tbuckley/cabot-search huggingface dataset:
Zoledronic acid enhances docetaxel-induced apoptosis through pMEK and MCL-1 inhibition in hormone sensitive prostate carcinoma cell lines
Authors: Francesco Fabbri, Dino Amadori, Silvia Carloni, Giovanni Brigliadori, Anna Tesei, Paola Ulivi, Ivan Vannini, Chiara Arienti, Wainer Zoli, Rosella Silvestrini
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2812 

Aims. To identify the most active combination treatment schedule with zoledronic acid and docetaxel in hormone sensitive prostate cancer (HSPC) cell lines and to investigate underlying molecular mechanisms.    Methods. The study was performed on a HSPC cell line grown in normal (LNCaP) or in hormone-deprived charcoal stripped (LNCaP c.s.) medium. Cell viability was determined using the sulforhodamine-B assay. Apoptosis was assessed by Annexin-V and TUNEL assays using flow cytometry. Expression levels of the active form of caspase-3, pMEK and MCL-1 were detected by western blotting.    Results. The simultaneous exposure of zoledronic acid [100 μM] and docetaxel [0.01 μM] for 1 h followed by exposure to zoledronic acid ranging from 72 to 120 h produced a high synergistic interaction (R index = 5.1) with a strong decrease in cell viability. This cytotoxic effect was associated with a high induction of apoptosis , which involved up to 70% of cells after the longest treatment times in both LNCaP and LNCaP c.s. cells. The induction of apoptosis was paralleled by a decrease in pMEK and MCL-1 expression.    Conclusions . Short-term exposure (1 h) to zoledronic acid and to very low docetaxel concentrations before long-term (72-120 h) bisphosphonate treatment produced a highly significant synergistic effect on LNCaP cell line grown in either normal or in hormone-deprived medium. Apoptosis induction and decreased pMEK and MCL-1 expression were the principal molecular mechanisms observed with this treatment. This experimentally derived schedule could therefore represent an interesting alternative to the standard hormone deprivation therapy used in the management of hormone sensitive prostate carcinoma with the advantage of preventing the selection and growth of hormone resistant cell clones.
A randomized, pharmacologic intervention study evaluating the effect of the angiotensin II-receptor blocker candesartan versus placebo to prevent trastuzumab-associated cardiotoxicity in women with early breast cancer.
Authors: R. Altena, A. H. Boekhout
Journal: Journal of Clinical Oncology (2010)

TPS108 Background: Trastuzumab-associated cardiotoxicity leads to morbidity and a potentially less optimal treatment in a part of patients (pts) adjuvantly treated for HER2+ breast cancer (BC). Interventions that reduce the chance to develop this toxicity are needed. Drugs interfering with the renin-angiotensin-aldosterone system, e.g. angiotensin II-receptor blockers (ARB), are used to treat various types of cardiac dysfunction. The aim of this study is to investigate whether ARB treatment can ameliorate or prevent trastuzumab-associated cardiotoxicity during adjuvant treatment for HER2+ BC, thereby reducing treatment-related morbidity in pts with early BC. Methods: In this multicenter, double blind study (EUDRACT 2006-001707-11), women with early HER2+ BC are randomized between treatment with ARB (candesartan 32 mg once daily) or placebo. Inclusion-criteria: age ≥ 18 yrs, adjuvant regimen with anthracycline followed by trastuzumab, Left Ventricular Ejection Fraction (LVEF) ≥ 50% prior to treatment, adequate blood pressure [(BP) systolic ≥ 100/ ≤ 180 mmHg, diastolic ≥ 60/ ≤ 100 mmHg], normal organ function. Exclusion criteria: previous anthracycline-treatment, pre-existent heart failure or myocardial infarction < 6 months prior to randomization. Study medication (ARB/placebo) starts the same day as the first trastuzumab infusion, continuing up to 26 wks after completion of 1 year trastuzumab treatment. 3-monthly assessments include physical examination, BP, LVEF and blood sampling (Natriuretic Peptides, troponins), and continue up to 3 months after completion of study medication. Primary endpoint: occurrence of a cardiac event during treatment and up to 40 wks after cessation of trastuzumab. Cardiac event is defined as decline in LVEF of > 15% or decrease to a value < 45%. In total 200 randomized pts are needed (80% power, α 0.05) to detect a significant reduction in cardiotoxicity rate from 0.30 to 0.13 (odds ratio 0.35). Currently 124 pts are registered. From a recent planned safety analysis after 10 cardiac events the IDMC found no reason for discontinuation of accrual. No significant financial relationships to disclose.
Randomized phase II study of R-CHOP plus enzastaurin versus R-CHOP in the first-line treatment of patients with intermediate- and high-risk diffuse large B-cell lymphoma (DLBCL): Preliminary analysis.
Authors: J. D. Hainsworth, E. Arrowsmith, M. McCleod, L. Fayad, O. Hamid, L. Davis, B. K. Lin
Journal: Journal of Clinical Oncology (2011)

