Linked Life Data

1540981

Source:http://linkedlifedata.com/resource/pubmed/id/1540981

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
1992-4-7
pubmed:abstractText
The selective targeting of tumors by enzymes conjugated to monoclonal antibodies (mAb) may be an ideal approach to convert relatively nontoxic prodrugs into active agents at the tumour site. We used the anti-carcinoembryonic antigen mAb BW431/26 conjugated to alkaline phosphatase (AP) and phosphorylated etoposide (etoposide-P) as a prodrug to study the feasibility of this concept. Etoposide was phosphorylated with POCl3. Quantitative hydrolysis of etoposide-P to etoposide occurred within 10 min in the presence of AP. BW431/26 and AP were conjugated using a thioether bond. The AP conjugate retained 93% of its calculated activity. 125I-labelled AP conjugate did not show a reduction of immunoreactivity as determined by a cell-binding assay. SW1398 colon cancer cells were used to analyse the cytotoxicity of etoposide and etoposide-P. Etoposide (IC50 22 microM) was 100 times more toxic than etoposide-P (20% growth inhibition at 200 microM). Pretreatment of the cells with BW431/26-AP prior to etoposide-P exposure resulted in a dramatic increase in cytotoxicity (IC50 70 microM). The pharmacokinetics and tumour-localizing properties of BW431/27 and the AP conjugate were assessed in nude mice bearing SW1398 tumours. BW431/26 showed excellent tumour localization (10% of the injected dose/g tissue retained from 8 h to 120 h), whereas the AP conjugate showed a reduced tumour uptake (3%-0.3% of the injected dose/g tissue at 8-120 h), a faster clearance from the circulation and a high liver uptake. Radiolabelled AP showed a similar pharmacokinetic profile to the AP conjugate. Gel filtration analysis of blood, liver, and tumour samples indicated good stability of the conjugate.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0340-7004
pubmed:author
pubmed:issnType
Print
pubmed:volume
34
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
343-8
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed:year
1992
pubmed:articleTitle
Analysis of a conjugate between anti-carcinoembryonic antigen monoclonal antibody and alkaline phosphatase for specific activation of the prodrug etoposide phosphate.
pubmed:affiliation
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
pubmed:publicationType
Journal Article