MISRII) gene promoter, were derived from TgMISIIR-TAg transgenic mice. rhMIS was tested against MOVCAR cells in growth inhibition assays in vitro, and in vivo in 6-week-old female nude mice. Tumor growth in animals was measured at weekly intervals for up to 20 weeks.
Results: MOVCAR cells and tumors express MISRII by Western blot, immunohistochemical, and Northern blot analyses. rhMIS significantly inhibited MOVCAR cell growth in vitro and in vivo in three separate long-term allotransplantation experiments.
Conclusions: Because rhMIS is an effective anticancer agent in in vitro and in long-term in vivo preclinical experiments against MISRII-positive tumors, we predict that rhMIS can be used safely and effectively to treat human ovarian malignancies.
Novel Mechanisms of Resistance to Endocrine Therapy: Genomic and Nongenomic Considerations
Authors: Gururaj Anupama E. , Rayala Suresh K. , Vadlamudi Ratna K. , Kumar Rakesh 
Published: March 2006

AbstractSelective estrogen receptor (ER) modulators have been the most commonly used neoadjuvant therapy for hormone-dependent breast cancer. However, resistance to endocrine therapy, either inherent or acquired during treatment, presents a major challenge in disease management. The causes of resistance to hormone therapy are not well understood and are the subject of active investigation. It is increasingly clear that decreasing sensitivity of ER-positive breast cancer cells to antiestrogens is caused by several factors. Cross talk between ER and growth factor signaling has emerged as a critical factor in endocrine resistance. Here, we present evidence that receptor tyrosine kinase signaling also plays a role in resistance by controlling the subcellular localization of ER signaling components. Localization of ER in either the nuclear or cytoplasmic compartments has functional implications. Recent work suggests that dynein light chain 1, a recently identified substrate of p21-activated kinase 1, modulates ER transactivation functions through a novel ER coactivator function. Likewise, receptor tyrosine kinase signaling can also alter the expression of ER coregulators such as metastasis-associated antigen 1, leading to hormonal independence. Furthermore, proline-, glutamic acid-, leucine-rich protein 1, an ER coactivator involved in both genomic and nongenomic signaling pathways, is activated by epidermal growth factor receptor and plays a prominent role in resistance to tamoxifen. These recent advances suggest new targeted therapeutic approaches that may lead to either reversion or prevention of endocrine resistance in breast tumors.
Proliferation and Apoptosis as Markers of Benefit in Neoadjuvant Endocrine Therapy of Breast Cancer
Authors: Dowsett Mitch , Smith Ian E. , Ebbs Steve R. , Dixon J. Michael , Skene Anthony , Griffith Clive , Boeddinghaus Irene , Salter Janine , Detre Simone , Hills Margaret , Ashley Susan , Francis Stephen , Walsh Geraldine , A'Hern Roger 
Published: March 2006

AbstractThe study of changes in proliferation as a marker of treatment benefit during presurgical endocrine treatment of breast cancer has become increasingly popular, particularly using the nuclear marker Ki67, and holds the potential for prioritizing new treatments for full clinical development. There are weakly significant relationships between Ki67 change and clinical response that differ according to data handling. In the neoadjuvant Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen trial, suppression of Ki67 at both 2 and 12 weeks was greater with the aromatase inhibitor anastrozole than with either tamoxifen or the combination of anastrozole and tamoxifen. We report here that absolute values of Ki67 after 2 weeks were also significantly lower with anastrozole than with tamoxifen and the combination. This indicates that it may be possible to make such comparisons using surgical samples only. We argue that these changes in proliferation and concurrent changes in apoptosis may be expected to be more predictive of adjuvant benefit from endocrine therapy than clinical response.
Progesterone Receptor Loss Correlates with Human Epidermal Growth Factor Receptor 2 Overexpression in Estrogen Receptor–Positive Breast Cancer
Authors: Kim Hyun-Jung , Cui Xiaojiang , Hilsenbeck Susan G. , Lee Adrian V. 
Published: March 2006

