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Author (up) Allen, S.L.; Lundberg, A.S. file  url
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  Title Amonafide: a potential role in treating acute myeloid leukemia Type Journal Article
  Year 2011 Publication Expert Opinion on Investigational Drugs Abbreviated Journal Expert Opin Investig Drugs  
  Volume 20 Issue 7 Pages 995-1003  
  Keywords Animals; Antineoplastic Agents--pharmacokinetics, therapeutic use; Clinical Trials as Topic--methods; DNA Topoisomerases, Type II--metabolism; Drug Resistance, Neoplasm; Enzyme Inhibitors--pharmacokinetics, therapeutic use; Humans; Leukemia, Myeloid, Acute--drug therapy, enzymology, mortality; Naphthalimides--pharmacokinetics, therapeutic use; Survival Rate--trends; Treatment Outcome  
  Abstract INTRODUCTION: Amonafide is a novel topoisomerase II (Topo II) inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA. Amonafide retains cytotoxic activity even in the presence of P-glycoprotein (Pgp)-mediated multi-drug resistance (MDR), a major contributor to clinical treatment failure. AREAS COVERED: In vitro, Pgp-mediated transport (efflux) of amonafide from myeloblasts obtained from patients with secondary acute myeloid leukemia (sAML) was significantly less than efflux of daunorubicin. Amonafide has shown efficacy in patients with sAML, as well as in patients with poor prognostic characteristics such as older age and unfavorable cytogenetics, all associated with MDR. Improved antileukemic activity is observed when amonafide is given together with cytarabine, rather than as monotherapy, with a complete remission rate of approximately 40% in a recent Phase II trial in sAML. The efficacy of amonafide was maintained among poor-risk subsets of patients, including older patients and patients who had previous myelodysplastic syndrome or previous leukemogenic therapy. The safety profile was acceptable and manageable. EXPERT OPINION: Amonafide plus cytarabine may have clinical utility in patients with sAML and in other poor-risk subgroups of acute myeloid leukemia (AML). Ongoing trials will help define the role for amonafide in the treatment of poor-risk AML.  
  Call Number Serial 199  
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Author (up) Henkenius, K.; Greene, B.H.; Barckhausen, C.; Hartmann, R.; Marken, M.; Kaiser, T.; Rehberger, M.; Metzelder, S.K.; Parak, W.J.; Neubauer, A.; Brendel, C.; Mack, E. file  url
openurl 
  Title Maintenance of cellular respiration indicates drug resistance in acute myeloid leukemia Type Journal Article
  Year 2017 Publication Leukemia Research Abbreviated Journal Leuk Res  
  Volume 62 Issue Pages 56-63  
  Keywords Cell Line, Tumor; Cell Respiration/*physiology; Drug Resistance, Neoplasm/*physiology; Glycolysis/drug effects/physiology; Humans; Leukemia, Myeloid, Acute/*metabolism; Oxidative Phosphorylation/drug effects; Aml; Drug resistance; Mitochondrial membrane potential; Respiration  
  Abstract Primary resistance to induction therapy is an unsolved clinical problem in acute myeloid leukemia (AML). Here we investigated drug resistance in AML at the level of cellular metabolism in order to identify early predictors of therapeutic response. Using extracellular flux analysis, we compared metabolic drug responses in AML cell lines sensitive or resistant to cytarabine or sorafenib after 24h of drug treatment to a small cell lung cancer (SCLC) cell line exposed to etoposide. Only drug-resistant AML cells maintained oxidative metabolism upon drug exposure while SCLC cells displayed an overall metabolic shift towards glycolysis, i.e. a Warburg effect to escape drug toxicity. Moreover, primary AML blasts displayed very low glycolytic activity, while oxygen consumption was readily detectable, indicating an essential role of oxidative pathways in the bioenergetics of AML blasts. In line with these observations, analysis of the mitochondrial membrane potential using tetramethylrhodamine ethyl ester staining and flow cytometry allowed for clear discrimination between drug sensitive and resistant AML cell line clones and primary blasts after 24h of treatment with cytarabine or sorafenib. Our data reveal a distinct metabolic phenotype of resistant AML cells and suggest that disrupting oxidative metabolism rather than glycolysis may enhance the cytotoxic effects of chemotherapy in AML.  
  Call Number Serial 2125  
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Author (up) Jakubikova, J.; Duraj, J.; Hunakova, L.; Chorvath, B.; Sedlak, J. file  url
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  Title PK11195, an isoquinoline carboxamide ligand of the mitochondrial benzodiazepine receptor, increased drug uptake and facilitated drug-induced apoptosis in human multidrug-resistant leukemia cells in vitro Type Journal Article
  Year 2002 Publication Neoplasma Abbreviated Journal Neoplasma  
  Volume 49 Issue 4 Pages 231-236  
  Keywords Antineoplastic Agents/*metabolism/*pharmacology/toxicity; Apoptosis/*drug effects; Biological Transport; Carcinoma/drug therapy/metabolism; Daunorubicin/*metabolism/toxicity; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Female; Fluoresceins/metabolism; Fluorescent Dyes/metabolism; HL-60 Cells; Humans; Isoquinolines/metabolism/*pharmacology; Leukemia, Myeloid/*drug therapy/metabolism; Ligands; Mitochondrial Proteins/metabolism; Ovarian Neoplasms/drug therapy/metabolism; P-Glycoprotein/genetics; Receptors, GABA-A/metabolism; Tumor Cells, Cultured  
  Abstract The isoquinoline peripheral benzodiazepine receptor ligand PK11195 increased drug (daunomycin)- and fluorochrome (calcein-AM) uptake and induced apoptosis detected by flow cytometry (FCM) technique, DNA electrophoretic analysis and poly(ADP-ribose) polymerase (PARP) cleavage in human multidrug-resistant myeloid leukemia (BL-60/VCR) and ovarian carcinoma (A2780/ADR) cells in vitro. The position of PK11195 with respect to drug-resistance modulator (DRM) efficiency, compared to the reference DRMs with the aid of FCM technique, was as follows: PSC833 > verapamil > PK11195 > vincristine. Our data show up to now not indicated observation that PK11195 possesses multidrug resistance modulating activity.  
