Linked Life Data

7488229

Source:http://linkedlifedata.com/resource/pubmed/id/7488229

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
1995-12-14
pubmed:abstractText
Penclomedine (PEN) is a synthetic pyridine derivative that has been selected for clinical development based on its activity against human and mouse breast tumors implanted in mice. Its mechanism of action was unclear, and we were interested in determining its mechanism of cytotoxicity in vitro and in vivo. We found chromosome breaks, gaps, and exchanges in P388 ascites cells from BD2F1 mice treated with 200 mg/kg PEN. Maximal observed damage occurred 24 hr after drug administration. Alkaline elution indicated only limited DNA strand breaks and interstrand cross-linking. In vitro, PEN (75 micrograms/mL) inhibited RNA and DNA syntheses almost completely. In addition, incubation of [14C]PEN with rat liver S-9 fraction in the presence of calf thymus DNA resulted in the stable transfer of radioactivity to DNA. Addition of butylated hydroxytoluene, a free radical scavenger, to the incubation mixture inhibited the binding of drug to DNA, implicating free radicals as the ultimate reactive species. These data suggest that PEN can be metabolized to free radical, DNA-reactive products, and that its cytotoxicity is due to chromosomal damage produced by monofunctional alkylation. As an alternate mechanism, the ability of PEN to inhibit cellular dihydroorotate dehydrogenase was explored. Although PEN is an inhibitor of this enzyme in cells in vivo, in vitro, and in isolated cell sonicates, HPLC analyses of ribonucleotide triphosphate pools in P388 cells showed that all triphosphates had increased, especially UTP. Addition of uridine to the cell culture failed to prevent PEN-mediated cytotoxicity, suggesting that inhibition of de novo pyrimidine biosynthesis was not likely to be an important mechanism of action of this drug. These data suggest that PEN is activated in cells to a free radical that binds DNA.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
12
pubmed:volume
50
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1157-64
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1995
pubmed:articleTitle
Biochemical pharmacology of penclomedine (NSC-338720).
pubmed:affiliation
Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.