Abstract
Response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. It was originally hypothesized that the ability of PR to predict response to endocrine therapy was due to the fact that PR is an estrogen-regulated gene and that its levels represented a marker of functional ER activity. However, it is now known that loss of PR can occur via multiple mechanisms, many of which do not include ER function, e.g., hypermethylation of the PR promoter and loss of heterozygosity of the PR gene. We have shown that growth factor signaling pathways can directly down-regulate PR levels via the phosphatidylinositol 3′-kinase (PI3K)/Akt/mTOR pathway, and that this can occur independent of ER. For example, overexpression of myr-Akt in MCF-7 cells causes complete loss of PR protein and mRNA but does not reduce ER levels or activity, thus generating ER+/PR− MCF-7 cells. Therefore, the absence of PR may not simply reflect a lack of ER activity but rather may reflect hyperactive cross-talk between ER and growth factor signaling pathways. Consistent with this hypothesis, several recent clinical studies have found that ER+/PR− breast cancers overexpress human epidermal growth factor receptor (HER) 1 and HER2 compared with ER+/PR+ breast cancers. Although HER receptors can lower ER levels, one study showed that loss of PR correlated with high HER2 levels in a multivariate analysis. Furthermore, loss of PTEN, a negative regulator of the PI3K/Akt signaling pathway, has been shown to be associated with specific loss of PR and no change in ER levels. Given the well-recognized resistance of ER+/PR− breast cancer to antiestrogens, more studies are needed to better understand the etiology of ER+/PR− breast cancer, particularly the analysis of other growth factor receptors and their downstream signaling intermediates with respect to PR status.
Irinotecan Inactivation Is Modulated by Epigenetic Silencing ofUGT1A1in Colon Cancer
Authors: Gagnon Jean-François , Bernard Olivier , Villeneuve Lyne , Têtu Bernard , Guillemette Chantal 
Published: March 2006

AbstractPurpose: Irinotecan is used in the first-line treatment of metastatic colorectal cancer. The UGT1A1-metabolizing enzyme, expressed in liver and colon, is primarily involved in the inactivation of its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Herein, we explored the role of DNA methylation in the silencing of UGT1A1 gene expression in colon cancer and its influence on cellular SN-38 detoxification.Experimental Design and Results: UGT1A1 mRNA was repressed in most primary tumors (41 of 50; 82%) and in three colon cancer cell lines (HCT-116, HCT-15, and COLO-320DM). Bisulfite sequencing of the UGT1A1 gene revealed the aberrant methylation of specific CpG islands in UGT1A1-negative cells. Conversely, hypomethylation was observed in HT-29, HT-115, and LOVO cells that overexpress UGT1A1. Direct methylation of the UGT1A1 promoter resulted in the complete repression of transcriptional activity. Treatment with demethylating and histone deacetylase inhibitor agents had the capacity to reverse aberrant hypermethylation and to restore UGT1A1 expression in hypermethylated UGT1A1-negative cells but not in hypomethylated cells. Loss of UGT1A1 methylation was further associated with an increase in UGT1A1 protein content and with an enhanced inactivation of SN-38 by 300% in HCT-116 cells.Conclusions: We conclude that DNA methylation represses UGT1A1 expression in colon cancer and that this process may contribute to the level of tumoral inactivation of the anticancer agent SN-38 and potentially influence clinical response.
Intraperitoneal Immunotherapy for Metastatic Ovarian Carcinoma: Resistance of Intratumoral Collagen to Antibody Penetration
Authors: Choi Jaehwa , Credit Kimberly , Henderson Karla , Deverkadra Ravi , He Zhi , Wiig Helge , Vanpelt Heather , Flessner Michael F. 
Published: March 2006

Abstract
Purpose: Convective transport of macromolecules from the peritoneal cavity into tumor is determined by its hydraulic permeability and the pressure gradient. Previous studies showed that establishing a pressure gradient into the tumor failed to result in significant penetration. This study addresses the hypothesis that the extracellular matrix is the major resistance to the penetration of an i.p. injected antibody.
Experimental Design: Human ovarian tumors (SKOV-3 and OVCAR-3) were established in the abdominal wall of athymic rats. After anesthesia, the tumor serosal surface was treated for 2 hours with Krebs solution (control), collagenase (37.5 unit/mL), or hyaluronidase (10 unit/mL) followed by 3 hours of convective delivery of radiolabeled IgG. Transport of antibody into the tumor was measured with quantitative autoradiography along with the tumor interstitial pressure, concentration of collagen and hyaluronic acid, and IgG volume of distribution.
Results: Antibody was excluded from 42% to 53% of tumor extracellular volume. Exposure of tumors to hyaluronidase did not enhance IgG transport despite removal of 90% of the hyaluronan from the exposed tumor. In contrast, collagenase reduced collagen content, lowered tumor interstitial pressure, and markedly enhanced antibody penetration.
Conclusions: Reduction of collagen, but not hyaluronan, in the matrix of ovarian xenografts enhanced the transport of i.p. injected antibody. Although high interstitial pressure is a deterrent to convective transport of macromolecules into the tumor parenchyma, the structure of the interstitial matrix provides an inherent resistance, which must be overcome before effective delivery of an antibody.