Mitigation of Insulin Resistance by Natural Products from a New Class of Molecules, Membrane-Active Immunomodulators.

Insulin resistance (IR), accompanied by an impaired cellular glucose uptake, characterizes diverse pathologies that include, but are not limited to, metabolic disease, prediabetes and type 2 diabetes. Chronic inflammation associated with deranged cellular signaling is thought to contribute to IR. The key molecular players in IR are plasma membrane proteins, including the insulin receptor and glucose transporter 4.

Membrane Active Immunomodulator As a Novel Therapy for an Infectious Bacterial Disease, Buruli Ulcer.

Background/aim: Mycobacterium ulcerans causes the necrotizing skin disease Buruli ulcer (BU), characterized by the formation of subcutaneous lesions and immunosuppression thought to be mediated by the virulence factor mycolactone. Since early BU lesions are typically painless, patients often seek standard oral antibiotic therapy at the advanced stages when the treatment is less effective. Given that currently there is no curative topical treatment for BU, our objective was to evaluate a plasma membrane fluidizer, diethyl azelate (DEA), as a potential novel topical therapy for BU.

Adaptive Membrane Fluidity Modulation: A Feedback Regulated Homeostatic System and Target for Pharmacological Intervention.

Background/aim: Alterations of plasma membrane fluidity are characteristic of many diseases but the intentional modulation of membrane fluidity with drugs has been less studied. We examined the therapeutic potential of the membrane fluidizer diethyl azelate (DEA) and related azelates.

Materials And Methods: The effects of azelates on plasma membrane fluidity and cell signaling were examined in primary human and murine cells and in vivo.

Adaptive Membrane Fluidity Modulation: A Feedback Regulated Homeostatic System Hiding in Plain Sight.

The structure of the plasma membrane affects its function. Changes in membrane fluidity with concomitant effects on membrane protein activities and cellular communication often accompany the transition from a healthy to a diseased state. Although deliberate modulation of membrane fluidity with drugs has not been exploited to date, the latest data suggest the "druggability" of the membrane.

Oral Azelaic Acid Ester Decreases Markers of Insulin Resistance in Overweight Human Male Subjects.

Background/aim: Insulin resistance (IR) is linked to increased risk of cardiovascular disease and cancer. We examined safety and efficacy of the natural product diethyl azelate (DEA) in overweight males with a varying degree of IR.

Patients And Methods: Seventeen subjects [age 18-42, hemoglobin A1c (A1c) of 5.

Development and antitumor activity of a BCL-2 targeted single-stranded DNA oligonucleotide.

PNT100 is a 24-base, chemically unmodified DNA oligonucleotide sequence that is complementary to a region upstream of the BCL-2 gene. Exposure of tumor cells to PNT100 results in suppression of proliferation and cell death by a process called DNA interference. PNT2258 is PNT100 that is encapsulated in protective amphoteric liposomes developed to efficiently encapsulate the PNT100 oligonucleotide, provide enhanced serum stability, optimized pharmacokinetic properties and antitumor activity of the nanoparticle both in vivo and in vitro.

Plasma biomarkers distinguish non-small cell lung cancer from asthma and differ in men and women.

Background: Lung cancer (LC) is the leading cause of deaths caused by cancer worldwide. A diagnostic test for LC is needed for monitoring high-risk populations.

Patients And Methods: Fifty-seven markers were measured using multiplex immunoassays of plasma of patients with non-small cell lung cancer (NSCLC); (245 men, 114 women, 1 unknown), asthma (67 men, 111 women, 2 unknown) and of healthy controls (165 men, 122 women, 1 unknown).

Effects of alpha-difluoromethylornithine on markers of proliferation, invasion, and apoptosis in breast cancer.

Aim: To examine changes in biomarkers expressed in breast tumors in response to patient treatment with the polyamine synthesis inhibitor alpha-difluoromethylornithine (DFMO).

Patients And Methods: The expression of Ki-67 (MIB-1), matrix metalloproteinases (MMP) 2 and 9, urokinase-type plasminogen activator (uPA) were examined by immunohistochemistry in breast tissue specimens (controls: n=15, 13 evaluable, and DFMO group; n=27, 21 evaluable). Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL).

Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives.