  Call Number Serial 398  
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Author (up) Kim, Y.-I. file  url
doi  openurl
  Title Role of the MTHFR polymorphisms in cancer risk modification and treatment Type Journal Article
  Year 2009 Publication Future Oncology (London, England) Abbreviated Journal Future Oncol  
  Volume 5 Issue 4 Pages 523-542  
  Keywords Antineoplastic Agents/therapeutic use; Drug Resistance, Neoplasm/*genetics; Fluorouracil/therapeutic use; Folic Acid/metabolism; *Genetic Predisposition to Disease; Humans; Methotrexate/therapeutic use; Methylenetetrahydrofolate Reductase (NADPH2)/*genetics; Neoplasms/drug therapy/*genetics; Polymorphism, Single Nucleotide; Risk Factors  
  Abstract The role of folate, a water-soluble B vitamin, and single nucleotide polymorphisms (SNPs) in the folate metabolic pathway in human health and disease has been rapidly expanding. Recently, functionally significant SNPs in 5,10-methylenetetrahydrofolate reductase (MTHFR), a critical enzyme for intracellular folate homeostasis and metabolism, have been identified and characterized. The MTHFR SNPs are ideal candidates for investigating the role of SNPs in cancer risk modification and treatment because of their well-defined and highly relevant biochemical effects on intracellular folate composition and one-carbon transfer reactions. Indeed, a large body of molecular epidemiologic evidence suggests that the MTHFR 677 variant T allele is associated with cancer risk in a site-specific manner. Furthermore, biologically plausible mechanisms based on the functional consequences of changes in intracellular folate cofactors resulting from the MTHFR 677T variant exist to readily explain cancer risk modification associated with this variant. In addition, a growing body of in vitro and clinical evidence suggests that the MTHFR SNPs may be an important pharmacogenetic determinant of response to and toxicity of 5-fluorouracil (5FU) and methotrexate (MTX)-based cancer and anti-inflammatory chemotherapy. Furthermore, studies suggest that MTHFR inhibition may be a potential target for increasing chemosensitvity of cancer cells to 5FU-based chemotherapy. Because the MTHFR SNPs are prevalent and MTX and 5FU are widely used for the treatment of common cancers and inflammatory conditions, the pharmacogenetic role of the MTHFR SNPs has significant clinical implications. MTHFR SNPs may play an important role in providing rational, effective and safe tailored treatment to patients with cancer and inflammatory disorders requiring 5FU and MTX-based therapy. As such, largescale human studies and in vitro mechanistic studies are warranted to clarify the pharmacogenetic role of the MTHFR SNPs.  
  Call Number Serial 182  
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Author (up) Lash, T.L.; Lien, E.A.; Sorensen, H.T.; Hamilton-Dutoit, S. file  url
doi  openurl
  Title Genotype-guided tamoxifen therapy: time to pause for reflection? Type Journal Article
  Year 2009 Publication The Lancet Oncology Abbreviated Journal Lancet Oncol  
  Volume 10 Issue 8 Pages 825-833  
  Keywords Antineoplastic Agents, Hormonal/*therapeutic use; Breast Neoplasms/*drug therapy/*genetics; Cytochrome P-450 CYP2D6/genetics; Drug Resistance, Neoplasm/*genetics; Female; Genotype; Humans; Neoplasm Recurrence, Local/genetics; Receptors, Estrogen/genetics; Tamoxifen/metabolism/*therapeutic use; Tumor Markers, Biological/genetics  
  Abstract Tamoxifen remains a cornerstone of adjuvant therapy for patients with early stage breast cancer and oestrogen-receptor-positive tumours. Accurate markers of tamoxifen resistance would allow prediction of tamoxifen response and personalisation of combined therapies. Recently, it has been suggested that patients with inherited non-functional alleles of the cytochrome P450 CYP2D6 might be poor candidates for adjuvant tamoxifen therapy, because women with these variant alleles have reduced concentrations of the tamoxifen metabolites that most strongly bind the oestrogen receptor. In some studies, women with these alleles have a higher risk of recurrence than women with two functional alleles. However, dose-setting studies with clinical and biomarker outcomes, studies associating clinical outcomes with serum concentrations of tamoxifen and its metabolites, and a simple model of receptor binding, all suggest that tamoxifen and its metabolites should reach concentrations sufficient to achieve the therapeutic effect regardless of CYP2D6 inhibition. Ten epidemiology studies on the association between CYP2D6 genotype and breast cancer recurrence report widely heterogeneous results with relative-risk estimates outside the range of reasonable bounds. None of the explanations proposed for the heterogeneity of these results adequately account for the variability and no design feature sets apart any study or subset of studies as most likely to be accurate. The studies reporting a positive association might receive the most attention, because they report a result consistent with the profile of metabolite concentrations; not because they are more reliable by design. We argue that a recommendation for CYP2D6 genotyping of candidates for tamoxifen therapy, and its implicit conclusion regarding the association between genotype and recurrence risk, is premature.  
  Call Number Serial 197  
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