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New Angiopep-Modified Doxorubicin (ANG1007) and Etoposide (ANG1009) Chemotherapeutics With Increased Brain Penetration

Ché, Christian ; Yang, Gaoqiang ; Thiot, Carine ; Lacoste, Marie-Claude ; Currie, Jean-Christophe ; Demeule, Michel ; Régina, Anthony ; Béliveau, Richard ; Castaigne, Jean-Paul

Journal of medicinal chemistry, 2010-04, Vol.53 (7), p.2814-2824 [Periódico revisado por pares]

United States: American Chemical Society

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Título:
New Angiopep-Modified Doxorubicin (ANG1007) and Etoposide (ANG1009) Chemotherapeutics With Increased Brain Penetration
Autor: Ché, Christian ; Yang, Gaoqiang ; Thiot, Carine ; Lacoste, Marie-Claude ; Currie, Jean-Christophe ; Demeule, Michel ; Régina, Anthony ; Béliveau, Richard ; Castaigne, Jean-Paul
Assuntos: Amino Acid Sequence ; Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; ATP Binding Cassette Transporter, Sub-Family B - deficiency ; Biological Transport ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - metabolism ; Brain - cytology ; Brain - metabolism ; Brain - pathology ; Brain Neoplasms - drug therapy ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Cell Cycle - drug effects ; Cell Line, Tumor ; Doxorubicin - analogs & derivatives ; Doxorubicin - chemistry ; Doxorubicin - metabolism ; Doxorubicin - pharmacology ; Doxorubicin - therapeutic use ; Etoposide - analogs & derivatives ; Etoposide - chemistry ; Etoposide - metabolism ; Etoposide - pharmacology ; Etoposide - therapeutic use ; Etoposide - toxicity ; Female ; Humans ; Inhibitory Concentration 50 ; Kinetics ; Male ; Mice ; Peptides - chemistry ; Peptides - metabolism ; Peptides - pharmacology ; Peptides - therapeutic use ; Peptides - toxicity
É parte de: Journal of medicinal chemistry, 2010-04, Vol.53 (7), p.2814-2824
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: This report describes the synthesis and preliminary biological characterization of 2 (ANG1007) and 3 (ANG1009), two new chemical entities under development for the treatment of primary and secondary brain cancers. 2 consists of three doxorubicin molecules conjugated to Angiopep-2, a 19-mer peptide that crosses the blood−brain barrier (BBB) by an LRP-1 receptor-mediated transcytosis mechanism. 3 has a similar structure, with the exception that three etoposide moieties are conjugated to Angiopep-2. Both agents killed cancer cell lines in vitro with similar IC50 values and with apparently similar cytotoxic mechanisms as unconjugated doxorubicin and etoposide. 2 and 3 exhibited dramatically higher BBB influx rate constants than unconjugated doxorubicin and etoposide and pooled within brain parenchymal tissue. Passage through the BBB was similar in Mdr1a (−/−) and wild type mice. These results provide further evidence of the potential of this drug development platform in the isolation of novel therapeutics with increased brain penetration.
Editor: United States: American Chemical Society
Idioma: Inglês

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New Angiopep-Modified Doxorubicin (ANG1007) and Etoposide (ANG1009) Chemotherapeutics With Increased Brain Penetration

Ché, Christian ; Yang, Gaoqiang ; Thiot, Carine ; Lacoste, Marie-Claude ; Currie, Jean-Christophe ; Demeule, Michel ; Régina, Anthony ; Béliveau, Richard ; Castaigne, Jean-Paul

United States: American Chemical Society

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