8016
Abstract #4602: Resveratrol attenuates the anticancer efficacy of paclitaxel in MDA-MB-435s human breast cancer cells in vitro and in vivo
Authors: Masayuki Fukui, Noriko Yamabe, Bao Ting Zhu
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Background: Recent studies reported that resveratrol can induce apoptosis in cancer cells and also sensitize them to anticancer drugs. Paclitaxel is an effective chemotherapeutic agent for various cancers by disrupting the formation of normal spindles at metaphase and resulting in G2/M cell cycle arrest and apoptosis. In addition, combination of paclitaxel with resveratrol was shown to have a synergistic apoptotic activity in some cancer cell lines in vitro . In the present study, we studied the modulating effect of resveratrol on paclitaxel-induced cell death in the estrogen receptor-negative MDA-MB-435s human breast cancer cells in vitro and also in vivo . Methods: Cell viability and cell cycle were analyzed. The levels of MAPKs and apoptosis-related proteins were also determined by Western blotting. To evaluate the effect in vivo , experiments using cancer cell xenografts were performed in female athymic BALB/c nu/nu mice, and the animals were treated with paclitaxel (10 mg/kg, i.p., once a week), resveratrol (16.5 mg/kg, i.p., three times a week), or combination of both for 4 weeks. Results: Resveratrol diminished the susceptibility of MDA-MB-435s human breast cancer cells to paclitaxel-induced cell death in vitro in a concentration-dependent manner. Cell cycle analysis revealed that while paclitaxel alone predominantly induced G2/M cell cycle arrest and resveratrol alone induced S-phase arrest, combination of paclitaxel and resveratrol mainly induced S-phase arrest. Mechanistically, the observed suppression of paclitaxel-induced cell death by resveratrol was largely not attributable to its antioxidant activity. Paclitaxel inactivated anti-apoptotic Bcl-2 family protein Bcl-xL, but combination of paclitaxel and resveratrol failed to inactivate Bcl-xL. In vivo experiments using athymic nude mice showed that after 2 or 4 weeks of treatment with paclitaxel alone, the tumor growth was significantly suppressed by 64.8-72.4% compared to the control. However, combination of resveratrol with paclitaxel strongly diminished the anticancer activity of paclitaxel (based on tumor volume). TUNEL analysis of the tumor tissue collected at the end of the experiments showed that animals receiving combination treatment had significantly fewer TUNEL-positive cells compared with animals treated with paclitaxel alone. Conclusion: The results of the present study showed that co-administration of resveratrol with paclitaxel significantly diminished the anticancer efficacy of paclitaxel in athymic nude mice grafted with MDA-MB-435s cells, suggesting that the strategy of combined use of resveratrol with paclitaxel may not be suitable for certain types of cancer. (Grant support - NIH CA92391 and CA97019).

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4602.
Complete rescue from established emesis by the NK-1 receptor antagonist, casopitant mesylate, in cisplatin-induced delayed emesis in the ferret
Authors: A. G. King
Journal: Journal of Clinical Oncology (2006)

