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Biomedical subjects

David J Newman

Publications and source records attributed to David J Newman.

At least 19 recordsLinked to original sources
PubMed2007

Reactivation of Kaposi's sarcoma-associated herpesvirus by natural products from Kaposi's sarcoma endemic regions.

Kaposi's sarcoma (KS) and its causative agent, Kaposi's sarcoma associated herpesvirus (KSHV/HHV-8), a gamma2 herpesvirus, have distinctive geographical distributions that are largely unexplained. We propose the "oncoweed" hypothesis to explain these differences, namely that environmental cofactors present in KS endemic regions cause frequent reactivation of KSHV in infected subjects, leading to increased viral shedding and transmission leading to increased prevalence of KSHV infection as well as high viral load levels and antibody titers. Reactivation also plays a role in the pathogenesis of KSHV-associated malignancies. To test this hypothesis, we employed an in vitro KSHV reactivation assay that measured increases in KSHV viral load in KSHV infected primary effusion lymphoma (PEL) cells and screened aqueous natural product extracts from KS endemic regions. Of 4,842 extracts from 38 countries, 184 (5%) caused KSHV reactivation. Extracts that caused reactivation came from a wide variety of plant families, and extracts from Africa, where KSHV is highly prevalent, caused the greatest level of reactivation. Time course experiments were performed using 28 extracts that caused the highest levels of reactivation. The specificity of the effects on viral replication was examined using transcriptional profiling of all viral mRNAs. The array data indicated that the natural extracts caused an ordered cascade of lytic replication similar to that seen after induction with synthetic activators. These in vitro data provide support for the "oncoweed" hypothesis by demonstrating basic biological plausibility.

Biological Assay↗
PubMed2006

New drugs from marine microbes: the tide is turning.

This is a mini-review demonstrating that investigation of the genomics of marine microbes from all three domains has the potential to revolutionize the search for secondary metabolites originally thought to be the product of marine invertebrates. The basis for the review was a symposium at the 2005 Annual Meeting of the SIM covering some aspects of the potential for marine microbes to be the primary producers of such metabolites. The work reported at that symposium has been integrated into a fuller discussion of current published literature on the subject with examples drawn from bacteria, cyanophytes and fungi.

Actinobacteria↗
PubMed2006

The US National Cancer Institute's natural products repository; origins and utility.

The US National Cancer Institute's natural products collection program has been running since 1986 and over the years the materials collected and processed have been stored in a repository that as a result of initial planning, has permitted the establishment of a national resource that is now being utilized as a drug discovery tool for any disease of interest to the NIH by researchers world-wide. This paper describes the history of the program.

Biological Products↗
PubMed2006

A natural products chemist looks at the bystander effect!

The bystander effect is a process whereby the medium in which cells are irradiated at very low levels is presumed to contain a "low molecular weight" entity that will induce cell death and/or genetic changes in fresh mammalian cells when they are incubated in the medium. Following discussions at a recent meeting in McMaster University, suggestions are made in this paper as to the possibility for the "entity" to be nitric oxide and recommendations are given as to methods that will permit a systematic (bio)chemical search to be performed in order to identify the "activator" and prove/disprove the hypothesis.

Animals↗
PubMed2006

Natural product extracts of plant and marine origin having antileukemia potential. The NCI experience.

While effective treatments exist for acute lymphocytic leukemia (ALL), particularly in the case of children, and for chronic mylogenous leukemia (CML), more efficacious treatments for other forms of acute and chronic forms of the disease are still needed. The National Cancer Institute has tested over 90,000 extracts of terrestrial plants and marine plants and invertebrates in its human cancer one-dose/60-cell-line prescreen, and the results for plants and marine organisms meeting criteria established for activity against selected leukemia cell lines are presented. Taxonomic data are limited to family and genus in the case of plants, and phylum for marine organisms, and those groups of organisms exhibiting significant activity (so-called "hot" families and genera) are discussed. The "hot" terrestrial plant families Myrsinaceae and Sapindaceae have not been studied to any extent and appear to merit special attention, although leukemia cell line selectivity is also noted for other families.