Background: A maximum entropy approach is proposed to predict the cytotoxic effects of a panel of colchicine derivatives in several human cancer cell lines. Data was obtained from cytotoxicity assays performed with 21 drug molecules from the same family of colchicine compounds and correlate these results with independent tubulin isoform expression measurements for several cancer cell lines. The maximum entropy method is then used in conjunction with computed relative binding energy values for each of the drug molecules against tubulin isotypes to which these compounds bind with different affinities.

Analytical validation of serum proteomic profiling for diagnosis of prostate cancer: sources of sample bias.

Background: This report and a companion report describe a validation of the ability of serum proteomic profiling via SELDI-TOF mass spectrometry to detect prostatic cancer. Details of this 3-stage process have been described. This report describes the development of the algorithm and results of the blinded test for stage 1.

Regulation of tumor signaling pathways by AZD3409 in vitro.

Background: The antineoplastic activity of AZD3409 was evaluated in relation to paclitaxel in human breast (MDA-MB-231, BT-474) and ovarian (A2780, A2780cp) cancer cell lines. Biomarkers of apoptosis, protein prenylation, survival, angiogenesis and cellular growth were determined.

Materials And Methods: Cytotoxicity was evaluated by MTS assay, and apoptosis was evaluated by TUNEL.

Prognostic significance of biochemical heterogeneity of catecholaminergic clones in neuroblastoma.

Background/purpose: Genetic heterogeneity of neuroblastic tumors leads to biochemical changes that manifest themselves in different symptoms and clinical courses, which may vary from spontaneous regression and remission to progression with fatal outcome.

Methods: To test the hypothesis that ratios of dopamine (DA) to noradrenaline and of DA to vanillylmandelic acid reflect the composition of adrenergic clones and tumor heterogeneity, we determined urinary DA/noradrenaline and DA/vanillylmandelic acid ratios that presumably reflect DA-beta-hydroxylase (DBH) activity and the prognostic values thereof.

Results: Based on catecholamine metabolism, 4 model situations were defined: (a) complete block of DBH in all cells; (b) block of DBH in some cells; (c) a different enzymatic block; and (d) normal DBH activity in the population of tumor-forming cells.

Molecular determinants of differential sensitivity to docetaxel and paclitaxel in human pediatric cancer models.

Background: The differential sensitivity of some tumors to paclitaxel and docetaxel raises questions regarding the specific mechanisms responsible for the discrepant sensitivity to these taxanes.

Materials And Methods: Docetaxel and paclitaxel were evaluated and compared at maximum tolerated doses (MTD) and 0.5 MTDs against the human pediatric tumor xenograft models SK-N-MC and IMR32 (neuroblastoma), RH1 and RH30 (rhabdomyosarcoma) and KHOS/NP (osteosarcoma), with 8-10 animals per group.

A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma.

Purpose: This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination.

Patients And Methods: Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib.

Results: Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated.

Therapeutic strategies for the treatment of neuroblastoma.

Neuroblastoma, the most common extracranial solid tumor in children, has a highly heterogeneous clinical presentation and course. Current risk-based therapy is usually effective in patients who have intermediate risk features, however, intensive treatment of advanced neuroblastoma in children over two years of age is far from satisfactory. Current therapeutic approaches include the optimization of pharmacokinetic and pharmacodynamic properties of conventional agents, as well as the development of novel targeted drugs, such as signal transduction and angiogenesis inhibitors, apoptosis/differentiation stimulators and immunotherapeutics.

Biomarkers of anticancer activity of R115777 (Tipifarnib, Zarnestra) in human breast cancer models in vitro.

Background: Farnesyltransferase inhibitor R115777 (Tipifamib, Zarnestra) is active in breast cancer, but its efficacy in drug combinations has not been extensively investigated.

Materials And Methods: The activity of R115777 and paclitaxel, alone and in combination, was studied in the human breast cancer cell lines, BT-474 (overexpressed HER2/neu) and MDA-MB-231 (low HER2/neu), with cell viability and biomarkers for farnesylation (HDJ-2, Rho B), tumor growth (Raf/MEK/ERK), survival (PI3K/Akt) and angiogenesis (VEGF, FGF-2, MMP-1, MMP-2, MMP-9) as the endpoints.

