Linked Life Data

10571245

Source:http://linkedlifedata.com/resource/pubmed/id/10571245

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
1999-12-17
pubmed:abstractText
DNA-damaging agents such as cisplatin arrest cell cycle progression at either the G1, S, or G2 phase, although the G1 arrest is seen only in cells expressing the wild-type p53 tumor suppressor protein. Caffeine has been shown to abrogate the S and G2 arrest in p53-defective cells and to enhance cytotoxicity, but at concentrations too toxic to administer to humans. We have reported that 7-hydroxystaurosporine (UCN-01) also overcomes S and G2 phase arrest and enhances the cytotoxicity of cisplatin. We show here that UCN-01 at non-cytotoxic concentrations abrogated S and G2 arrest induced by cisplatin in two p53-defective human breast cancer cell lines. UCN-01 pushed the cells through S phase and mitosis, with subsequent apoptosis. Inhibition of mitosis with nocodazole reduced the apoptosis induced by UCN-01 plus cisplatin. Seven staurosporine analogs were compared for their ability to abrogate cell cycle arrest. Staurosporine was as effective as UCN-01 at abrogating S and G2 arrest, but the concentrations required were cytotoxic. K252a abrogated S phase arrest but failed to abrogate G2 arrest because alone it induced G2 arrest. Hence, K252a did not enhance cisplatin-induced cytotoxicity because it failed to push the cells through a lethal mitosis. None of the other analogs influenced cell cycle progression at the concentrations tested. Accordingly, UCN-01 was the only analog that overcame cell cycle arrest and enhanced the cytotoxicity of cisplatin while exhibiting no cytotoxicity of its own. Hence, UCN-01 remains the most promising candidate for testing clinically in combination with cisplatin.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
58
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1713-21
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1999
pubmed:articleTitle
Comparison of the efficacy of 7-hydroxystaurosporine (UCN-01) and other staurosporine analogs to abrogate cisplatin-induced cell cycle arrest in human breast cancer cell lines.
pubmed:affiliation
Department of Pharmacology and Toxicology, and the Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03755, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't