Antineoplastic Agents↗
PubMed2005

Plants as a source of anti-cancer agents.

Plant-derived compounds have been an important source of several clinically useful anti-cancer agents. These include vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, etoposide, derived from epipodophyllotoxin, and paclitaxel (taxol A number of promising new agents are in clinical development based on selective activity against cancer-related molecular targets, including flavopiridol and combretastin A4 phosphate, while some agents which failed in earlier clinical studies are stimulating renewed interest.

Animals↗
PubMed2005

Umbelactonyl cinnamate derivatives from Crypteronia paniculata that mediate DNA strand scission.

As part of an initiative to discover functional natural product analogues of bleomycin guided by the use of the COMPARE algorithm, a CH(2)Cl(2)-MeOH extract prepared from Crypteronia paniculata was found to exhibit relaxation of supercoiled pSP64 DNA in the presence of Cu(2+). Bioassay-guided fractionation employing a DNA strand scission assay resulted in the isolation of three novel DNA cleavage agents. Their structures were elucidated as umbelactonyl cinnamate derivatives 1-3 through their NMR and MS spectral data analyses. This is the first example of the isolation and structural characterization of naturally occurring umbelactonyl cinnamate derivatives. Compound 1 exhibited strong Cu(2+)-dependent relaxation of supercoiled pSP64 DNA, while compounds 2 and 3 had only weak DNA cleavage activity.

Algorithms↗
PubMed2005

The search for novel drug leads for predominately antitumor therapies by utilizing mother nature's pharmacophoric libraries.

Recent advances in the use of natural products and compounds derivedfrom natural products as agents for the treatment of cancer and other diseases are reviewed. The antitumor agents discussed include tubulin interactive agents, inhibitors of topoisomerases I and II, caspase activators, proteasome inhibitors, histone deacetylase inhibitors, heat shock protein 90 inhibitors, protein kinase inhibitors, and inhibitors of hypoxia inducible factor 1. It can be concluded that, despite a perceived lack of popularity in recent years, the use of natural product scaffolds in searching for drug leads is still being practiced.

Animals↗
PubMed2005

Natural products as drug leads: an old process or the new hope for drug discovery?

Although the use of natural products as leads to drugs waned in the early 1980s with the rise of combinatorial chemistry as a putative discovery tool, inspection of the chemical literature shows that research in natural products, in one guise or another, is alive and active and the 'chemical inspiration' from these privileged structures is leading to novel approaches in drug design and discovery. In this short article, we propose why we consider natural products are poised for a renaissance as tools for drug discovery.

Animals↗
PubMed2004

The adaptor disabled-2 binds to the third psi xNPxY sequence on the cytoplasmic tail of megalin.

The cytoplasmic tail (CT) of megalin possesses several functional motifs likely to participate in protein-protein interactions within the proximal tubular epithelial cell (PTEC) of the kidney. One such interaction is with the phosphotyrosine interaction domain (PID) of the adaptor protein disabled-2 (Dab2), a mitogen-responsive phosphoprotein, which interacts via its PID with Psi xNPxY (where Psi represents a hydrophobic residue) motifs on its binding partners. Megalin CT has three such motifs; it has been established that there is no interaction of Dab2 with the first (from N to C) (Biochem. J. 3 (2000) 613). Here, we analyse in real-time the binding of recombinant megalin CT, and of synthetic peptide sequences encompassing the second and third Psi xNPxY motifs, to Dab2PID in real-time using surface plasmon resonance (SPR). We report a binding affinity of DabPID for megalin CT of K(D) = 2.6 x 10(-7) +/- 5.3 x 10(-8). Direct binding and competition studies indicate that this interaction is with the third Psi xNPxY motif. The dissociation of Dab2 from the third Psi xNPxY peptide was significantly slower than that from the second (k(off) (mean +/- S.E.M.) (per s) = 0.002 +/- 0.002 vs. 0.007 +/- 0.002, P < 0.05). Synthetic peptide sequences encompassing the third Psi xNPxY but not the second inhibited Dab2PID binding both to intact megalin CT and to the third Psi xNPxY motif. Tyrosine phosphorylation of either motif did not exert a major effect upon competition efficacy. We further demonstrate for the first time the presence of Dab2 expression in primary human PTEC.