18601 Background: Postoperative and chemotherapy-induced nausea and vomiting (PONV, CINV) can be major complications in patients undergoing surgery or cancer treatment with emetogenic drugs. Nausea and vomiting may extend beyond the postoperative recovery period or in a delayed manner following chemotherapy. Prophylaxis with 5-HT 3 receptor antagonists may fail in some patients, requiring the use of rescue medications. Selective NK-1 receptor antagonists provide incremental improvement in efficacy when used in combination with 5-HT 3 antagonists and dexamethasone, both in preclinical animal models and in the clinical setting. Methods: The anti-emetic and anti-nausea properties of a potent and selective NK-1 receptor antagonist, casopitant mesylate ( GW679769 ), were evaluated in the ferret using single-dose rescue treatment in a cisplatin-based delayed emesis model. In the delayed model (72 hr), a single dose of saline, ondansetron, or casopitant mesylate was administered ip at 44.8 hrs post cisplatin (5 mg/kg, ip). This time corresponds to peak emetic frequency in this model. Results: Ondansetron (1 mg/kg) significantly delayed further emetic events for ∼8 hours post injection. Emetic frequency after this latency period then paralleled the saline treated group. In contrast, casopitant mesylate resulted in an immediate dose-dependent rescue from further emetic events, with minor effects on latency. Complete rescue from further emetic events were achieved at casopitant mesylate doses ≥0.5 mg/kg. Casopitant mesylate rescue treatment also reduced nausea-like behaviors in a dose-dependent manner; however, higher doses were required to achieve statistical significance. Conclusions: Single-dose ondansetron rescue treatment failed to reduce nausea-like behaviors. These unique results, along with previously described anti-emetic prophylactic activity, support the ongoing clinical evaluation of casopitant mesylate, which is currently in phase III trials for the prevention of PONV and CINV from moderately and highly emetogenic chemotherapy. It is also in clinical development for depression and anxiety. [Table: see text]
Phase I study of vorinostat for patients with advanced solid tumors and hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI #8057).
Authors: M. J. Egorin, S. Kummar, J. Sarantopoulos, S. Shibata, P. LoRusso, M. Yerk, Y. Lin, S. P. Ivy, C. P. Belani, S. S. Ramalingam
Journal: Journal of Clinical Oncology (2010)

2545
Impact of the number of cycles on efficacy of denileukin diftitox (Dd) in subjects with cutaneous T-cell lymphoma (CTCL)
Authors: L. Geskin, Y. Sun, J. Gao
Journal: Journal of Clinical Oncology (2009)

e19549 Background: Dd, a recombinant fusion protein designed to target interleukin-2 receptor-expressing malignancies, is the most extensively studied agent in patients with CTCL. Dd is approved for 8 cycles in CTCL. Here, we present data from study L4389–11 on the effect of treatment course on the efficacy of Dd. Methods: Subjects received Dd doses of 9 or 18 mcg/kg IV daily for 5 days, repeating every 21 days for up to 8 courses. The majority of subjects had CTCL stage ≤ IIa at baseline. Thirty three percent of subjects had received 2 prior anticancer therapies and 23% had received 3 prior anticancer therapies. For all subjects (n=144), the overall median age was 59 years. Tumor burden in skin, blood and lymph nodes and a physician's global assessment were determined at each study visit relative to baseline. Response confirmation was adjudicated by an independent Data Endpoint Review Committee (DERC) after 3 consecutive courses. The primary endpoint was ORR including CR (no clinical evidence of disease based on tumor burden assessments and photography and histopathology of skin biopsy indicated absence of atypical cells), CCR (no clinical evidence of disease based on tumor burden assessments and photography and either the presence of atypical cells was indicated by histopathology of a skin biopsy or histopathology was unavailable) and PR (≥ 50% reduction in measured tumor burden). Data reflect the first treatment course in which the best response was recorded for Dd-treated subjects who responded (n=44) based on the DERC assessment. All responses counted were confirmed in 2 successive assessments. Results: 45% of best responses occurred in cycles 4 thru 8 and the evolution to CR occurred from 4 cycles and beyond. Conclusions: These data support the approved 8 cycles of Dd therapy in CTCL. [Table: see text]
Abstract 1198: The Relation Between Age and Serum Markers of Collagen Turnover in Healthy Elderly Individuals; The Cardiovascular Health Study
Authors: Eddy Barasch, John S Gottdiener, Jing Han, Gerard P Aurigemma, Dalane W Kitzman, Russell Tracy
Journal: Circulation (2008)

Background: Significant changes in the cardiac anatomy, morphology and function occur with aging. Increased collagen deposition in the myocardial matrix has been associated with prevalent heart failure (HF) in the elderly. The relation between age with serum level of procollagen type III aminoterminal peptide-PIIINP-, carboxyl-terminal propeptide type I -PIP-, reflecting collagen synthesis, and carboxyl-terminal telopeptide of collagen type I -CITP-marker of collagen type I degradation, is largely unknown in healthy free-living elderly individuals. Aim: To determine the relation between age with serum biomarkers of fibrosis (SBF) in a large group of community-dwelling elderly individuals. Methods: In 880 participants (ppts), mean age 77 ± 6 yrs, 52 % males, 79 % white, enrolled in the Cardiovascular Health Study, serum levels of PIIINP, PIP and CITP were measured; 179 had HF with normal LVEF (DHF), 131 had HF with LVEF &lt; 55% (SHF), 287 controls (no HF), and 283 healthy ppts. Kruskal-Wallis test, one-way ANOVA, chi-square test and Spearman correlation were performed as appropriate. Results: SFB values and the main demographic variables are displayed in the table . The association between age with the 3 SBF for the entire study population were: PIP: r = 0.13 (p &lt;0.0001), CITP: r = 0.13, p &lt; 0.0001, PIIINP: r = 0.04, p = 0.20. For the individuals groups, the associations were: PIP with DHF (r = 0.25, p=0.001), CITP with DHF (r = 0.15, p =0.05), controls (r= 0.27, p &lt; 0.0001) and healthy control groups (r = 0.19, p = 0.001). PIIINP was associated with age only in the control group (r = 0.12, p = 0.04). No association was found between age and SBF in the SHF group.
Correlation of RRM1 promoter region single nucleotide polymorphisms (SNPs) with response and outcome in breast cancer patients treated with gemcitabine-based chemotherapy
Authors: W. Yeo, R. C. Soong, B. Y. Chuah, S. Tan, S. Lim, M. T. Cordero, L. Wang, S. Ng, B. C. Goh, S. Lee
Journal: Journal of Clinical Oncology (2008)

