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Chemotherapy Resistance (chemotherapy + resistance)
Selected AbstractsIntrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 1 2005Roisean E. Ferguson Abstract Renal cancer is one of the most chemoresistant tumor types. Using a panel of 10 established renal cancer cell lines that have not been subjected to prior drug selection, the range of functional resistance phenotypes to the tubulin-binding agents paclitaxel, vinblastine, vincristine and patupilone (epothilone B, EPO906) was determined, together with expression of P-glycoprotein (PgP), multidrug resistance associated protein-2 (MRP2) and major vault protein (MVP) proteins. The IC50 values for vincristine correlated positively with PgP expression (r = 0.73; p = 0.031), with values for paclitaxel and vinblastine just failing to reach significance. A significant positive correlation was observed for sensitivity to paclitaxel and MRP2 expression only (r = 0.8; p = 0.013). MVP expression did not correlate with sensitivity to any of the drugs examined. All cell lines exhibited much greater sensitivity to patupilone, demonstrating for the first time the potential use of patupilone in this cancer. In tissue samples from chemotherapy-naive renal cell carcinoma (RCC) patients, marked downregulation or absence of PgP in many tumor cells with expression levels more similar to sensitive cell lines rather than the resistant lines was seen. Similarly, MRP2 was absent or only weakly present in tumor cells, whereas MVP was very strongly upregulated in most tumor samples. This study illustrating discrepancies between results exclusively based on studies in cell lines and findings in vivo suggests that the role of PgP and MRP2 in intrinsic resistance in RCC in vivo may be less than expected from the in vitro findings and supports a potential role for MVP on the basis of in vivo expression studies. © 2004 Wiley-Liss, Inc. [source] Role of hypoxia in the hallmarks of human cancerJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2009Kai Ruan Abstract Hypoxia has been recognized as one of the fundamentally important features of solid tumors and plays a critical role in various cellular and physiologic events, including cell proliferation, survival, angiogenesis, immunosurveillance, metabolism, as well as tumor invasion and metastasis. These responses to hypoxia are at least partially orchestrated by activation of the hypoxia-inducible factors (HIFs). HIF-1 is a key regulator of the response of mammalian cells to oxygen deprivation and plays critical roles in the adaptation of tumor cells to a hypoxic microenvironment. Hypoxia and overexpression of HIF-1 have been associated with radiation therapy and chemotherapy resistance, an increased risk of invasion and metastasis, and a poor clinical prognosis of solid tumors. The discovery of HIF-1 signaling has led to a rapidly increasing understanding of the complex mechanisms involved in tumor hypoxia and has helped greatly in screening novel anticancer agents. In this review, we will first introduce the cellular responses to hypoxia and HIF-1 signaling pathway in hypoxia, and then summarize the multifaceted role of hypoxia in the hallmarks of human cancers. J. Cell. Biochem. 107: 1053,1062, 2009. © 2009 Wiley-Liss, Inc. [source] Role of mathematical modeling on the optimal control of HIV-1 pathogenesisAICHE JOURNAL, Issue 3 2006Marcel Joly Abstract Mathematical modeling of HIV-1 infection has proven to be instrumental for the modern understanding basis of the AIDS pathogenesis, since it offers the unique means to adequately pose hypotheses concerning AIDS dynamics and treatment protocols. Focusing on the HIV-1 subtype-B epidemic, a comprehensive review and discussion of the state-of-the-art in the area is presented. Based on recent results, this multidisciplinary study is then extended to a more in-depth view at the cellular and molecular biology levels that address key issues concerned with the natural history of AIDS, as the basic human anatomic model, the host cell entry of HIV-1, the quantification the HIV-1 infectivity in terms of viral coreceptor specificity, as well as regulation and expression of CCR5 and CXCR4 molecules on the target cell, the T-lymphocyte generation and infection models, and the immune response model. In the sequence, modeling techniques for AIDS pathogenesis are revised and models concerned with either the general HIV-1 dynamics or specifically related to the HIV-1 primary infection are discussed. Ultimately, a general framework for the real-world problem of optimizing the highly active antiretroviral therapy (HAART) benefits is proposed regarding the important questions associated with the drug chemotherapy resistance, side effects and costs. © 2005 American Institute of Chemical Engineers AIChE J, 2006 [source] Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: A children's oncology group study,,PEDIATRIC BLOOD & CANCER, Issue 4 2010MRCP, Rani E. George MD Abstract Background Demethylating agents may alter the expression of genes involved in chemotherapy resistance. We conducted a phase I trial to determine the toxicity and molecular effects of the demethylating agent, decitabine, followed by doxorubicin and cyclophosphamide in children with refractory solid tumors. Procedure Stratum A included children with any solid tumor; Stratum B included neuroblastoma patients only. Patients received a 1-hr