|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
4
|
|
pubmed:dateCreated |
2003-4-17
|
|
pubmed:abstractText |
We have previously shown that nitric oxide (NO) inhibits growth and induces differentiation and apoptosis in acute myeloid leukemia cells, with the HL-60 human myeloid leukemia line being particularly sensitive to NO-mediated cytolysis. With the goal of identifying a prodrug that can target NO to the leukemia cells without inducing NO-mediated systemic hypotension, we have screened a series of O(2)-aryl diazeniumdiolates designed to be stable at physiological pH but to release NO upon reaction with glutathione. O(2)-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) proved to be the most active antiproliferative agent among those tested in HL-60 cells, with an IC(50) of 0.2-0.5 microM. After 5 days of exposure to 0.5 micro M JS-K, HL-60 cells had differentiated and acquired some of the phenotypic features of normal monocytes. One- to 2-day treatment with JS-K at concentrations of 0.5-1 microM resulted in apoptosis induction in a concentration- and caspase-dependent manner. JS-K also inhibited the growth of solid tumor cell lines but to a lesser extent than HL-60 cells. JS-K was administered i.v. to nonobese diabetic-severe combined immune deficient mice at doses of up to 4 micromol/kg without inducing significant hypotension. The growth of s.c. implanted HL-60 cells was reduced by approximately 50% when the mice received i.v. injections three times/week with 4 micromol/kg boluses of JS-K. Histological examination of tumor explants from JS-K-treated animals revealed extensive necrosis. Similar results were seen with s.c. human prostate cancer (PPC-1) xenografts. Our data indicate that JS-K is a promising lead compound for the possible development of a novel class of antineoplastic agents.
|
|
pubmed:grant |
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Apr
|
|
pubmed:issn |
1535-7163
|
|
pubmed:author |
pubmed-author:BonifantChallice LCL,
pubmed-author:BuzardGregory SGS,
pubmed-author:CitroMichael LML,
pubmed-author:DaviesKeith MKM,
pubmed-author:DiwanBhalchandra ABA,
pubmed-author:FoxStephen DSD,
pubmed-author:GuYijunY,
pubmed-author:JiXinhuaX,
pubmed-author:KeeferLarry KLK,
pubmed-author:SaavedraJoseph EJE,
pubmed-author:ShamiPaul JPJ,
pubmed-author:SinghShivendra VSV,
pubmed-author:WangLai YLY,
pubmed-author:WaterhouseDavid JDJ
|
|
pubmed:issnType |
Print
|
|
pubmed:volume |
2
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
409-17
|
|
pubmed:dateRevised |
2007-11-14
|
|
pubmed:meshHeading |
pubmed-meshheading:12700285-Animals,
pubmed-meshheading:12700285-Antineoplastic Agents,
pubmed-meshheading:12700285-Apoptosis,
pubmed-meshheading:12700285-Azo Compounds,
pubmed-meshheading:12700285-Cell Differentiation,
pubmed-meshheading:12700285-Cell Division,
pubmed-meshheading:12700285-Cell Line, Tumor,
pubmed-meshheading:12700285-Dose-Response Relationship, Drug,
pubmed-meshheading:12700285-Glutathione,
pubmed-meshheading:12700285-Glutathione Transferase,
pubmed-meshheading:12700285-HL-60 Cells,
pubmed-meshheading:12700285-Humans,
pubmed-meshheading:12700285-Hydrogen-Ion Concentration,
pubmed-meshheading:12700285-Hydrolysis,
pubmed-meshheading:12700285-Leukemia,
pubmed-meshheading:12700285-Mass Spectrometry,
pubmed-meshheading:12700285-Mice,
pubmed-meshheading:12700285-Mice, Inbred NOD,
pubmed-meshheading:12700285-Mice, SCID,
pubmed-meshheading:12700285-Models, Chemical,
pubmed-meshheading:12700285-Models, Molecular,
pubmed-meshheading:12700285-Monocytes,
pubmed-meshheading:12700285-Neoplasm Transplantation,
pubmed-meshheading:12700285-Nitric Oxide,
pubmed-meshheading:12700285-Nitric Oxide Donors,
pubmed-meshheading:12700285-Phenotype,
pubmed-meshheading:12700285-Piperazines,
pubmed-meshheading:12700285-Prodrugs,
pubmed-meshheading:12700285-Time Factors,
pubmed-meshheading:12700285-U937 Cells
|
|
pubmed:year |
2003
|
|
pubmed:articleTitle |
JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity.
|
|
pubmed:affiliation |
Division of Medical Oncology, Department of Internal Medicine, University of Utah and Salt Lake City Veterans' Administration Medical Centers, Salt Lake City, Utah 84148, USA. p.shami@m.cc.utsh.edu
|
|
pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
|