14513 Background: RRM1 promoter region SNPs and tumoral gene expression correlate with survival in gemcitabine-treated lung cancers, while RRM1 coding region SNPs predict for toxicity in gemcitabine-treated breast cancers. Methods: We studied 4 coding and 2 promoter region SNPs in RRM1 (17G>A, 536A>C, 589T>G, 2333T>C, −524T>C, −37C>A) in germline DNA of metastatic breast cancer patients treated with 3-weekly carboplatin (AUC 5, D1) and gemcitabine (1g/m2 over 30 minutes, D1 and 8) in a phase 2 study. Intracellular and serum gemcitabine pharmacokinetics (PK) were performed with HPLC. Tumoral RRM1 expression was analyzed in a subset of patients with available tumor specimens using the Affymetrix HG-U133+2 gene array. Results: 41 patients were enrolled. All had prior anthracyclines and taxanes, median age was 52 years (range 33–67), 71% had hormone receptor positive disease, 88% had at least 1 prior line of palliative chemotherapy, and 93% had visceral metastases. Median number of gemcitabine/carboplatin cycles received was 4 (range 1–6). 38 patients were evaluable for response, with 1 CR, 16 PR, 11 SD, and 10 PD. At analysis, all patients have progressed and 37/41 had died. The 4 RRM1 coding region SNPs were non- polymorphic in our cohort, while the two promoter region SNPs, −524T>C and −37C>A, had allele frequencies of 0.39 each, and showed linkage (p<0.001). RRM1 −524 T allele was associated with better tumor response (CR/PR as best overall response, 49% vs 20%, TT/TC vs CC, p=0.032), longer PFS (4.63 vs 1.71 months, TT/TC vs CC, p=0.02) and longer OS (10.65 vs 5.75 months, TT/TC vs CC, p=0.009). RRM1 -37 C allele was associated with longer PFS (4.63 vs 1.68 months, CC/CA vs AA, p=0.035) and longer OS (10.45 vs 5.75 months, CC/CA vs AA, p=0.013). In 11 patients with tumoral gene expression data, the RRM1 -524 T allele was associated with lower tumoral RRM1 levels (759±203, 1091±568 and 1322 for TT, TC and CC respectively). There was no correlation between RRM1 genotype and gemcitabine PK or toxicity. Conclusions: RRM1 promoter region SNPs predict for response, PFS and OS in gemcitabine/carboplatin treated breast cancers. Prospective studies to validate these findings are warranted. No significant financial relationships to disclose.
Is computed tomography necessary for clinical T1 gastric cancer?
Authors: Hirohito Fujikawa, Takaki Yoshikawa, Junya Shirai, Kenichi Iwasaki, Shinichi Hasegawa, Tsutomu Hayashi, Toru Aoyama, Takashi Ogata, Haruhiko Cho, Takashi Oshima, Yasushi Rino, Munetaka Masuda, Akira Tsuburaya
Journal: Journal of Clinical Oncology (2013)

