Current status in chemotherapy for advanced pancreatic adenocarcinoma.
ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal types of cancer in the United States. Surgical resection remains the only curative treatment, but fewer than 20% of patients qualify as candidates. The past two decades saw major changes in the treatment of advanced PDA, a shift of standard protocol from 5-fluorouracil to gemcitabine and gemcitabine-based combinations, the introduction of molecular target therapy and multi-agent regimens. However, even with advancements in medicine, PDA is still extremely resistant to currently available regimens, which results in poor prognosis, with only 5.2% of patients alive at three years. This provides a challenge to scientists as they seek to find the best active regimen with the least side-effects. In this article, we review the current recommended guidelines from the National Comprehensive Cancer Network. In addition, we highlight major clinical trials since 2011.
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ABSTRACT: There is an increasing interest in targeting the MDM2 oncogene for cancer therapy. SP-141, a novel designed small molecule MDM2 inhibitor, exerts excellent in vitro and in vivo anticancer activity. To facilitate the preclinical development of this candidate anticancer agent, we have developed an HPLC method for the quantitative analysis of SP-141. The method was validated to be precise, accurate, and specific, with a linear range of 16.2–32,400 ng/mL in plasma, 16.2–6480 ng/mL in homogenates of brain, heart, liver, kidneys, lungs, muscle and tumor, and 32.4–6480 ng/mL in spleen homogenates. The lower limit of quantification was 16.2 ng/mL in plasma and all the tissue homogenates, except for spleen homogenates, where it was 32.4 ng/mL. The intra- and inter-assay precisions (coefficient of variation) were between 0.86 and 13.39%, and accuracies (relative errors) ranged from −8.50 to 13.92%. The relative recoveries were 85.6–113.38%. SP-141 was stable in mouse plasma, modestly plasma bound and metabolized by S9 microsomal enzymes. We performed an initial pharmacokinetic study in tumor-bearing nude mice, demonstrating that SP-141 has a short half-life in plasma and wide tissue distribution. In summary, this HPLC method can be used in future preclinical and clinical investigations of SP-141. Copyright © 2014 John Wiley & Sons, Ltd.Biomedical Chromatography 10/2014; 29(5). DOI:10.1002/bmc.3327
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ABSTRACT: The membrane mucin MUC4 is aberrantly expressed in multiple cancers and is of clinical significance to diagnosis and prognosis in pancreatic cancer. However, the role of MUC4 in angiogenesis and the potential association among these malignant capabilities have not been explored. In this study, we investigated the collective signaling mechanisms associated with MUC4-induced growth, metastasis and angiogenesis in pancreatic cancer. Knockdown of MUC4 in two pancreatic cancer cell lines led to downregulation of lysosomal degradation of E-cadherin by Src kinase through downregulation of pFAK and pSrc pathway. The downregulation of lysosomal degradation of E-cadherin in turn induced the formation of E-cadherin/β-catenin complex and membrane translocation of β-catenin, resulting in the downregulation of Wnt/β-catenin signaling pathway. Thus, the Wnt/β-catenin target genes c-Myc, Cyclin D1, CD44 and VEGF were down-regulated and their malignant functions proliferation, metastasis and angiogenesis were reduced. Taken together, MUC4-induced nuclear translocation of β-catenin is a novel mechanism for growth, metastasis and angiogenesis of pancreatic cancer.Cancer letters 12/2013; 346(1). DOI:10.1016/j.canlet.2013.12.021
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ABSTRACT: Results of an observational study on docetaxel-based therapy in non-small cell lung cancer (NSCLC) with focus on symptom control and therapy response, are reported. A total of 233 patients with NSCLC treated with docetaxel-containing therapy were analyzed. The pre-existing symptoms of cough, dyspnea and pain markedly improved after three cycles of docetaxel-based therapy. Regression of symptoms was strongly associated with therapy response, but unexpectedly, patients with stable disease had also a substantial benefit. Alltogether, the response after three cycles was complete in 0.9% and partial in 26.6% of patients, respectively. Symptom control was achieved in the majority of cases, which received three cycles of docetaxel-based therapy. Thus, a clinical benefit was regularly reached shortly after initiation of chemotherapy.Anticancer research 09/2013; 33(9):3831-6.