Results: The drug combination resulted in additive cytotoxicity.

Biomarkers for Sensitivity to Docetaxel and Paclitaxel in Human Tumor Cell Lines .

Background: Paclitaxel and docetaxel affect microtubule polymerization, yet surprising differences in tumor sensitivity to the taxanes have been observed. Docetaxel was superior to paclitaxel in inhibiting in vivo growth of human lung and prostate but not breast cancer models.

Materials And Methods: We compared drug cytotoxicity, effects on β-tubulin isoforms, markers of apoptosis and proteomic profiles in human prostate (LNCaP), lung (SK-MES, MV-522) and breast (MCF-7, MDA-231) cancer cell lines in vitro.

A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer.

Purpose: To determine the antitumor activity and safety of oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the bcl-2 mRNA, with docetaxel in patients with hormone-refractory prostate cancer (HRPC) and to determine if relevant pharmacokinetic and pharmacodynamic variables of oblimersen or docetaxel influence response to this therapy.

Experimental Design: Patients with HRPC were treated with oblimersen sodium by continuous i.v.

Evaluation of serum protein profiling by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry for the detection of prostate cancer: I. Assessment of platform reproducibility.

Background: Protein expression profiling for differences indicative of early cancer has promise for improving diagnostics. This report describes the first stage of a National Cancer Institute/Early Detection Research Network-sponsored multiinstitutional evaluation and validation of this approach for detection of prostate cancer.

Methods: Two sequential experimental phases were conducted to establish interlaboratory calibration and standardization of the surface-enhanced laser desorption (SELDI) instrumental and assay platform output.

Investigation of HMN-176 anticancer activity in human tumor specimens in vitro and the effects of HMN-176 on differential gene expression.

HMN-176, (E)-4-(2-[2-(N-[4-methoxybenzene-sulfonyl]amino)phenyl]ethenyl) pyridine 1-oxide, is a stilbene derivative which inhibits mitosis without significant effect on tubulin polymerization and displays potent cytotoxicity against a variety of human tumor cell lines. The present study evaluated the activity profile of the antineoplastic agent HMN-176 in an ex-vivo soft agar cloning assay (human tumor colony-forming assay) in a panel of 132 human tumor specimens under 14-day continuous exposure at 0.1, 1.

A Phase I pharmacokinetic and biological correlative study of oblimersen sodium (genasense, g3139), an antisense oligonucleotide to the bcl-2 mRNA, and of docetaxel in patients with hormone-refractory prostate cancer.

Purpose: To assess the feasibility of administering oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the Bcl-2 mRNA, with docetaxel to patients with hormone-refractory prostate cancer; to characterize the pertinent pharmacokinetic parameters, Bcl-2 protein inhibition in peripheral blood mononuclear cell(s) (PBMC) and tumor; and to seek preliminary evidence of antitumor activity.

Experimental Design: Patients were treated with increasing doses of oblimersen sodium administered by continuous i.v.

The early detection research network surface-enhanced laser desorption and ionization prostate cancer detection study: A study in biomarker validation in genitourinary oncology.

Prostate-specific antigen (PSA) screening has led to a dramatic increase in prostate cancer detection with a concurrent stage migration. Although the test has revolutionized prostate cancer detection by identifying disease that is potentially curable in the majority of men, only 25% of men receiving test results of PSA > 4 ng/ml will have prostate cancer and many men receiving a normal PSA will have disease, including high-grade disease. There is a need for improved biomarkers for detecting prostate cancer.

Serum protein expression profiling for cancer detection: validation of a SELDI-based approach for prostate cancer.

Multiple studies have reported that analysis of serum and other bodily fluids using surface enhanced laser desorption/ionization time of flight mass spectroscopy (SELDI-TOF-MS) can identify a "fingerprint" or "signature" of spectral peaks that can separate patients with a specific disease from normal control patients. Ultimately, classification by SELDI-TOF-MS relies on spectral differences in position and amplitude of resolved peaks. Since the reproducibility of quantitation, resolution and mass accuracy of the SELDI-TOF-MS, or any high throughput mass spectrometric technique, has never been determined this method has come under some skepticism as to its clinical usefulness.