Linked Life Data

10425102

Source:http://linkedlifedata.com/resource/pubmed/id/10425102

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
1999-8-31
pubmed:abstractText
The antitumor drug NB-506, which is currently undergoing phase I/II clinical trials, contains a DNA-intercalating indolocarbazole chromophore substituted with a glucose residue. In addition to interacting with DNA, the drug stabilizes the topoisomerase I-DNA covalent complex. To reinforce the DNA binding and anti-topoisomerase I activities of NB-506, an analogue containing a new substituent on the naphthalimide ring F was synthesized. The N-formylamino group of NB-506 has been replaced with a more hydrophilic group, N-bis(hydroxymethyl)methylamino. In this study we show that the incorporation of a longer substituent on the N6 position effectively reinforces both the interaction with DNA and the capacity of the drug to maintain the integrity of the topoisomerase I-DNA covalent complexes. The strength and the mode of binding of the drugs to DNA were studied by complementary biophysical techniques including absorption, fluorescence, and circular and linear dichroism. Various biochemical procedures were applied to investigate the effects on human topoisomerase I using plasmid DNA as well as restriction fragments. The drug binding sites and the positions of the topoisomerase I-mediated cleavage sites were mapped with nucleotide resolution using footprinting and sequencing techniques. Cytotoxicity measurements performed with various human cancer cell lines (HCT-116, DLD-1, MKN-45) indicate that the newly designed drug is 3 to 4 times more toxic to colon and gastric cancer cells than NB-506. Therefore, the results suggest that the antitumor activity of indolocarbazole-based drugs can be enhanced by incorporating DNA and/or topoisomerase I reactive groups. They also support the hypothesis that the substituent on the imide nitrogen on the F ring of NB-506 has direct interaction with the molecular target. The study helps to define the structure-activity relationships in the indolocarbazole series of antitumor agents targeting topoisomerase I.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
29
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2927-35
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:10425102-Animals, pubmed-meshheading:10425102-Antineoplastic Agents, pubmed-meshheading:10425102-Carbazoles, pubmed-meshheading:10425102-Cattle, pubmed-meshheading:10425102-Circular Dichroism, pubmed-meshheading:10425102-DNA, pubmed-meshheading:10425102-DNA, Neoplasm, pubmed-meshheading:10425102-Drug Screening Assays, Antitumor, pubmed-meshheading:10425102-Enzyme Inhibitors, pubmed-meshheading:10425102-Glucosides, pubmed-meshheading:10425102-Humans, pubmed-meshheading:10425102-Inhibitory Concentration 50, pubmed-meshheading:10425102-Intercalating Agents, pubmed-meshheading:10425102-Sequence Analysis, DNA, pubmed-meshheading:10425102-Spectrometry, Fluorescence, pubmed-meshheading:10425102-Spectrophotometry, Ultraviolet, pubmed-meshheading:10425102-Structure-Activity Relationship, pubmed-meshheading:10425102-Topoisomerase I Inhibitors, pubmed-meshheading:10425102-Tumor Cells, Cultured
pubmed:year
1999
pubmed:articleTitle
Substitution at the F-ring N-imide of the indolocarbazole antitumor drug NB-506 increases the cytotoxicity, DNA binding, and topoisomerase I inhibition activities.
pubmed:affiliation
Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret and INSERM U-524, IRCL, Lille 59045, France. bailly@lille.inserm.fr
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't