1 Background: Initial diagnosis of gastric cancer is based on upper gastrointestinal tract endoscopy (GF) and/or upper gastrointestinal series (UGI) which also determines invasion depth of T1 or Non-T1. Subsequently, TNM is evaluated by Multi Detector-row Computed Tomography (MDCT). TNM is indispensable to decide treatment of gastric cancer, however, T1 disease has low metastatic potential and is almost curable only by local treatment. It remained unclear whether MDCT is necessary for clinical T1 (cT1). Methods: Patients were selected from the prospective database of Kanagawa Cancer Center between Oct 2000 and Oct 2007 based on the following criteria; (1) histologically proven adenocarcinoma of the stomach, confirmed by endoscopic biopsy (2) patients were diagnosed with cT1 by GF/UGI, (3) patients received MDCT, (4) patients received no prior treatment before the examination, and (5) patients received endoscopic mucosal dissection (ESD) or radical surgery with D1 or more lymphadenectomy as a primary treatment. Efficacy of MDCT was evaluated by incidence of cM1 in all patients with cT1 disease and by accuracy to diagnose pathological N+ in patients who received surgery. Regional lymph nodes were considered to be involved by metastases if they were larger than 8 mm in the short-axis diameter. Results: A total of 761 patients were entered into this study. Of these, 236 patients received ESD while 525 underwent surgery. No cM1 disease was found in 761 patients. Among 525 patients who underwent surgery, 484 were pathologically diagnosed with T1 (pT1, 92.2%), 31 with pT2 (5.9%), 5 with pT3 (0.9%), and 5 with pT4 (0.9%). Clinical N+ was observed in 8 patients (1.5%), while pathological N+ in 45 (8.6%). The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value was 90.3%, 4.3%, 98.7%, 25%, and 91.3%, respectively. Conclusions: The present study suggested that MDCT was unnecessary for cT1 gastric cancer because cM1 was extremely rare and diagnosis of N+ was unreliable in cT1 disease.
Evidence That the RHDVI Deletion Genotype Does Not Exist
Authors: P.A. Maaskant-van Wijk, E.A.M. Beckers, D.J. van Rhenen, I. Mouro, Y. Colin, J.P. Cartron, B.H.W. Faas, C.E. van der Schoot, P.A. Apoil, A. Blancher, A.E.G. Kr. von dem Borne
Journal: Blood (1997)
Phase I trial of chemoradiation with capecitabine and vorinostat in pancreatic cancer.
Authors: Emily Chan, Lori R. Arlinghaus, Dana Backlund Cardin, Laura Williams Goff, Thomas E. Yankeelov, Jordan Berlin, Pamela McClanahan, Melanie Holloway, Alexander A. Parikh, Richard G. Abramson, Nipun B. Merchant, Scott Hiebert, Anuradha Bapsi Chakravarthy
Journal: Journal of Clinical Oncology (2013)

225 Background: Histone deacetylase inhibitors (HDACi) and fluoropyrimidines are synergistic and are radiation (R) sensitizers. The combination of the fluoropyrimidine capecitabine ( C) and the HDACi vorinostat (V) with R was evaluated in the treatment (tx) of non-metastatic pancreatic cancer (NMPC). Methods: Patients (Pts) with NMPC were treated with C + V + R. C dose was 1000 mg q12 Monday (M) - Friday (F) on the days of R. R was given via 3D conformal therapy to a total dose of 3000 cGy in 10 fractions over 2 weeks (wk). V dose was given daily M-F x 4 wk. V doses evaluated were: 100, 200, 300, and 400 mg. Resectability assessment occurred within 6 wk after completion of tx. Diffusion weighted- MRIs (DW-MRIs) were obtained pre tx and one wk after tx initiation to assess tumor cellularity. Peripheral blood mononuclear cells (PBMCs) were collected pre tx, during tx, and after completion to assess whole cell HDAC activity. Unresectable pts could opt for continuation of C and V (CCV) at systemic doses (C 1000 mg q12 x 14 days and V 300 mg QD x 14 days of every 21 day cycle) or come off study. Results: 18 pts were enrolled and evaluable. Disease statuses pre-tx were: resectable (n=1), borderline resectable (n=9), and unresectable (n=8). One DLT occurred at dose levels 1, 3, and 4, 2 GI toxicities and one thrombocytopenia. Most common adverse events were lymphopenia, GI toxicity, and fatigue. On MRI, the apparent diffusion coefficient (ADC) increased in most, but not all, tumors after one wk of tx but did not correlate to change in tumor size at completion. PBMC histone acetylation increased in some pts. Eight pts (Pre-tx status: 1 resectable and 7 borderline resectable) underwent exploration with 4 undergoing tumor resection. No unresectable pt converted to resectable. Four of ten potential pts opted for CCV after being deemed unresectable, 2 with stable disease for 6 cycles. Conclusions: C + V + R is feasible with no unexpected toxicity. HDAC inhibition and ADC decrease on DWI-MRI was seen. Accrual to the final cohort (V 400 mg) is ongoing. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Merck &amp; Co., Inc. Study was also supported by the Vanderbilt-Ingram Center Support Grant P30CA68485. Clinical trial information: NCT00983268.