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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
|
| pubmed:dateCreated |
1995-2-28
|
| pubmed:abstractText |
The development of camptothecin-like compounds as inhibitors of topoisomerase I for the treatment of resistant tumors has generated clinical excitement in this new class of drugs. We have developed two novel water-soluble camptothecin analogues which are specific inhibitors of topoisomerase I and are potent cytotoxins with significant antitumor activity. We added water-solubilizing groups off position 7 in the B ring of either 10,11-ethylenedioxy- or 10,11-methylenedioxy-20(S)-camptothecin. These water-soluble camptothecin analogues were demonstrated to be nanamolar inhibitors of the topoisomerase I enzyme in the cleavable complex assay. The compounds, GI147211 [7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camp tot hecin], and GI149893 [7-(4-methylpiperazinomethylene)-10,11-methylenedioxy-20(S)-cam pto thecin], were compared to topotecan, a known water-soluble inhibitor of topoisomerase I. Both GI compounds were found to be slightly more potent than topotecan as inhibitors of topoisomerase I in the cleavable complex assay and were 1.5-2 times more soluble. Tumor cell cytotoxicity assays using 5 separate cell lines demonstrated that both GI compounds were 5-10 times more potent than topotecan, although by comparison all three topoisomerase I inhibitors were unaffected by the multidrug resistance P-glycoprotein. The antitumor activity of all three topoisomerase I inhibitors was compared concomitantly in two human colon xenograft models. In both models, GI147211 and GI149893 were able to induce regression of established HT-29 and SW-48 colon tumors by as much as 60%. The antitumor activity of both compounds were also demonstrated in the MX-1 and PC-3 xenografts. Microscopic examination of selected tissues indicated that drug-induced toxicity was primarily limited to the gastrointestinal tract and was comparable among the three compounds. Further clinical development of this class of compounds is ongoing.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Feb
|
| pubmed:issn |
0008-5472
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
1
|
| pubmed:volume |
55
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
603-9
|
| pubmed:dateRevised |
2010-11-18
|
| pubmed:meshHeading |
pubmed-meshheading:7834631-Animals,
pubmed-meshheading:7834631-Antineoplastic Agents,
pubmed-meshheading:7834631-Body Weight,
pubmed-meshheading:7834631-Camptothecin,
pubmed-meshheading:7834631-Cattle,
pubmed-meshheading:7834631-Cell Division,
pubmed-meshheading:7834631-Cell Line,
pubmed-meshheading:7834631-Cell Survival,
pubmed-meshheading:7834631-Colonic Neoplasms,
pubmed-meshheading:7834631-Drug Screening Assays, Antitumor,
pubmed-meshheading:7834631-Female,
pubmed-meshheading:7834631-Humans,
pubmed-meshheading:7834631-Mice,
pubmed-meshheading:7834631-Mice, Nude,
pubmed-meshheading:7834631-Thymus Gland,
pubmed-meshheading:7834631-Topoisomerase I Inhibitors,
pubmed-meshheading:7834631-Topotecan,
pubmed-meshheading:7834631-Transplantation, Heterologous,
pubmed-meshheading:7834631-Tumor Cells, Cultured
|
| pubmed:year |
1995
|
| pubmed:articleTitle |
In vivo antitumor activity of two new seven-substituted water-soluble camptothecin analogues.
|
| pubmed:affiliation |
Department of Pharmacology, Glaxo Research Institute, Research Triangle Park, North Carolina 27709.
|
| pubmed:publicationType |
Journal Article,
Comparative Study
|