Linked Life Data

11911842

Source:http://linkedlifedata.com/resource/pubmed/id/11911842

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2002-3-25
pubmed:abstractText
There is increasing interest in the exploitation of molecular addresses for the targeting of tumor imaging or therapeutic agents. A recent study demonstrated anticancer activity in human xenografts of doxorubicin (DOX)-peptide conjugates targeted to the tumor vascular endothelium, among them DOX coupled to the cyclic pentapeptide CNGRC [Science 279 (1998) 377]. In order to learn more about the mechanism of action of this type of DOX-peptide conjugates, we have studied the interaction of DOX-CNGRC with primary human umbilical cord vein endothelial cells (HUVEC) and tumor cells under defined in vitro conditions. We used a DOX conjugate, in which the cyclic CNGRC peptide, for which an in vivo endothelial address has recently been identified as aminopeptidase N (APN)/CD13, has been coupled via a hydrolysable spacer to the C-14 anthracycline-side chain. First we determined that the t(1/2) of DOX-CNGRC conjugate in human blood was 442 min (at 37 degrees ) allowing sufficient time for endothelial targeting when administered i.v. When cultured cells were exposed for 30 min to DOX-CNGRC a more cytoplasmic localization of fluorescent drug was seen when compared to DOX exposure and intracellular DOX-CNGRC was identified after extraction from the cells. This revealed differences in the cellular uptake process of the conjugate compared to DOX. The antiproliferative effect of DOX-CNGRC was determined by 30 min exposure in medium with a high protein content in order to mimick the in vivo targeting situation. In this medium, the IC(50) was 1.1 microM for highly CD13 expressing HT-1080, 1.45 microM for CD13 negative SK-UT-1 sarcoma cells and 6.5 microM for CD13 positive HUVEC. The IC(50) of DOX for these cells were 1.0, 2.0 and 7.3 microM, respectively. Although DOX-CNGRC inhibited the peptidase activity of CD13 up to 50%, our data do not favor an important role for the enzyme inhibition in the cytotoxic effect of the conjugate. The antitumor activity was tested in nude mice bearing human ovarian cancer xenografts (OVCAR-3). A weekly i.v. administration (3mg/kg DOX-equivalent, 3x) showed a minor (40%) growth delay, which does not indicate efficacy better than that expected for free DOX. In conclusion, this study indicates that the antiproliferative and anti-angiogenic effects of DOX-CNGRC as reported before, are likely caused by the cytostatic effects of intracellularly released parent drug DOX, independent of CD13 expression/activity. More research is needed to identify the optimal specific chemical configuration of DOX-peptide conjugates for in vivo targeting and receptor-mediated cellular uptake.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
63
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
897-908
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:11911842-Animals, pubmed-meshheading:11911842-Antigens, CD13, pubmed-meshheading:11911842-Antineoplastic Agents, pubmed-meshheading:11911842-Cell Division, pubmed-meshheading:11911842-Disease Models, Animal, pubmed-meshheading:11911842-Doxorubicin, pubmed-meshheading:11911842-Drug Carriers, pubmed-meshheading:11911842-Drug Stability, pubmed-meshheading:11911842-Endothelium, Vascular, pubmed-meshheading:11911842-Female, pubmed-meshheading:11911842-Humans, pubmed-meshheading:11911842-Mice, pubmed-meshheading:11911842-Mice, Nude, pubmed-meshheading:11911842-Neoplasm Transplantation, pubmed-meshheading:11911842-Neoplasms, Experimental, pubmed-meshheading:11911842-Oligopeptides, pubmed-meshheading:11911842-Prodrugs, pubmed-meshheading:11911842-Subcellular Fractions, pubmed-meshheading:11911842-Tumor Cells, Cultured, pubmed-meshheading:11911842-Xenograft Model Antitumor Assays
pubmed:year
2002
pubmed:articleTitle
A doxorubicin-CNGRC-peptide conjugate with prodrug properties.
pubmed:affiliation
Department of Medical Oncology, Vrije Universiteit Medical Centre, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't