Adaptor Proteins, Signal Transducing↗
PubMed2004

A tale of two tumor targets: topoisomerase I and tubulin. The Wall and Wani contribution to cancer chemotherapy.

The seminal discoveries of camptothecin and Taxol by Wall and Wani are discussed in a manner that demonstrates the influence that these two compounds has had on the further development of natural product, natural product-derived, and (some) synthetic entities as potential drug leads that interact either with tubulin or with topoisomerase I. The major categories of tubulin interactive agents in terms of inhibition and promotion of tubulin polymerization are briefly discussed. Likewise, a brief discussion of topoisomerase I inhibitors is presented. Lists of tubulin interactive agents and topoisomerase I inhibitors in preclinical and clinical development are given in Tables 2 and 3, respectively. This review is not meant to be exhaustive, but does illustrate the profound impact that these two plant-derived agents have had on cancer chemotherapy.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Marine natural products and related compounds in clinical and advanced preclinical trials.

The marine environment has proven to be a very rich source of extremely potent compounds that have demonstrated significant activities in antitumor, antiinflammatory, analgesia, immunomodulation, allergy, and anti-viral assays. Although the case can and has been made that the nucleosides such as Ara-A and Ara-C are derived from knowledge gained from investigations of bioactive marine nucleosides, no drug directly from marine sources (whether isolated or by total synthesis) has yet made it to the commercial sector in any disease. However, as shown in this review, there are now significant numbers of very interesting molecules that have come from marine sources, or have been synthesized as a result of knowledge gained from a prototypical compound, that are either in or approaching Phase II/III clinical trials in cancer, analgesia, allergy, and cognitive diseases. A substantial number of other potential agents are following in their wake in preclinical trials in these and in other diseases.

Animals↗
PubMed2004

Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: the chronic renal impairment in Birmingham (CRIB) study.

BACKGROUND: Studies in the general population suggest that low-grade inflammation, endothelial dysfunction, and platelet activation are associated with an increased risk of cardiovascular events. METHODS: Markers of inflammation, endothelial dysfunction, and platelet activation were measured in 334 patients with chronic kidney disease (serum creatinine >1.47 mg/dL [>130 micromol/L] at screening) and compared with 2 age- and sex-matched control groups, 1 comprising 92 patients with coronary artery disease and the other comprising 96 apparently healthy individuals with no history of cardiovascular or kidney disease. RESULTS: There was evidence of low-grade inflammation in the chronic renal impairment group compared with healthy controls, with higher concentrations of C-reactive protein (3.70 versus 2.18 mg/L, P < 0.01) and fibrinogen (3.48 versus 2.67 g/L, P < 0.001) and lower serum albumin concentration (41.8 versus 44.0 g/dL [418 versus 440 g/L], P < 0.001). More severe renal impairment was associated with a trend towards higher fibrinogen and lower albumin concentrations (both P < 0.001), although there was no association with higher C-reactive protein level. As compared to healthy controls, plasma von Willebrand factor (142 versus 108 IU/dL, P < 0.001) and soluble P-selectin concentrations (57.0 versus 43.3 ng/mL, P < 0.001) were also higher in the chronic renal impairment group. More severe renal impairment was associated with a trend towards higher levels of von Willebrand factor (P < 0.001) and of soluble P selectin (P < 0.05). CONCLUSION: This cross-sectional analysis demonstrates that chronic kidney disease is associated with low-grade inflammation, endothelial dysfunction, and platelet activation, even among patients with moderate renal impairment.

Adult↗
PubMed2004

Advanced preclinical and clinical trials of natural products and related compounds from marine sources.

The marine environment has proven to be a very rich source of extremely potent compounds that have demonstrated significant activities in anti-tumor, anti-inflammatory, analgesia, immuno-modulation, allergy and anti-viral assays. Although the case can and has been made that the nucleosides such as Ara-A and Ara-C are derived from knowledge gained from investigations of bioactive marine nucleosides, no drug directly from marine sources (whether isolated or by total synthesis) has yet made it to the commercial sector in any human disease. However, as shown in this review, there are now significant numbers of very interesting molecules that have come from marine sources, or have been synthesized as a result of knowledge gained from a prototypical compound, that are either in or approaching Phase III clinical trials in cancer, analgesia and allergy, with a very substantial number of other, quite different potential agents following in their wake, in these and in other diseases.

