Linked Life Data

2168281

Source:http://linkedlifedata.com/resource/pubmed/id/2168281

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
18
pubmed:dateCreated
1990-10-9
pubmed:abstractText
The cytotoxic actions of several classes of antitumor DNA intercalators are thought to result from some disturbance to DNA metabolism following trapping of the nuclear enzyme DNA topoisomerase II as a covalent complex on DNA. Here we have studied topoisomerase II trapping and DNA synthesis patterns in relation to the acute cytotoxic actions of 4'-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA) or mitoxantrone on SV40 transformed human fibroblasts. These two DNA intercalators differed significantly in their cytotoxic potential, mitoxantrone being 24-fold more toxic than mAMSA when assayed by the inhibition of clonogenicity. Although both drugs induced G2 delay at cytotoxic concentrations, mAMSA-treated cells recovered normal cell cycle phase distributions within 24 h of removal of drug, while mitoxantrone-treated cells continued to accumulate in G2 up to 48 h following drug treatment with evidence of complete inhibition of entry into mitosis. Compared with mAMSA, mitoxantrone showed a similar capacity to induce cleavable complexes in cellular DNA, and only a 2-fold greater ability to inhibit DNA synthesis. Within a 4-h posttreatment period, mAMSA-treated cells recovered normal rates of DNA synthesis, whereas a continued depression of DNA synthesis was observed in mitoxantrone-treated cells. The recovery patterns of DNA synthesis correlated with the rapid disappearance of mAMSA-induced complexes (less than 27% lesions remaining 2 h after drug removal) and the persistence of mitoxantrone-induced complexes during a 4-h posttreatment period. This difference in complex longevity was observed in other human transformed fibroblast cell lines irrespective of differences in the absolute levels of complexes induced by either agent. We suggest that the results provide evidence that DNA intercalators may differ in the forms of complexes induced and that the comparatively high cytotoxicity of mitoxantrone relates to the ability of the drug to trap topoisomerase II complexes in a form which effects a long-term inhibition of DNA replication and G2 traverse.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
50
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5813-8
pubmed:dateRevised
2004-11-17
pubmed:meshHeading
pubmed:year
1990
pubmed:articleTitle
Long-term inhibition of DNA synthesis and the persistence of trapped topoisomerase II complexes in determining the toxicity of the antitumor DNA intercalators mAMSA and mitoxantrone.
pubmed:affiliation
Medical Research Council Clinical Oncology, Medical Research Council Centre, Cambridge, United Kingdom.
pubmed:publicationType
Journal Article