decitabine infusion for 7 days, followed by doxorubicin (45,mg/m2) and cyclophosphamide (1,g/m2) on day 7. Pharmacokinetic studies were performed after the first dose of decitabine. Biological studies included methylation and gene expression analyses of caspase-8, MAGE-1 and fetal hemoglobin (HbF), and expression profiling of pre- and post-treatment peripheral blood and bone marrow cells. Results The maximum-tolerated dose of decitabine was 5,mg/m2/day for 7 days. Dose-limiting toxicities at 10,mg/m2/day were neutropenia and thrombocytopenia. Decitabine exhibited rapid clearance from plasma. Three of 9 patients in Stratum A and 4/12 patients in Stratum B had stable disease for ,4 months. Sustained MAGE-1 demethylation and increased HbF expression were observed in the majority of patients post-treatment (12/20 and 14/16, respectively). Caspase-8 promoter demethylation and gene expression were seen in 2/7 bone marrow samples. Differentially expressed genes were identified by microarray analysis. Conclusion Low-dose decitabine when combined with doxorubicin/cyclophosphamide has tolerable toxicity in children. However, doses of decitabine capable of producing clinically relevant biologic effects were not well tolerated with this combination. Alternative strategies of combining demethylating agents with non-cytotoxic, biologically targeted agents such as histone deactelyase inhibitors should be explored. Pediatr Blood Cancer. 2010;55:629,638. © 2010 Wiley-Liss, Inc. [source] High serum levels of B-lymphocyte stimulator are associated with clinical,pathological features and outcome in classical Hodgkin lymphomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2007C. Tecchio Summary B-lymphocyte stimulator (BLyS) acts as survival factor for B lymphocytes. As Hodgkin and Reed-Sternberg (HRS) cells express receptors through which BLyS promotes their growth and chemotherapy resistance, we investgated whether this molecule was increased in sera from patients with classical Hodgkin lymphoma (cHL) and whether it correlates with clinical-pathological features and outcomes. Enzyme-linked immunosorbent assay was used to measure soluble BLyS (sBLyS) in sera from 87 patients and 33 donors; higher levels were detected in patients (mean ± standard error 4493·9 ± 264·9 pg/ml vs. 2687·0 ± 200·9 pg/ml; P < 0·0001). Levels above the median value (4242·0 pg/ml) were associated with age ,45 years (P = 0·042), advanced stages of disease (P = 0·005), systemic symptoms (P = 0·014) and extranodal involvement (P = 0·009). Five-year failure-free survival (FFS) of patients with sBLyS below or equal to median levels was 88·6% as compared to 65·1% of those with levels above the median (P = 0·009). Statistical analyses confirmed the prognostic significance of sBLyS (P = 0·046). When patients were analysed according to variables associated with high levels, sBLyS showed an independent predictive power in terms of FFS. Our findings support the involvement of BLyS in cHL pathogenesis. The association between high serum levels and an inferior FFS indicates that sBLyS is a possible prognostic predictor with a potential significance as a therapeutic target. [source] Overexpression of synuclein-, in pancreatic adenocarcinomaCANCER, Issue 1 2004Zhongkui Li Ph.D. Abstract BACKGROUND Currently, pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Despite the advances in pancreatic carcinoma research, patients with this devastating disease have a very poor prognosis. To identify the gene expression profile of pancreatic carcinoma, an important step in the process of developing new diagnostic and therapeutic strategies, the authors investigated the alteration of gene expression in this disease. METHODS The authors analyzed a public serial analysis of gene expression (SAGE) database and examined in greater detail the expression of synuclein-, mRNA in several pancreatic carcinoma cell lines and tumor tissue samples by reverse transcriptase,polymerase chain reaction (RT-PCR) analysis and Northern blot analysis. The expression of synuclein-, protein was investigated further by immunohistochemical and Western blot analyses using tumor cell lines, tumor tissue, and serum samples. RESULTS Synuclein-, mRNA was overexpressed in 11 of 12 pancreatic carcinoma cell lines, including AsPc-1, MDAPanc28, Capan-1, Capan-2, PANC-1, HS766T, MDAPanc3, MDAPanc48, Colo357FG, MiaPaCa2, CFPac1, and BxPc3. The expression of synuclein-, protein was detectable in 8 of 12 pancreatic carcinoma cell lines (67%) and in 22 of 32 pancreatic tumor tissue samples (69%) by Western blot analysis. On immunohistochemical staining, synuclein-, protein was present in 61% of the tumor tissue samples examined from patients with Stage I and II pancreatic carcinoma. The overexpression of synuclein-, is correlated with perineural and lymph node invasion. Synuclein-, protein also was detectable by Western blot in serum samples from 21 of 56 patients (38%) with pancreatic carcinoma. CONCLUSIONS Synuclein-,, which initially was described as a breast carcinoma,specific gene involved in invasion, metastasis, and chemotherapy resistance, was frequently overexpressed in pancreatic carcinoma. Overexpression of synuclein-, may play a role in pancreatic carcinoma invasion. Further studies will be necessary to determine the role of synuclein-, in pancreatic carcinoma. Cancer 2004. © 2004 American Cancer Society. 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