Alzheimer Disease↗
PubMed2003

Investigations of the marine flora and fauna of the Islands of Palau.

The Islands of Palau have proven to be an excellent source of bioactive marine natural products primarily as a result of the systematic studies from the late 1970s by the research groups of Scheuer at the University of Hawaii, Faulkner at the Scripps Oceanographic Institution/University of California at San Diego, and Paul at the University of Guam. Their efforts were materially aided by the excellent facilities provided by the Government of Palau and for the last 10 years, those of the NCI's shallow water collection contractor, the Coral Reef Research Foundation. This review covers the structures and biological activities where noted, of the multitudinous marine-derived natural products isolated from the marine flora and fauna of this nation and demonstrates the enormous variety of novel structures elaborated by these organisms.

Animals↗
PubMed2003

Natural products as sources of new drugs over the period 1981-2002.

This review is an updated and expanded version of a paper that was published in this journal in 1997. The time frame has been extended in both directions to include the 22 years from 1981 to 2002, and a new secondary subdivision related to the natural product source but applied to formally synthetic compounds has been introduced, using the concept of a "natural product mimic" or "NM" to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, the percentage of small molecule, new chemical entities that are nonsynthetic has remained at 62% averaged over the whole time frame. In other areas, the influence of natural product structures is quite marked, particularly in the antihypertensive area, where of the 74 formally synthetic drugs, 48 can be traced to natural product structures/mimics. Similarly, with the 10 antimigraine drugs, seven are based on the serotonin molecule or derivatives thereof. Finally, although combinatorial techniques have succeeded as methods of optimizing structures and have, in fact, been used in the optimization of a number of recently approved agents, we have not been able to identify a de novo combinatorial compound approved as a drug in this time frame.

Biological Products↗
PubMed2003

Estimation of glomerular filtration rate in older patients with chronic renal insufficiency: is the modification of diet in renal disease formula an improvement?

OBJECTIVES: To evaluate a new formula for glomerular filtration rate (GFR), derived from the Modification of Diet in Renal Disease (MDRD) study in older people. DESIGN: An observational study of the performance of the MDRD formula compared with other formulae and creatinine clearance (ClCr) as measures of the GFR. SETTING: Volunteers were recruited via outpatient clinics. PARTICIPANTS: Fifty-two patients (27 men, 25 women: mean age 80, range 69-92) with a variety of medical diagnoses. Mean GFR was 53.3 mL/min/1.73 m2 (range 15.9-100.2). Exclusion criteria included renal replacement therapy/renal transplantation and cognitive impairment. MEASUREMENTS: 51Chromium ethylenediaminetetraacetic acid (51Cr EDTA) was used as the reference method against which the formulaic estimates of GFR were compared using bias plot and regression analyses. RESULTS: The MDRD and Cockcroft and Gault formulae (both coefficient of determination (R2) = 0.84) gave the best fit with GFR, followed by the Jelliffe formula (R2 = 0.81), ClCr (R2 = 0.73) and the Baracskay formula (R2 = 0.56). ClCr (-1.2%) demonstrated minimal bias compared with the MDRD (8.0%) and Cockcroft and Gault (-10.4%) formulae. However, imprecision compared with 51Cr EDTA was lowest for the Cockcroft and Gault formula, with 50% of estimates lying between -9.5 and -0.5 mL/min/1.73 m2 of measured 51Cr EDTA clearance. This compares with -6.7 and 10.1 mL/min/1.73 m2 for ClCr and 0.0 and 12.7 mL/min/1.73 m2 for the MDRD formula. CONCLUSION: Calculated estimates of GFR are an improvement over ClCr estimation. On balance, the MDRD formula does not improve the estimate of GFR compared with the Cockcroft and Gault formula in older Caucasian patients with chronic renal insufficiency.

Age Factors↗